case study for genetic diseases

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Current Clinical Studies

Researchers at the National Human Genome Research Institute (NHGRI) are working with patients and families to better understand of how genes can cause or influence diseases and develop new and more effective diagnostics and treatments.

Value of Clinical Studies

Clinical studies give us a better understanding of how genes can cause or influence diseases. NHGRI researchers are working with patients, and with families with a history of inherited diseases, to learn more about the genetic components of common and rare disorders, and to develop new and more effective tests and treatments.

Deciding whether to participate in a clinical study is an important and personal process. Some reasons people choose to participate include:

• Participants in clinical studies help current and future generations. Through these studies, researchers develop new diagnostic tests, more effective treatments, and better ways of managing diseases with genetic components.
• Participants in studies are actively involved in understanding their disorder and current research.
• Participants in some studies gain access to new tests and treatments before they are widely available.

Featured Clinical Studies

Metabolism, Infection and Immunity (MINI) Section

The MINI section aims to define the relationship between infection, immunity and clinical decline in individuals with mitochondrial disease.

Other Clinical Studies

The following are conducted by NHGRI researchers. For eligibility requirements and contact information, visit the study on clinicaltrials.gov.

Last updated: January 12, 2023

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Case 1: Genetic testing to support disorder diagnosis

Welcome to Your Patient!

(P.S.  He's now in his mid-30s and doing well!)

Learn more about Jordan's proposed diagnosis

• To learn more about the proposed diagnosis of Malignant Hyperthermia,  search MedGen ( https://www.ncbi.nlm.nih.gov/medgen/ ) with: 

• Relevant publications available in  PubMed.
• Clinical Trials in  ClinicalTrials.gov .

• Genetic tests are decreasing in cost & are not particularly invasive.
• A well-known genetic lesion can sometimes help in diagnosis and/or drug/therapy selection -  may  provide actionable information.
• A finding  may  predict disorders before symptoms begin for proactive & preventative care.
• We are early in our understanding of genes, gene variants and disease:   Failure to detect a pathogenic variant  does not rule out  the diagnosis.
• Prediction isn’t guaranteed - as pathogenic variants sometimes do not have consistent phenotypic impact in all patients  (penetrance, severity, multi-genic & environmental influences).
• Lack of coverage by  some  insurance companies…

Find a genetic test to order and examine the results

4.  In the  Genetic Testing Registry section of the  MedGen record  (on the right), click on the See all link to retrieve information on all of the genetic test information that has been submitted to us by providers for this disorder or condition. 

• Hopefully, you already knew what to do with the information (potential impact of a genetic variant on the patient’s physiology and phenotype and how this relates to your choice of case management) – before the test was ordered.
• A patient may ask: “ What is wrong with me and how can we fix it?"     A great reason to consult with a Genetic Counselor!
• Implications for the patient -  beyond this particular surgery:   Consider having them discuss this with their primary care physician, dentist, and any other clinical professionals who may need to know for their care.
• Implications for the patient’s family members:  Should they tell others?

Validate the genetic test result assertion and find more information about a genetic variant

•  To validate what is asserted by this clinical testing laboratory,  search NCBI’s ClinVar database ( https://www.ncbi.nlm.nih.gov/clinvar/ ) with:

Important!   Assertions about the clinical significance or interpretation are provided to NCBI by submitters. All those who have provided information are listed in the  Submitted interpretations and evidence  section of the record, so that you can look at them all and learn more about what each submitter provided.

Find a practice guideline to identify actionable recommendations

Find patient education materials to share with the patient and his family.

• Professional literature such as a  the full GeneReviews Chapter on the  NCBI Bookshelf ,  OMIM  or one of the  Reviews in PubMed .
• For a more lay audience, you could find information in MedlinePlus   or MedlinePlus Genetics (GHR) or NIH's NCATS Genetic and Rare Diseases Information Center
• Halogenated volatile anesthetics, such as enflurane, methoxyflurane, desflurane, halothane, isoflurane, sevoflurane.
• The depolarizing neuromuscular blocker succinylcholine.
• Anesthetics such as propofol supplemented by benzodiazepines, opioids, nitrous oxide, or regional anesthetic techniques. Amide and ester local anesthetic agents can also be used in these patients.
• Non-depolarizing neuromuscular blockers such as mivacurium, atracurium, rocuronium, pancuronium, cisatracurium, and vecuronium.
• Jordan may want to inform other healthcare practicioners, in case they need to do procedures involving triggering agents, such as his dentist.
• Because of a possible risk for exposure to non-anesthetic triggering conditions, such as Exertional heat stroke or Exertional rhabdomyolysis, Jordan may want to discuss that mid-summer athletic camp with his care team.

Take-away Message!

This case study was an example of how genetic testing for diagnosis of a disorder might impact the optimal case management plan for a particular patient based on their genetics.  It also showed that understanding a patient's particular risk may have wide implications for both themselves and their families and could help to inform health and medical care beyond one incident.

Last Reviewed: April 18, 2023

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Open Access

Peer-reviewed

Research Article

The population genetics of human disease: The case of recessive, lethal mutations

Roles Conceptualization, Data curation, Formal analysis, Investigation, Validation, Visualization, Writing – original draft

* E-mail: [email protected]

Affiliations Department of Biological Sciences, Columbia University, New York, NY, United States of America, CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, Brazil

Roles Conceptualization, Formal analysis, Investigation, Methodology, Validation, Writing – original draft

Affiliation Howard Hughes Medical Institution, Stanford University, Stanford, CA, United States of America

Roles Data curation

Affiliation Department of Systems Biology, Columbia University, New York, NY, United States of America

Affiliation Universidade Federal de Santa Maria, Santa Maria, RS, Brazil

Roles Software, Writing – review & editing

Affiliation Department of Biological Sciences, Columbia University, New York, NY, United States of America

Roles Data curation, Resources, Writing – review & editing

Current address: Freenome, South San Francisco, CA, United States of America

Affiliation Counsyl, 180 Kimball Way, South San Francisco, CA, United States of America

Roles Conceptualization, Data curation, Funding acquisition, Methodology, Project administration, Supervision, Writing – review & editing

¶ ‡ These authors co-supervised this work.

Affiliations Department of Biological Sciences, Columbia University, New York, NY, United States of America, New York Genome Center, New York, NY, United States of America

Roles Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Writing – original draft

Affiliations Department of Biological Sciences, Columbia University, New York, NY, United States of America, Department of Systems Biology, Columbia University, New York, NY, United States of America

• Carlos Eduardo G. Amorim, 
• Ziyue Gao, 
• Zachary Baker, 
• José Francisco Diesel, 
• Yuval B. Simons, 
• Imran S. Haque, 
• Joseph Pickrell, 
• Molly Przeworski

• Published: September 28, 2017
• https://doi.org/10.1371/journal.pgen.1006915
• See the preprint
• Reader Comments

2 Jul 2018: Amorim CEG, Gao Z, Baker Z, Diesel JF, Simons YB, et al. (2018) Correction: The population genetics of human disease: The case of recessive, lethal mutations. PLOS Genetics 14(7): e1007499. https://doi.org/10.1371/journal.pgen.1007499 View correction

Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases or complete sterility. To this end, we generated a hand-curated set of 417 Mendelian mutations in 32 genes reported to cause a recessive, lethal Mendelian disease. We then considered analytic models of mutation-selection balance in infinite and finite populations of constant sizes and simulations of purifying selection in a more realistic demographic setting, and tested how well these models fit allele frequencies estimated from 33,370 individuals of European ancestry. In doing so, we distinguished between CpG transitions, which occur at a substantially elevated rate, and three other mutation types. Intriguingly, the observed frequency for CpG transitions is slightly higher than expectation but close, whereas the frequencies observed for the three other mutation types are an order of magnitude higher than expected, with a bigger deviation from expectation seen for less mutable types. This discrepancy is even larger when subtle fitness effects in heterozygotes or lethal compound heterozygotes are taken into account. In principle, higher than expected frequencies of disease mutations could be due to widespread errors in reporting causal variants, compensation by other mutations, or balancing selection. It is unclear why these factors would have a greater impact on disease mutations that occur at lower rates, however. We argue instead that the unexpectedly high frequency of disease mutations and the relationship to the mutation rate likely reflect an ascertainment bias: of all the mutations that cause recessive lethal diseases, those that by chance have reached higher frequencies are more likely to have been identified and thus to have been included in this study. Beyond the specific application, this study highlights the parameters likely to be important in shaping the frequencies of Mendelian disease alleles.

Author summary

What determines the frequencies of disease mutations in human populations? To begin to answer this question, we focus on one of the simplest cases: mutations that cause completely recessive, lethal Mendelian diseases. We first review theory about what to expect from mutation and selection in a population of finite size and generate predictions based on simulations using a plausible demographic scenario of recent human evolution. For a highly mutable type of mutation, transitions at CpG sites, we find that the predictions are close to the observed frequencies of recessive lethal disease mutations. For less mutable types, however, predictions substantially under-estimate the observed frequency. We discuss possible explanations for the discrepancy and point to a complication that, to our knowledge, is not widely appreciated: that there exists ascertainment bias in disease mutation discovery. Specifically, we suggest that alleles that have been identified to date are likely the ones that by chance have reached higher frequencies and are thus more likely to have been mapped. More generally, our study highlights the factors that influence the frequencies of Mendelian disease alleles.

Citation: Amorim CEG, Gao Z, Baker Z, Diesel JF, Simons YB, Haque IS, et al. (2017) The population genetics of human disease: The case of recessive, lethal mutations. PLoS Genet 13(9): e1006915. https://doi.org/10.1371/journal.pgen.1006915

Editor: Philipp W. Messer, Cornell University, UNITED STATES

Received: December 4, 2016; Accepted: July 9, 2017; Published: September 28, 2017

Copyright: © 2017 Amorim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper and its Supporting Information files and code from gitHub ( https://github.com/cegamorim/PopGenHumDisease ; https://github.com/sellalab/ForwardSimulator ).

Funding: CEGA was partially funded by a Science Without Borders fellowship from CAPES foundation (BEX 8279/11-0) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (PDE 201145/2015-4), Brazil. ZG was partially supported by a postdoctoral fellowship funded by Stanford Center for Computational, Evolutionary and Human Genomics. JFD was funded by a Science Without Borders fellowship from CAPES foundation (88888.038761/2013-00). YBS was supported by NIH grant GM115889. The work was partially supported by a Research Initiative in Science and Engineering grant from Columbia University and NIGMS grants (GM121372) to JKP and MP. The computing in this project was supported by two National Institutes of Health instrumentation grants (S10OD012351 and S10OD021764) received by the Department of Systems Biology at Columbia University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

New disease mutations arise in heterozygotes and either drift to higher frequencies or are rapidly purged from the population, depending on the strength of selection and the demographic history of the population [ 1 – 6 ]. Elucidating the relative contributions of mutation, natural selection and genetic drift will help to understand why disease alleles persist in humans. Answers to these questions are also of practical importance, in informing how genetic variation data can be used to identify additional disease mutations [ 7 ].

In this regard, rare, Mendelian diseases, which are caused by single highly penetrant and deleterious alleles, are perhaps most amenable to investigation. A simple model for the persistence of mutations that lead to Mendelian diseases is that their frequencies reflect an equilibrium between their introduction by mutation and elimination by purifying selection, i.e., that they should be found at “mutation-selection balance” [ 4 ]. In finite populations, random drift leads to stochastic changes in the frequency of any mutation, so demographic history, in addition to mutation and natural selection, plays an important role in shaping the frequency distribution of deleterious mutations [ 3 ].

Another factor that may be important in determining the frequencies of highly penetrant disease mutations is genetic interactions. The mutation-selection balance model has been extended to scenarios with more than one disease allele, as is often seen for Mendelian diseases [ 8 , 9 ]. When compound heterozygotes have the same fitness as homozygotes for the disease allele (i.e., there is no complementation), the combined frequency of all disease alleles can be modeled similarly as the bi-allelic case, with the mutation rate given by the sum of the mutation rate to each disease allele [ 8 ]. In other cases, a disease mutation may be rescued by another mutation in the same gene [ 10 – 12 ] or by a modifier locus elsewhere in the genome that modulates the severity of the disease symptoms or the penetrance of the disease allele (e.g. [ 13 – 15 ]).

For a subset of disease alleles that are recessive, an alternative model for their persistence in the population is that there is an advantage to carrying one copy but a disadvantage to carrying two or none, such that the alleles persist due to overdominance, a form of balancing selection. Well known examples include sickle cell anemia, thalassemia and G6PD deficiency in populations living where malaria exerts strong selection pressures [ 16 ]. The importance of overdominance in maintaining the high frequency of disease mutations is unknown beyond these specific cases.

To this end, we compiled genetic information for a set of 417 mutations reported to cause fatal, recessive Mendelian diseases and estimated the frequencies of the disease-causing alleles from large exome datasets. We then compared these data to the expected frequencies of deleterious alleles based on models of mutation-selection balance in order to evaluate the effects of mutation rates and other factors in influencing these frequencies.

Mendelian recessive disease allele set

We relied on two datasets, one that describes 173 autosomal recessive diseases [ 19 ] and another from a genetic testing laboratory (Counsyl [ 20 ]; < https://www.counsyl.com/ >) that includes 110 recessive diseases of clinical interest. From these lists, we obtained a set of 44 “recessive lethal” diseases associated with 45 genes ( S1 Table ), requiring that at least one of the following conditions is met: (i) in the absence of treatment, the affected individuals die of the disease before reproductive age, (ii) reproduction is completely impaired in patients of both sexes, (iii) the phenotype includes severe mental retardation that in practice precludes reproduction, or (iv) the phenotype includes severely compromised physical development, again precluding reproduction.

Based on clinical genetics datasets and the medical literature (see Methods for details), we were able to confirm that 417 Single Nucleotide Variants (SNVs) in 32 (of the 44) genes had been reported with compelling evidence of association to the severe form of the corresponding disease and an early-onset, as well as no indication of effects in heterozygote carriers ( S2 Table ). By this approach, we obtained a set of mutations for which, at least in principle, there is no heterozygote effect, i.e., for which the dominance coefficient h = 0 in a model with relative fitness of 1 for the homozygote for the reference allele, 1- hs for the heterozygote, and 1- s for the homozygote for the deleterious allele, and the selective coefficient s is 1.

A large subset of these mutations (29.3%) consists of transitions at CpG sites (henceforth CpGti), which occur at a highly elevated rates (~17-fold higher on average) compared to other mutation types, namely CpG transversions, and non-CpG transitions and transversions [ 18 ]. This proportion is in agreement with previous estimates for a smaller set of disease genes [ 21 ] and for DMD [ 22 ].

Empirical distribution of allele frequencies of disease mutations in Europe

Allele frequency data for the 417 variants were obtained from the Exome Aggregation Consortium (ExAC) for 60,706 individuals, of whom 33,370 are non-Finnish Europeans [ 23 ]. Out of the 417 variants associated with putative recessive lethal diseases, three were found homozygous in at least one individual in this dataset (rs35269064, p.Arg108Leu in ASS1 ; rs28933375, p.Asn252Ser in PRF1 ; and rs113857788, p.Gln1352His in CFTR ). Available data quality information for these variants does not suggest genotype calling artifacts ( S2 Table ). Since these diseases have severe symptoms that lead to early death without treatment and these ExAC individuals are healthy (i.e., do not manifest severe Mendelian diseases) [ 23 ], the reported mutations are likely errors in pathogenicity classification or cases of incomplete penetrance (see a similar observation for CFTR and DHCR7 in [ 24 ]). We therefore excluded them from our analyses. In addition to the mutations present in homozygotes, we also filtered out sites that had lower coverage in ExAC (see Methods ), resulting in a final dataset of 385 variants in 32 genes ( S2 Table ).

Genotypes for a subset (91) of these mutations were also available for a larger sample size (76,314 individuals with self-reported European ancestry) generated by the company Counsyl ( S3 Table ). A comparison of the allele frequencies in this larger dataset to that of ExAC suggests that the allele frequencies for individual variants are concordant between the two datasets (Pearson’s correlation coefficient of 0.79, S1 Fig ) and that the overall distributions do not differ appreciably (Kolmogorov–Smirnov test, p-value = 0.23). Thus, both data sets appear to reflect the general distribution of these disease alleles in Europeans. In what follows, we focused on ExAC, which includes a greater number of disease mutations.

Models of mutation-selection balance

To generate expectations for the frequencies of these disease mutations under mutation-selection balance, we considered models of infinite and finite populations of constant size [ 3 ] and conducted forward simulations using a plausible demographic model for African and European populations [ 25 ] (see Methods for details). In all these models, there is a wild-type allele (A) and a deleterious allele (a, which could also represent a class of distinct deleterious alleles with the same fitness effect) at each site, such that the relative fitness of individuals of genotypes AA, Aa, or aa is given respectively by:

• w Aa = 1- hs ;
• w aa = 1- s ;

The mutation rate from A to a is u; we assume that there are no back mutations.

We note that Nei [ 3 ] assumed a Wright-Fisher model, in which there is no distinction between census and the effective population sizes. However, when the two differ, it is the effective population size that governs the dynamics of deleterious alleles, so the N in the analytical results in fact represents the effective population size. In humans, the mutation rate at each bp is very small (on the order of 10 −8 [ 18 ]) and the effective population size not that large, even recently [ 27 , 28 ], so the second approximation should apply when considering each single site independently.

Comparing mutation-selection balance models

Although an infinite population size has often been assumed when modeling deleterious allele frequencies (e.g. [ 5 , 29 – 32 ]), predictions under this assumption can differ markedly from what is expected from models of finite population sizes, assuming plausible parameter values for humans. For example, the long-term estimate of the effective population size from total polymorphism levels is ~20,000 individuals (assuming a mutation rate of 1.2 x 10 −8 per bp per generation [ 18 ] and diversity levels of 0.1% [ 33 ]). In this case and considering a mutation rate of 1.5 x 10 −8 for exons (which have a higher mutation rate than the rest of the genome, because of their base composition [ 34 ]), the average deleterious allele frequency in the model of finite population size is ~23-fold lower than that in the infinite population model ( Fig 1 ).

• PPT PowerPoint slide
• PNG larger image
• TIFF original image

The blue bar denotes the expected allele frequency under an infinite population size, the green bar the mean under a finite constant population, and the red bar the mean under a plausible demographic model for European populations; for this last case, the entire distribution across 100,000 simulations is shown in the grey histogram. All models assume s = 1 and h = 0, i.e., fully recessive, lethal mutations. For the finite constant population size model, we present the mean frequency for a population size of 20,000 (see S2A Fig for other choices). Population allele frequencies ( q ) were transformed to log10( q ), and those q = 0 were set to 10 −7 for visual purposes, but indicated as “0” on the X-axis. The density of the distribution is plotted on a log-scale on the Y-axis. The mutation rate u was set to 1.5 x 10 −8 per bp per generation in all models.

https://doi.org/10.1371/journal.pgen.1006915.g001

Because the human population size has not been constant and changes in the population size can affect the frequencies of deleterious alleles in the population (e.g. [ 2 , 35 ]), we also simulated the population dynamics of disease alleles under a plausible demographic model for European populations based on Tennessen et al. [ 25 ]. The original model assumes a genome-wide mutation rate of 2.36 x 10 −8 per bp per generation, when current, more direct estimates are approximately two-fold smaller [ 18 , 34 , 36 ]. We therefore rescaled the demographic parameters of the Tennessen et al. model, based on a mutation rate of 1.2 x 10 −8 [ 18 ] (see Methods ). Assuming a mutation rate of 1.5 x 10 −8 per bp (as recently estimated for exons [ 34 ]), the mean allele frequency of a lethal, recessive disease allele obtained from this model was 7.10 x 10 −6 , ~1.33-fold higher than expected for a constant population size model with N e = 20,000 ( Fig 1 ). The mean frequency seen in simulations instead matches the expectation for a constant population size of 35,651 individuals (see Methods and S2A Fig ). Increasing the effective population size in a constant size model is not enough to capture the dynamics of disease alleles appropriately, however. For example, if simulation results obtained under the Tennessen et al. [ 25 ] demographic model are compared to those for simulations of a constant population size of N e = 35,651, the mean allele frequencies match, but the distributions of allele frequencies are significantly different (Kolmogorov-Smirnov test, p-value < 10 −15 ; S2B and S2C Fig ). These findings thus confirm the importance of incorporating demographic history into models for understanding the population dynamics of disease alleles [ 5 , 37 , 38 ]. In what follows, we therefore tested the fit of the more realistic demographic model [ 25 ] (and variants of it) to the observed allele frequencies.

Comparing empirical and expected distributions of disease allele frequencies

The mutation rate from wild-type allele to disease allele, u , is a critical parameter in predicting the frequencies of a deleterious allele [ 4 , 39 ]. To model disease alleles, we considered four mutation types separately, with the goal of capturing most of the fine-scale heterogeneity in mutation rates [ 27 , 36 , 40 , 41 ]: transitions in methylated CpG sites (CpGti) and three less mutable types, namely transversions in CpG sites (CpGtv) and transitions and transversions outside a CpG site (nonCpGti and nonCpGtv, respectively). In order to control for the methylation status of CpG sites, we excluded 12 CpGti that occurred in CpG islands, which tend not to be methylated and thus are likely to have a lower mutation rate [ 36 ] (following Moorjani et al. [ 42 ]). To allow for heterogeneity in mutation rates within each one of these four classes considered, we modeled the within-class variation in mutation rates according to a lognormal distribution (see details in Methods and [ 27 ]).

For each mutation type, we then compared the mean allele frequency obtained from simulations to what is observed in ExAC, running 100,000 replicates. To this end, we matched simulations to the empirical data with regard to the number of individuals sampled and number of mutations observed of each mutation type and focused the analysis on the largest sample of the same common ancestry, namely Non-Finnish Europeans ( n = 33,370) ( Fig 2A ). We found significant differences between empirical and expected mean frequencies for nonCpGtv (30-fold higher on average; two-tailed p-value < 1 x 10 −4 ; see Methods for details) and nonCpGti (15-fold higher on average, two-tailed p-value < 1 x 10 −4 ), but only marginally so for CpGtv (5-fold higher on average, two-tailed p-value = 0.08). The mean frequency for CpGti is also somewhat higher than expected, but insignificantly so (1.17-fold higher on average, two-tailed p-value = 0.59). Intriguingly, the discrepancy between observed and expected frequencies becomes smaller as the mutation rate increases ( Fig 2B ).

(A) Shown are the expected and observed mean sample frequencies of disease mutations for four different mutation types. The title of the panel indicates the mutation type, followed by K , the total number of mutations of that type considered in this study, with the p-value for the difference between observed and expected mean frequencies given below. Distributions in grey are the mean sample allele frequencies across K mutations based on 100,000 simulations, and rely on a plausible demographic model for European populations [ 25 ] (see Methods ). Blue bars represent the observed mean frequencies of the four mutation types, estimated from 33,370 individuals of European ancestry from ExAC. (B) Fold increase in the observed mean allele frequency in relation to the expected, as a function of the mutation rate u (on a log-scale), for each of the four mutation classes.

https://doi.org/10.1371/journal.pgen.1006915.g002

Two additional factors that we have not included in our model should further decrease the predicted frequencies of disease alleles. Given that frequencies in ExAC are already unexpectedly high, these factors would only exacerbate the discrepancy between observed and expected frequencies of deleterious alleles. First, we have ignored the effects of compound heterozygosity, the case in which combinations of two distinct pathogenic alleles in the same gene lead to lethality. This phenomenon is known to be common [ 43 ], and indeed, in the 320 cases in which we were able to obtain this information, 58.44% were initially identified in compound heterozygotes. In the presence of compound heterozygosity, each deleterious mutation will be selected against not only when present in two copies within the same individual, but also in the presence of lethal mutations at other sites. Since the purging effect of selection against compound heterozygotes was not modeled in simulations, we would predict the frequency of a deleterious mutation to be even lower than shown (e.g., in Fig 2A ).

In order to model the effect of compound heterozygosity in our simulations, we re-ran our simulations, but focusing on a gene rather than a single site and so considering the sum of frequencies of all known recessive lethal alleles within a gene. In these simulations, we used the same set-up as in the site level analysis, except for the mutation rate, U , which is now the sum of the mutation rates u j at each site j that is known to cause a severe and early onset form of the disease [ 8 ] ( S2 Table ; see Methods for details). This approach does not consider the contribution of other mutations in the genes that cause the mild and/or late onset forms of the disease, and implicitly assumes that all combinations of known recessive lethal alleles of the same gene have the same fitness effect as homozygotes. Comparing observed frequencies of disease alleles for each gene to predictions generated by simulation, about a fourth of the 27 genes for which we implemented the gene-level analysis (see Methods ) differ from the expected distribution at the 5% level, with a clear overall trend for observed frequencies to be above expectation ( S4 Table ; Fig 3 ; Fisher’s combined probability test p-value = 6 x 10 −8 ).

The expectation (grey) is based on 1000 simulations, assuming no fitness decrease in heterozygotes, but allowing for compound heterozygosity (see Methods for details). The sum of allele frequencies of known recessive lethal disease mutations in each gene (purple bars) was obtained from ExAC considering 33,370 European individuals. Genes are ordered according to the two-tailed p-value ( S4 Table ; see Methods ). Genes are bolded when they differ significantly from expectation (at the 5% level). Violin plots show the distribution of the log 10 combined allele frequency of all segregating alleles obtained from simulations and boxes represent the fraction of simulations in which no deleterious allele was observed in the simulated sample at present time.

https://doi.org/10.1371/journal.pgen.1006915.g003

This finding is even more surprising than it may seem, because we are far from knowing the complete mutation target for each gene, i.e., all the sites at which mutations could cause the disease. If there are additional, undiscovered sites in the gene at which mutations are fatal when carried in combination with a known recessive lethal mutation, the purging effect of purifying selection on the known mutations will be under-estimated in our simulations, leading us to over-estimate the expected frequencies of the known mutations in simulations. Therefore, our predictions are, if anything, an over-estimate of the expected allele frequency, and the discrepancy between predicted and the observed is likely even larger than what we found.

The other factor that we did not consider in simulations but would reduce the expected allele frequencies is a subtle fitness decrease in heterozygotes, as has been documented in Drosophila for example [ 44 ]. To evaluate potential fitness effects in heterozygotes when none had been documented in humans, we considered the phenotypic consequences of orthologous gene knockouts in mouse. We were able to retrieve information on phenotypes for both homozygote and heterozygote mice for only eight out of the 32 genes, namely ASS1 , CFTR , DHCR7 , NPC1 , POLG , PRF1 , SLC22A5 , and SMPD1 . For all eight, homozygote knockout mice presented similar phenotypes as affected humans, and heterozygotes showed a milder but detectable phenotype ( S5 Table ). The magnitude of the heterozygote effect of these mutations in humans is unclear, but the finding with knockout mice makes it plausible that there exists a very small fitness decrease in heterozygotes in humans as well, potentially not enough to have been recognized in clinical investigations but enough to have a marked impact on the allele frequencies of the disease mutations. Indeed, even if the fitness effect in heterozygotes were as small as h = 1%, a 79% decrease in the mean allele frequency of the disease allele is expected relative to the case with complete recessivity ( h = 0) ( S3 Fig ).

To investigate the population genetics of human disease, we focused on mutations that cause Mendelian, recessive disorders that lead to early death or completely impaired reproduction. We sought to understand to what extent the frequencies of these mutations fit the expectation based on a simple balance between the input of mutations and the purging by purifying selection, as well as how other mechanisms might affect these frequencies. Many studies implicitly or explicitly compare known disease allele frequencies to expectations from mutation-selection balance [ 5 , 29 – 32 ]. In this study, we tested whether known recessive lethal disease alleles as a class fit these expectations, and found that, under a sensible demographic model for European population history with purifying selection only in homozygotes, the expectations fit the observed disease allele frequencies poorly: the mean empirical frequencies of disease alleles are substantially above expectation for all mutation types (although not significantly so for CpGti), and the fold increase in observed mean allele frequency in relation to the expectation decreases with increased mutation rate ( Fig 2 ). Furthermore, including possible effects of compound heterozygosity and subtle fitness decrease in heterozygotes will only exacerbate the discrepancy.

In principle, higher than expected disease allele frequencies could be explained by at least six (non-mutually exclusive) factors: (i) widespread errors in reporting the causal variants; (ii) misspecification of the demographic model, (iii) misspecification of the mutation rate; (iv) reproductive compensation; (v) overdominance of disease alleles; and (vi) low penetrance of disease mutations. Because widespread mis-annotation of the causal variants in disease mutation databases had previously been reported [ 23 , 45 , 46 ], we tried to minimize the effect of such errors on our analyses by filtering out any case that lacked compelling evidence of association with a recessive lethal disease, reducing our initial set of 769 mutations to 385 in which we had greater confidence (see Methods for details).

We also explored the effects of having misspecified recent demographic history or the mutation rate. Based on very large samples, it has been estimated that population growth in Europe was stronger than what we considered in our simulations [ 47 , 48 ]. When we considered higher growth rates, such that the current effective population size is up to 10-fold larger than that of the rescaled Tennessen model, we observed an increase in the expected frequency of recessive disease alleles and a larger number of segregating sites ( S4 Fig , columns A-E). However, the impact of larger growth rate is insufficient to explain the observed discrepancy: the allele frequencies observed in ExAC are still on average an order of magnitude larger than expected based on a model with a 10-fold larger current effective population size than the one initially considered [ 25 ] ( S4 Fig ). In turn, population substructure within Europe would only increase the number of homozygotes relative to what was modeled in our simulations (through the Wahlund effect [ 49 ]) and expose more recessive alleles to selection, thus decreasing the expected allele frequencies and exacerbating the discrepancy that we report.

To explore the effects of error in the mutation rate, we considered a 50% higher mean mutation rate than what has been estimated for exons [ 34 ], beyond what seems plausible based on current estimates on human mutation rates [ 42 ]. Except for the mean mutation rate (now set to 2.25 x 10 −8 ), all other parameters used for these simulations (i.e. the variance in mutation rate across simulations, the demographic model [ 25 ], absence of selective effect in heterozygotes, and selection coefficient) were kept the same as the ones used for generating S4 Fig , column A. The observed mean frequency remains significantly above what those predicted and qualitative conclusions are unchanged ( S4 Fig , column F).

Another factor to consider is that for disease phenotypes that are lethal very early on in life, there may be partial or complete reproductive compensation (e.g. [ 50 ]). This phenomenon would decrease the fitness effects of the recessive lethal mutations and could therefore lead to an increase in the allele frequency in data relative to what we predict for a selection coefficient of 1. There are no reasons, however, for this phenomenon to correlate with the mutation rate, as seen in Fig 2B .

The other two factors, overdominance and low penetrance, are likely explanations for a subset of cases. For instance, CFTR , the gene in which some mutations lead to cystic fibrosis, is the farthest above expectation (p-value < 0.004; Fig 3 ). It was long noted that there is an unusually high frequency of the CFTR deletion ΔF508 in Europeans, which led to speculation that disease alleles of this gene may be subject to over-dominance ([ 51 , 52 ], but see [ 53 ]). Regardless, it is known that disease mutations in this gene can complement one another [ 10 , 11 ] and that modifier loci in other genes also influence their penetrance [ 11 , 14 ]. Consistent with variable penetrance, Chen et al. [ 24 ] identified three purportedly healthy individuals carrying two copies of disease mutations in this gene. Similarly, DHCR7 , the gene associated with the Smith-Lemli-Opitz syndrome, is somewhat above expectation in our analysis (p-value = 0.056; Fig 3 ) and healthy individuals were found to be homozygous carriers of putatively lethal disease alleles in other studies [ 24 ]. These observations make it plausible that, in a subset of cases (particularly for CFTR ), the high frequency of deleterious mutations associated with recessive, lethal diseases are due to genetic interactions that modify the penetrance of certain recessive disease mutations. It is hard to assess the importance of this phenomenon in driving the general pattern that we observe, but two factors argue against it being a sufficient explanation for our findings at the level of single sites. First, when we removed 130 mutations in CFTR and 12 in DHCR7 , the two genes that were outliers at the gene level ( Fig 3 ; S4 Table ) and for which there is evidence of incomplete penetrance [ 24 ], the discrepancy between observed and expected allele frequencies is barely impacted ( S5 Fig ). Moreover, there is no obvious reason why the degree of incomplete penetrance would vary systematically with the mutation rate of a site, as observed ( Fig 2B ).

Instead, it seems plausible that there is an ascertainment bias in disease allele discovery and mutation identification [ 52 , 54 , 55 ]. Unlike missense or protein-truncating variants, Mendelian disease mutations cannot be annotated based solely on DNA sequences, and their identification requires reliable diagnosis of affected individuals (usually in more than one pedigree) followed by mapping of the underlying gene/mutation. Therefore, those mutations that have been identified to date are likely the ones that are segregating at higher frequencies in the population. Moreover, mutation-selection balance models predict that the frequency of a deleterious mutation should correlate with the mutation rate. Together, these considerations suggest that disease variants of a highly mutable class, such as CpGti, are more likely to have been mapped and that the mean frequency of mapped mutations will tend to be only slightly above all disease mutations in that class. In contrast, less mutable disease mutations are less likely to have been discovered to date, and the mean frequency of the subset of mutations that have been identified may tend to be far above that of all mutations in that class.

To quantify these effects, we modeled the ascertainment of disease mutations both analytically and in simulations. A large proportion of recessive Mendelian disease mutations were identified in inbred populations, likely because inbreeding leads to an excess of homozygotes compared to expected under random mating, increasing the probability that a recessive mutation would be discovered as causing a disease. Therefore, we modeled ascertainment in disease discovery in human populations with a plausible degree of inbreeding (see Methods ). As expected, we found that for a given mutation type, the probability of ascertainment increases with the sample size of the putative disease ascertainment study ( n a ) and the average inbreeding coefficient of the population under study ( F a ); in addition, the average allele frequency of mutations that have been identified is always higher than that of all existing mutations, and the discrepancy decreases as the ascertainment probability increases ( Table 1 ). Furthermore, comparison across different mutation types reveals that a higher mutation rate increases the probability of disease mutations being ascertained ( Table 1 and S6 Fig ) and decreases the magnitude of bias in the estimated allele frequency relative to the mutation class as a whole ( Table 1 ). In summary, among all the possible aforementioned explanations for the observed discrepancy between empirical and expected mean allele frequencies, the ascertainment bias hypothesis is the only one that also explains why it is more pronounced for less mutable mutation types ( Fig 2B ).

For a similar result derived from analytical modeling, see S6 Fig . Parameters for this step of the simulation correspond to plausible scenarios for human populations with widespread inbreeding (e.g., F a = 1/16 corresponds to offspring of first-cousin marriage). The last column in the bottom panel shows the fold increase of the mean allele frequency observed in ExAC in relation to simulations based on the Tennessen et al. [ 25 ] demographic model (see Methods ). Mutation rates u per bp, per generation were obtained from a large human pedigree study [ 18 ].

https://doi.org/10.1371/journal.pgen.1006915.t001

One implication of this hypothesis is that there are numerous sites at which mutations cause recessive lethal diseases yet to be discovered, particularly at non-CpG sites. More generally, this ascertainment bias complicates the interpretation of observed allele frequencies in terms of the selection pressures acting on disease alleles. Beyond this specific point, our study illustrates how the large sample sizes now made available to researchers in the context of projects like ExAC [ 23 ] can be used not only for direct discovery of disease variants, but also to test why disease alleles are segregating in the population and to understand at what frequencies we might expect to find them in the future.

Disease allele set

In order to identify single nucleotide variants within the 42 genes associated with lethal, recessive Mendelian diseases ( S1 Table ), we initially relied on the ClinVar dataset [ 56 ] (accessed on June 3 rd , 2015). We filtered out any variant that is an indel or a more complex copy number variant or that is ever classified as benign or likely benign in ClinVar (whether or not it is also classified as pathogenic or likely pathogenic). By this approach, we obtained 769 SNVs described as pathogenic or likely pathogenic. For each one of these variants, we searched the literature for evidence that it is exclusively associated to the lethal and early onset form of the disease and was never reported as causing the mild and/or late-onset form of the disease. We considered effects in the absence of medical treatment, as we were interested in the selection pressures acting on the alleles over evolutionary time scales rather than in the last one or two generations, i.e., the period over which treatment became available for some of diseases considered. To evaluate the impact of treatment, we decreased s from 1 to 0 (i.e., we assumed a complete absence of selective effects due to treatment) in the last three generations and compared the mean allele frequencies across 100,000 simulations implemented with or without this readjustment in selection coefficient. Because of the stochastic nature of the simulations, we repeated this pairwise comparison 10 times in order to get a range of expected increase in allele frequencies. We observed only a minor increase in the mean allele frequency (2.6% at most) across the 10 replicates. This simulation procedure corresponds to a scenario in which there is an extremely effective treatment for all diseases for the past three generations, which is an overestimate of the effect and length of treatment for the disease set considered.

Variants with mention of incomplete penetrance (i.e. for which homozygotes were not always affected) or with known effects in heterozygote carriers were removed from the analysis. This process yielded 417 SNVs in 32 genes associated with distinct Mendelian recessive lethal disorders ( S2 Table ). Although these mutations were purportedly associated with completely recessive diseases, we sought to examine whether there would be possible, unreported effects in heterozygous carriers. To this end, we used the Mouse Genome Database (MGD) [ 57 ] (accessed July 29 th , 2015) and were able to retrieve information for both homozygote and heterozygote mice for eight out of the 32 genes (all of which with a homologue in mice) ( S5 Table ).

In addition to the information provided by ClinVar for each one of these variants, we considered the immediate sequence context of each SNV, to tailor the mutation rate estimate accordingly [ 18 ]. To do so, we used an in-house Python script and the human genome reference sequence hg19 from UCSC (< http://hgdownload.soe.ucsc.edu/goldenPath/hg19/chromosomes/ >).

Genetic datasets

The Exome Aggregation Consortium (ExAC) [ 23 ] was accessed on August 9 th , 2016. The data consist of genotype frequencies for 60,706 individuals, assigned after Principal Component Analysis to one of seven population labels: African (n = 5,203), East Asian (n = 4,327), Finnish (n = 3,307), Latino (n = 5,789), Non-Finnish European (n = 33,370), South Asian (n = 8,256) and “other” (n = 454) [ 23 ]. We focused our analyses on those individuals of Non-Finnish European descent, because they constitute the largest sample size from a single ancestry group. We note that, some diseases mutations, for instance, those in ASPA , HEXA and SMPD1 , are known to be especially prevalent in Ashkenazi Jewish populations, which could potentially bias our results if Ashkenazi Jewish individuals constituted a great portion of the sample we considered. However, this sample includes only ~2,000 (~6%) Ashkenazi individuals (Dr. Daniel MacArthur, personal communication).

From the initial 417 mutations, we filtered out three that were homozygous in at least one individual in ExAC and 29 that had lower coverage, i.e., fewer than 80% of the individuals were sequenced to at least 15x. This approach left us with a set of 385 mutations with a minimum coverage of 27x per sample and an average coverage of 69x per sample ( S2 Table ). For 248 sites with non-zero sample frequencies, ExAC reported the number of non-Finnish European individuals that were sequenced, which was on average 32,881 individuals [ 23 ]. For the remaining 137 sites, we did not have this information. Nonetheless, the coverage across all samples is reported and does not differ significantly between the two sets of sites (by a Kolmogorov-Smirnov test, p-value = 0.90; S7 Fig ). We therefore assumed that mean number of individuals covered for all sites was 32,881 and used this number to obtain sample frequencies from simulations, as explained below.

A second genetic dataset was obtained from Counsyl (< https://www.counsyl.com/ >). Counsyl is a commercial genetic screening laboratory that offers, among other products, the “Family Prep Screen”, a genetic screening test intended to detect carrier status for up to 110 recessive Mendelian diseases in couples that are planning to have a child [ 20 ]. A subset of 294,000 of its customers was surveyed by genotyping or sequencing for “routine carrier screening”. This subset excludes individuals with indications for testing because of known personal or family history of Mendelian diseases, infertility, and consanguinity. It therefore represents a more random (with regard to the presence of disease alleles), population-based survey. For these individuals, we had details on self-reported ancestry (14 distinct ethnic/ancestry/geographic groups) and the allele frequencies for 98 mutations that match those that passed our variant selection criteria described above, of which 91 are also sequenced to high coverage in the ExAC database ( S2 Table ). We focused our analysis of this dataset on the 76,314 individuals of self-reported Northern or Southern European ancestry.

Simulating the evolution of disease alleles with population size change

We modeled the frequency of a deleterious allele in human populations by forward simulations based on a crude but plausible demographic model for human populations from Africa and Europe, inferred from exome data for African-Americans and European-Americans [ 25 ]. To this end, we used a program described in [ 1 ]. In brief, the demographic scenario consists of an Out-of-Africa demographic model, with changes in population size throughout the population history, including a severe bottleneck in Europeans following the split from the African population and a rapid, recent population growth in both populations [ 25 ]. As in Simons et al. [ 1 ], we simulated genetic drift and two-way gene flow between Africans and Europeans in recent history.

The original demographic model was inferred using a mutation rate u of 2.36 x 10 −8 per bp per generation [ 25 , 58 ]. More recent estimates, based on direct resequencing of human pedigrees, instead point to mutation rates about 50% smaller than that [ 18 , 34 , 36 ]. To incorporate what is believed to be a more accurate mutation rate estimate, we rescaled all demographic and time parameters in the original Tennessen et al. [ 25 ] model by a factor of 1.97, based on the difference between the mutation rate considered in the original study and that of Kong et al. [ 18 ] (which is similar to that found in other studies [ 48 ]). We refer to this model as the rescaled Tennessen model and rely on it throughout.

Negative selection acting on a single bi-allelic site was modeled as in the analytic models. Allele frequencies follow a Wright-Fisher sampling scheme in each generation according to these viabilities, with migration rate and population sizes varying according to the demographic scenario considered. Whenever a demographic event (e.g., growth) altered the number of individuals and the resulting number was not an integer, we rounded it to the nearest integer, as in Simons et al. [ 1 ]. A burn-in period of 10 Ne generations with constant population size Ne = 14,328 individuals was implemented in order to ensure an equilibrium distribution of segregating alleles at the onset of demographic changes in Africa, 11,643 generations ago.

In contrast to Simons et al. [ 1 ], our simulations always start with the ancestral allele A fixed and mutation occurs exclusively from this allele to the deleterious one (a), i.e., a mutation occurs with mean probability u per gamete, per generation, and there is no back-mutation. However, recurrent mutations at a site are allowed, as in Simons et al. [ 1 ].

For each mutation type, we then proceeded as follows:

• We ran two million simulations, thus obtaining the distribution of deleterious allele frequencies expected for the European population.
• We sampled K allele frequencies from the two million simulations implemented for each mutation type, where K is the number of identified mutations of that type. Sample allele frequencies were simulated from these population frequencies by Poisson sampling, so to match ExAC’s number of chromosomes.
• We repeated step (2) 100,000 times, thus obtaining a distribution for the mean allele frequency across K mutations.

To assess the significance of the deviation between observed and expected mean, we obtained a two-tailed p-value, defined as 2 x ( r +1)/(100000+1), where r is the number of simulated allele frequencies that were greater or equal to that of the empirical mean [ 60 ], for each mutation type separately.

A well-known source of heterogeneity in mutation rate within the CpGti class is methylation status, with a high transition rate seen only at methylated CpGs [ 21 ]. In our analyses, we tried to control for the methylation status of CpG sites by excluding sites located in CpG islands (CGIs), which tend to not be methylated [ 42 ]. The CGI annotation for hg19 was obtained from UCSC Genome Browser (track “Unmasked CpG”; < http://hgdownload.soe.ucsc.edu/goldenPath/hg19/database/cpgIslandExtUnmasked.txt.gz >, accessed in June 6th, 2016). BEDTools [ 61 ] was used to exclude those CpG sites located in CGIs. We note that the CpGti estimate from [ 18 ] includes CGIs, and in that sense the average mutation rate that we are using for CpGti may be a very slight underestimate of the mean rate for transitions at methylated CpG sites.

Unless otherwise noted, the expectation assumes fully recessive, lethal alleles with complete penetrance. Notably, by calculating the expected frequency one site at a time, we are ignoring possible interaction between genes (i.e., effects of the genetic background) and among different mutations within a gene (i.e., compound heterozygotes). These assumptions are relaxed in two ways. In one analysis ( S3 Fig ), we considered a very low selective effect in heterozygous individuals ( h = 1%), reasoning that such an effect could plausibly go undetected in medical examinations and yet would nonetheless impact the frequency of the disease allele. Second, when considering the gene-level analysis ( Fig 3 ), we implicitly allowed for compound heterozygosity between any pair of known lethal mutations [ 8 ]. For this analysis, we ran 1000 simulations for a total mutation rate U per gene that was calculated accounting for the heterogeneity and uncertainty in the mutation rates estimates as follows: (i) For j sites in a gene known to cause a recessive lethal disease and that passed our filtering criteria ( S2 Table ), we drew a mutation rate u j from the lognormal distribution, as described above; (ii) We then took the sum of u j as the total mutation rate U; (iii) We then ran one replicate with U as the mutation parameter, and other parameters as specified for site level analysis. Because the mutational target size considered in simulations is only comprised of those sites at which mutations are known to cause a lethal recessive disease, it is almost certainly an underestimate of the true mutation rate—potentially by a lot. We note further that by this approach, we are assuming that compound heterozygotes formed by any two lethal alleles have fitness zero, i.e., that they are identical in their effects to homozygotes for any of the lethal alleles. Moreover, we are implicitly ignoring the possibility of complementation, which is (somewhat) justified by our focus on mutations with severe effects and complete penetrance (but see Discussion ). Since we were interested in understanding the effect of compound heterozygosity, for this analysis, we did not consider the five genes in which only one mutation passed our filters ( BCS1L , FKTN , LAMA3 , PLA3G6 , and TCIRG1 ).

Modeling the effect of the ascertainment bias in disease discovery

To calculate the probability of ascertaining a recessive, lethal mutation, we assumed that all currently known disease mutations were identified in a putative ascertainment study of sample size n a in a population with an inbreeding coefficient of F a . Under this model, we can estimate P asc , the probability of ascertaining a disease mutation, as following:

We also demonstrate the relationship between the probability of ascertainment and mutation rate using simulations of ascertainment bias implemented according to the following steps:

• For each of the four mutation types considered, we generated 10 6 allele frequencies q from the results of the simulations based on a realistic demographic model [ 25 ].
• We generated n a independent diploid genotypes, given the allele frequencies from step 1 and an inbreeding coefficient F a . We ran this step for a range of n a and F a values ( Table 1 ).
• With a given combination of n a and F a values, we identified the cases (out of the 10 6 observations from step 1) where at least one homozygote individual was observed in step 2. These cases correspond to disease mutations that were ascertained; the reasoning being that given complete penetrance, a recessive disease mutation can only be identified if there is at least one affected individual in the studied population. With this step, we calculated the probability of ascertainment by taking the fraction of cases that satisfy the criteria above.
• Finally, for each one of the 10 6 simulations from step 1, we generated a sample allele frequency of the disease mutation, matching ExAC’s sample size (i.e., considering 2n = 65,762 chromosomes). We can then compare q u , the unbiased average allele frequency of all disease mutations, to q a , the mean frequency of the subset of cases ascertained in step 3, i.e., those cases for which at least one homozygote individual is observed.

These simulations were meant to illustrate the likely impact of ascertainment bias, rather than to precisely describe the disease mutation identification process or to quantify the expected effect. Notably, we performed these simulations for single sites, so the criteria for ascertainment in step 3 did not include the possibility of compound heterozygotes, despite the fact that an estimated 58.4% of the disease mutations included in our study were initially identified in compound heterozygotes. However, this simulation framework could readily be extended in this direction and it would not change our qualitative conclusion.

Supporting information

S1 table. list of lethal, recessive mendelian diseases considered in this study..

https://doi.org/10.1371/journal.pgen.1006915.s001

S2 Table. Information on 417 mutations associated with the severe form of lethal, recessive Mendelian diseases.

https://doi.org/10.1371/journal.pgen.1006915.s002

S3 Table. Information on 91 mutations associated with the severe form of lethal, recessive Mendelian diseases in Counsyl and ExAC databases.

https://doi.org/10.1371/journal.pgen.1006915.s003

S4 Table. P-values for each gene estimated by simulation, under a model of mutation-selection balance with a plausible demographic history.

https://doi.org/10.1371/journal.pgen.1006915.s004

S5 Table. Phenotypic effect of mouse knock-outs (see main text).

https://doi.org/10.1371/journal.pgen.1006915.s005

S1 Fig. Comparison of the empirical allele frequencies of recessive, lethal disease mutations in individuals of European ancestry from two large exome studies.

Shown are the allele frequencies for 91 variants associated with lethal, recessive diseases, as estimated from 33,370 individuals of non-Finnish, European ancestry in the Exome Aggregation Consortium (ExAC) database [ 23 ] and 76,314 European-ancestry individuals from a genetic testing laboratory (Counsyl [ 20 ]) (see Methods ). Points lie on the dashed blue line if the allele frequencies in Counsyl and ExAC are the same.

https://doi.org/10.1371/journal.pgen.1006915.s006

S2 Fig. Comparisons of mutation-selection balance models with constant versus changing population sizes.

(A) Population mean allele frequency as a function of effective population size, under a model of constant population size. The X-axis range corresponds to the range of effective population size over time estimated in [ 25 ]. The red bar indicates the value of a constant population size at which the mean allele frequency is the same as in simulations, for an average mutation rate of 1.5 x10 -8 per bp per generation [ 34 ]. (B-C) The allele frequency distribution (in grey) is presented for 2 x 10 6 simulations based on (B) the complex demographic scenario inferred by Tennessen et al. [ 25 ] for the evolution of European populations based on simulations (see Methods ) and of (C) the finite, constant size population model, with N set to 35,651 individuals to match the mean allele frequency with (B). Both models assume complete lethality ( s = 1) and recessivity ( h = 0).

https://doi.org/10.1371/journal.pgen.1006915.s007

S3 Fig. The impact on disease allele frequencies of a small fitness effect in heterozygotes ( h = 0.01).

Shown in each case is the distribution of the deleterious allele frequencies in the population, generated from 100,000 simulations. Means are represented by red vertical bars. For visualization, an allele frequency of q = 0 is set to 0.5 x 10 −6 . When a small fitness effect in heterozygotes is considered in the simulations, the mean allele frequency decreases by 79% relative to no effect. The two distributions differ significantly by a Kolmogorov-Smirnov test (p-value < 10 −15 ). The mutation rate u was set to 1.5 x 10 −8 per bp per generation, reflective of the mean mutation rate for exons [ 34 ].

https://doi.org/10.1371/journal.pgen.1006915.s008

S4 Fig. Effect of varying the end population size and the average mutation rate on the sample allele frequency of recessive, lethal mutations.

Tennessen et al. [ 25 ] inferred the present effective population size of Europeans to be 512,000 individuals based on a mutation rate of 2.36 x 10 −8 per bp per generation. We rescaled the parameters of this model based on a lower mutation rate estimate of 1.2 x 10 −8 [ 18 ] and show the expected distribution of sample allele frequencies of recessive, lethal mutations in column A. We further considered the effect of larger population sizes at present (2-, 4-, and 10-fold increase, denoted by columns B, C and D respectively), keeping other rescaled demographic parameters the same as in A. We also included a model (E) where rapid growth begins immediately after the out-of-Africa bottleneck, representing a more extreme scenario of population growth in comparison to the two-stage and more gradual scenario proposed by Tennessen et al. (2012). For A-E, we drew the mutation rate M from a lognormal distribution with parameters set as in Eq 8 , with u = 1.5 x 10 -8 (as implemented for Fig 2 ; see Methods ). Model F considers a larger u (2.25 x 10 −8 , i.e., a 1.5-fold increase from A-E), with all other parameters (e.g., variance in mutation rates across simulations, the demographic model) the same as in column A. The observed sample allele frequency distribution of 385 disease mutations in ExAC is shown in white. Violin plots show the density distribution of the log 10 allele frequencies for variants that were segregating in these samples, whereas boxes indicate the proportion of sites for which the deleterious mutation was not observed segregating in the sample. All distributions differ significantly from one another (i.e., all p-values are < 10 −15 by a Kolmogorov-Smirnov test).

https://doi.org/10.1371/journal.pgen.1006915.s009

S5 Fig. Expected distribution and the observed mean allele frequencies of recessive, lethal disease mutations (excluding mutations in CFTR and DHCR7 ).

As in Fig 2 , the four panels correspond to four different mutation types. The title of the panel indicates the mutation type, followed by K , the total number of mutations of that type, with p-values for the difference between observed and expected mean frequencies below. Distributions in grey are for 100,000 observations of the expected mean sample allele frequencies across K mutations, and were obtained from simulations based on a plausible demographic model for European populations [ 25 ] (see Methods ). Blue bars represent the observed values estimated from 33,370 individuals of European ancestry from ExAC. As opposed to in Fig 2 , here, we did not include mutations present in two genes ( CFTR and DHCR7 ) that were outliers in the gene-level analysis ( Fig 3 ) and were reported elsewhere to be carried by healthy homozygous individuals [ 24 ].

https://doi.org/10.1371/journal.pgen.1006915.s010

S6 Fig. The probability P asc of a mutation being ascertained, given its population allele frequency q , the sample size n a of the putative ascertainment study and the inbreeding coefficient F a in the population in which the ascertainment study was conducted.

In each case, we let only one parameter ( q , n a or F a ) vary, while fixing the others at q = 7.10 x 10 −6 (corresponding to the mean allele frequency from simulations), n a = 10,000, and F a = 1/16 (corresponding to marriage between first cousins, a plausible scenario for a population with widespread inbreeding).

https://doi.org/10.1371/journal.pgen.1006915.s011

S7 Fig. Depth of coverage for 385 mutations in ExAC known to cause lethal, Mendelian diseases.

Box plots show the mean (black bar) and the lower and upper quartiles for (A) the 248 sites with non-zero sample frequencies in ExAC, for which the number of sequenced non-Finnish European individuals was reported ( n = 32,881) and (B) the 137 sites for which we did not have this information. Since distributions of depth of coverage are similar between the two sets (by a Kolmogorov–Smirnov test, p-value = 0.90), we assumed that 32,881 individuals were sequenced at all sites, and used this number to subsample simulations to match the sample size of the ExAC data.

https://doi.org/10.1371/journal.pgen.1006915.s012

Acknowledgments

We thank Daniel MacArthur for his help with the ExAC data, Ellen Leffler for providing her Python script (available at https://github.com/cegamorim/PopGenHumDisease ), as well as members of the Pickrell, Przeworski and Sella labs, Aravinda Chakravarti, Brian Charlesworth, Damien Labuda and four anonymous reviewers for helpful discussions and comments on an earlier version of the manuscript. All codes and data to generate the figures in R [ 62 ] and the script used to get the sequence context of each mutation are available at https://github.com/cegamorim/PopGenHumDisease . The code to run the simulations is available at https://github.com/sellalab/ForwardSimulator . Allele frequencies and other information for the disease mutations employed in the analyses are in S2 and S3 Tables.

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• Published: 17 October 2022

Children with a rare congenital genetic disorder: a systematic review of parent experiences

• Charlotte von der Lippe   ORCID: orcid.org/0000-0003-3176-0160 1 ,
• Ingrid Neteland 1 &
• Kristin Billaud Feragen 1  

Orphanet Journal of Rare Diseases volume  17 , Article number:  375 ( 2022 ) Cite this article

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Caring for a child with a chronic disease may be demanding and stressful. When a child has a rare condition, the impact of care on parents is amplified due to the rarity of the diagnosis. In order to address the lack of generalized and synthesized knowledge regarding parents’ experiences of having a child with a rare genetic disorder, and give a holistic picture of these experiences, a systematic review of the available qualitative research was conducted.

We performed a systematic review, including qualitative studies on parents of children with rare genetic disorders, published between 2000 and 2020.

The review included 33 qualitative studies. Findings were synthesized and categorized according to three main themes: Parents’ experiences with health care, Responsibilities and challenges, and Factors promoting positive experiences in parents. The findings demonstrate that parents of children with rare genetic disorders share many common challenges, despite evident differences across conditions.

Coordinated care, and a more holistic approach in the follow up of children with rare genetic disorders is needed. International collaboration on research, diagnostics, producing scientific correct and understandable information available for health care professionals and lay people should be prioritized.

Introduction

Rare disorders are medical conditions that affect less than 1:2000 individuals or fewer [ 1 ]. In the USA, a disease is considered rare if it affects less than 200, 000 (~ 1:1600) individuals [ 2 ]. Most rare disorders are associated with a genetic cause [ 3 ].

Although rare disorders are rare by definition, it has been estimated that a rare disorder affects as many as one in 16 people [ 4 ]. Rare disorders are often chronic, with various degree of physical and psychological consequences [ 5 , 6 ] . Many rare disorders are congenital and identifiable at birth. For a few rare disorders, treatment may be available [ 7 ], however, for most there is only, if any, symptomatic treatment.

Caring for a child with a chronic disease may be demanding and stressful [ 8 , 9 ], and caregivers of children with health problems have a greater risk of having health problems than those of healthy children [ 10 ]. When a child has a rare condition, care demands may be complicated and possibly amplified because of the rarity of the condition, and parents of a child with a rare diagnosis may therefore experience increased physical and emotional stress [ 11 , 12 , 13 ]. However, parents of children with chronic diseases may also experience positive aspects of parenting, such as increased personal strength and greater appreciation for life [ 14 ].

There are between 6000 and 8000 rare diseases, and it has been estimated that rare conditions may affect as many as 30 million Europeans and 25 million North Americans [ 15 , 16 ]. Hence, many children and their families across the world have to live and cope with the medical, psychological, and social consequences of the rare condition. Due to a low prevalence of each rare disorder, knowledge about most rare disorders is sparse both in society and among health care professionals. Consequences of the lack of knowledge about rare disorders may lead to diagnostic mistakes, delays in diagnosis, and lack of information of high quality [ 17 , 18 , 19 ].

Increased awareness of rare disorders throughout society, and within the health care system, is one suggested action to improve the situation of people with rare disorders [ 20 , 21 ]. With 6000–8000 different rare conditions, the understanding of common experiences that may be present across conditions can be difficult to assess. Therefore, one way to increase knowledge, is to summarize research investigating psychological and social experiences of parents of children with rare disorders across conditions. A synthesis of qualitative studies may benefit from the depth of understanding uncovered by each qualitative inquiry, while also identifying shared experiences identified across studies, and their consequences in everyday life, which may shed light on unmet needs that require coordinated societal responses.

Qualitative methodology [ 22 ] is ideally suited for investigating the psychological, emotional, and social specificities of being the parent of a child with a rare genetic disorder, in order to gain deeper insight into people’s experiences and seeking to understand the meaning or nature of these experiences. Nevertheless, there is a lack of qualitative research exploring parents’ experiences of having a child with a rare genetic disorder, and whether these parents face challenges that are qualitatively different from those experienced by parents of children with more well-known medical conditions. Further, few papers include several different diagnoses in the same study, so that similarities and differences across conditions can be investigated from a psychological perspective, and last, a lack of literature reviews summarize shared experiences of parents of children with a rare genetic disorder.

In order to address the lack of generalized and synthesized knowledge regarding parents’ experiences of having a child with a rare genetic disorder, we conducted a systematic review of the available qualitative research on this population, in order to provide a holistic picture of common experiences across different diagnoses.

The aims of this systematic review were:

To provide an overview of parents’ experiences of having a child with a rare genetic disorder, and explore the psychosocial consequence of these experiences.

To address the overarching question: What experiences do parents of children with rare genetic disorders share?

Materials and methods

Inclusion and exclusion criteria.

A systematic review of the qualitative literature was performed, following the PRISMA statement [ 23 ]. A flow chart of the number of identified and selected articles can be found in Fig.  1 . All original, peer-reviewed articles published in English, addressing parents’ or primary caregivers’ experiences of having a child with a rare congenital genetic condition, based on qualitative or quantitative methodology, and published from January 2000 until November 2020 were included in the search. Quantitative articles were included in the search in order to get an overview also of the quantitative literature of the topic. The quantitative articles were not included in the qualitative synthesis.

Flowchart of identified and selected articles

Case studies were excluded. Studies on rare cancers, rare rheumatologic disorders, or rare acquired disorders were excluded, as many of these disorders do not have a clear genetic cause. Studies focusing mainly on the diagnostic process or with a focus on the use of internet were excluded. Reports, oral presentations or abstracts from posters were excluded.

Search strategy

The PROSPERO International prospective register of systematic reviews was searched to be sure a similar study was not started, and a protocol for this study was published (Prospero CRD42018111129).

The search strategy was developed in cooperation with a specialist librarian. We searched the following electronic databases to identify relevant studies, number of hits in parentheses: Ovid Medline (668), APA PsycInfo [ 70 ], Web of Science (163). Date of search was December 3rd, 2020. Total number of hits was 901. Number of hits after removal of duplicates was 793. We used the search words: rare, orphan, diseases, disorder*, diagnosis*, condition, parents, fathers, mothers, single parent, single-parents family, maternal behavior, paternal behavior, parent–child relations, father-child relations, mother–child relations, parenting, child rearing, caregivers, professional family relations, family, family relations, family conflict, parent*, caregiver*, caregiving, carer, carers, mother, father, maternal*, paternal*,family*, families, experienc*, lived experienc*, cope*, coping, parental characteristics, parental attitudes, parental role, parenting skills, parenting style, childrearing practices, child discipline, parent child communication, parent child relations, childrearing attitudes, parental involvement, including MeSH terms.

The search was restricted to English language, key words, titles and abstracts, and publication time was restricted to January 2000–November 2020.

Selection of included papers

Search results were merged using EndNoteX9 and duplicates were removed. Three independent reviewers examined the titles and abstracts, and selected papers for full-text reading. All three reviewers read full-text of selected papers, and papers were included in the study according to the agreed criteria (Additional file 1 : Appendix I). Questions used to include or exclude publications after full-text reading were (1) Is the study empirical and in English? (2) Is the child’s diagnosis rare and genetic? (3) Is the study about experiences of being parent to a child (any age)? (4) Is the study qualitative or quantitative?, and (5) Does the study follow standards for reporting qualitative research [ 24 ].

If the answers to questions 1- 3, and 5, were yes, and the study was qualitative, we included the study in the synthesis. Any potential disagreements between the authors were resolved through discussion.

Data extraction

All three co-authors collected data regarding citation/contact details, methods, design, participants, setting/context and results/findings (Additional file 2 : Appendix II).

Data synthesis

Qualitative research is specific to a particular context, time and group of participants, and caution is therefore needed when generalizing results. Having this in mind, it is however possible to extract results from different qualitative studies, and synthesize findings. Several methods for synthesizing qualitative data have been recommended [ 25 ], and thematic synthesis [ 26 ] was employed in the present review. All findings were extracted from the included studies’ result sections. Following extraction, the text was coded, and codes were grouped into meaningful categories, so called descriptive themes. CvdL and IN independently synthesized the data extracted, before discussing themes. Subsequently, KBF, familiar with all included papers, reviewed the themes before going through the codes to check whether they had been included in the themes. All three authors agreed on the final themes. The synthesis presents the overall findings in analytical themes and subthemes, and as presented by the authors in the publication’s result section. Rare genetic disorders are referred to as ‘rare disorders’ in the Results and Discussion.

In total, 33 qualitative articles were included, representing a wide range of rare diagnoses and conditions. An overview with details of the included articles can be found in Table 1 .

The findings demonstrate that parents shared a range of common experiences despite the uniqueness of their child’s condition. Three main themes were identified: (1) Parents’ experiences with health care, (2) Responsibilities and challenges, and (3) Factors promoting positive experiences in parents. All main themes included subthemes, which will be subsequently described. An overview of themes and subthemes in relation to all included studies can be found in Table 2 .

Theme 1: Parents’ experiences with health care

All studies except three explored parents’ experiences with health care services in charge of their child’s follow-up. The first theme was further categorised into three subthemes: Health care professionals’ lack of knowledge and experience with rare conditions, Lack of coordinated health care, and The many unknowns in terms of prognosis, treatment, and function.

Health care professionals’ lack of knowledge and experience with rare conditions

Twenty-nine of the papers raised issues related to an experienced lack of knowledge about and experience with rare conditions among health care professionals. As a consequence, parents experienced uncertainties regarding the child’s diagnosis, prognosis, treatment and/or consequences of the rare condition [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. More specifically, parents reported diagnostic delays [ 27 , 29 , 50 ], and health care professionals that could not provide the information they needed about the rare condition once diagnosis was set [ 27 , 30 , 34 , 35 , 36 , 39 , 48 ]. Parents did not receive the guidance normally provided within the health care system [ 27 , 33 , 41 , 42 , 43 ], which could lead to a loss of trust and confidence in those who are meant to be the experts [ 32 , 46 , 51 , 52 ]. Other consequences of a lack of knowledge within the health care system could be the unintended consequence of delaying treatment [ 27 , 37 ]. Parents felt frustrated or troublesome when health care professionals did not understand what they believed to be their child’s health care needs [ 35 , 41 , 42 ].

The lack of knowledge within the general population strengthened the parents’ needs for health care professionals to have relevant, deep, and extensive knowledge and expertise [ 53 ]. One study specified that it was not the lack of competence or knowledge per se that parents found difficult, but what they perceived as the physicians’ attitude; their (un)willingness to admit their shortcomings and to seek information and advice [ 51 ] or to properly prepare before the consultation [ 30 , 54 ].

Several categories of health care services were mentioned in the included studies, ranging from specialized health care services (such as specialized hospital settings and treatment teams), local health care services (such as general practitioners, local hospitals), and professional caregivers in the families’ homes (such as health care assistants). Eight studies specifically raised the issue of a lack of knowledge and diagnostic expertise within local levels, even after the child’s diagnosis had been set [ 31 , 33 , 37 , 40 , 49 , 51 , 52 , 55 ].

Lack of coordinated health care

Several studies mentioned a general lack of coordination across systems or sectors in the plan of care for the child with a rare condition, even in cases of complex care needs or long-term intensive support [ 27 , 29 , 31 , 36 , 49 , 52 ]. Several studies included overwhelming parental narratives of fragmented care, with medical teams working in silos instead of integrating the family’s needs, leading to repeated consultations and numerous medical appointments with a range of clinicians in different hospitals [ 27 , 29 , 30 , 31 , 37 , 40 , 44 , 50 ]. A lack of coordinated care could contribute to a delayed diagnosis [ 55 ] and feelings of depersonalization, since parents had to tell and re-tell their story to new health care providers [ 31 ].

Parents believed that treatment of rare conditions should be organized within standardized and specialized follow-up care systems or centers of expertise with a main health care provider to coordinate care [ 39 , 44 ]. In cases where parents had received advice and follow-up from specialized units, this was experienced as positive and strengthened their trust in the quality of the child’s care [ 33 , 45 , 48 ]. Having the same caregivers over time was perceived as extremely important for families, because it led to enhanced availability and continuity [ 53 ]. In one study however, parents explicitly said they did not feel the condition’s rarity was an issue, and they therefore did not feel a need for specialized support services [ 37 ].

The many unknowns

The lack of knowledge within the health care system led to many unknowns due to a delayed or complicated diagnostic and treatment process with several consultations [ 27 , 30 , 31 , 38 , 39 , 40 , 41 , 47 , 48 , 49 , 53 , 54 ]. The diagnostic process and first phase of the child’s life had therefore been demanding for many parents [ 32 , 40 , 48 , 53 , 56 ]. The longer and more complex the diagnostic process, the more stress the parents felt [ 50 ]. Although knowing their child had a rare condition was distressing, receiving a diagnosis was experienced as a relief and a first step towards treatment and support [ 40 , 50 ]. Parents felt that they were responsible for the next steps after a diagnosis was set [ 27 ], but the complexity of the child’s diagnosis could complicate their understanding of what was to come [ 36 ].

The many unknowns triggered parents’ feeling of being abandoned to their fate, having to cope with the child’s illness on their own, and with an overall feeling of not being understood [ 34 , 36 ], which complicated the parents’ process of adjustment and coping [ 28 , 37 , 50 ].

Caregivers had several questions regarding the child’s future, and were worried about whether their child would be capable of doing things independently, how cognitive development would unfold, and whether the child would be able to live on their own in the future [ 29 , 33 , 39 , 44 , 46 , 52 ]. The many unknowns called for more support and guidance [ 39 , 42 , 43 ]. However, advices from health professionals could be inadequate and vary across levels of health care services [ 34 , 42 ], and limited evidence-based guidance complicated parents’ efforts to understand and compare risks and benefits when considering treatment alternatives [ 33 ].

Theme 2: Responsibilities and challenges

All studies described how parents experienced responsibility for their child’s medical care and handled challenges associated with the child’s diagnosis and everyday life. Theme 2 was categorised into four subthemes: Society’s lack of information and knowledge, Changes and adjustments in everyday life (work, parenthood, social life), Parents as coordinators, advocates, and experts, and Emotional reactions.

Society’s lack of information and knowledge

Parents often spent considerable time explaining their child's condition when meeting new people in settings such as playgrounds, shopping centres, or schools, an information task some parents experienced as demanding [ 28 , 45 , 48 , 49 , 53 , 57 ]. Nevertheless, they felt responsible for raising awareness about the rare condition [ 45 , 57 ], even when it felt difficult to explain to other people what their daily life looked like [ 31 , 34 , 35 ]. The challenge of explaining could be even greater if the child’s diagnosis was not visible to others, since caregivers could struggle to explain the child’s needs for special support [ 39 , 43 ]. The condition’s complexity could complicate the process of sharing information to others, especially if parents did not feel knowledgeable themselves to adequately explain [ 50 ], and parents missed reliable sources of knowledge where they could find information [ 30 , 31 , 36 ]. Lack of knowledge also had consequences in school settings [ 28 , 39 , 42 ] or public institutions when applying for social rights or benefits [ 55 ]. In some studies, the lack of understanding was a challenge also within the extended family, which reduced the possibilities of social support [ 45 , 47 , 52 ].

Social experiences among strangers and a general lack of knowledge in society could be demanding due to staring or comments if the child looked different or behaved differently [ 28 , 37 , 38 , 41 , 43 , 44 , 46 , 49 , 50 , 57 ]. Questions from others and/or a need to explain the difference was experienced as demanding by some parents [ 45 ], and some used preemptive and active strategies, hoping to fend off questions and stares [ 57 ]. Parents also described anticipated or experienced social stigma and taboo as challenging [ 44 , 46 , 49 , 50 , 57 ].

Changes and adjustments in everyday life (work, parenthood, social life)

Parents described how having a child with a rare condition had an impact on the whole family, siblings included [ 29 , 32 , 33 , 38 , 41 , 44 , 45 , 48 , 50 , 52 , 53 , 55 , 58 , 59 ].

Responsibility for the children and their care was described as intensive and demanding, and affected parents’ day-to-day living [ 37 , 39 , 46 , 49 , 50 , 51 ]. Coping with challenging day-to-day experiences and in some cases living in high alert over time was described as exhausting [ 31 , 36 , 49 ]. Because of the many daily challenges, levels of conflict could arise between spouses/partners and affect their relationship [ 29 , 32 , 38 , 44 , 47 , 52 ]. In contrast, three studies mentioned that the challenges could strengthen feelings of togetherness between the parents or within the family [ 29 , 52 , 58 ]. In one study, parents had specific recommendations for couples in order to preserve marriage and other relationships [ 45 ]. Lack of support in the larger family system could also lead to a higher level of conflict within the affected family [ 52 ]. Nevertheless, the priority was given to the child’s needs [ 29 , 45 , 58 ].

Some rare conditions present with specific behavioural or medical challenges with an impact on the family’s daily life. Hence, parents had to handle nutritional problems [ 53 ], food-seeking behaviours [ 39 , 45 , 54 ], communication problems [ 39 , 43 , 53 ], and behavioural problems [ 49 ]. The child’s condition could affect, complicate, or challenge the parent–child relationship, due to problems with communication and cognitive functioning, and/or behavioural characteristics that could be associated with the condition [ 28 , 43 , 45 , 48 , 53 ]. Treatment demands could break the child’s trust in the parents as their guardians against painful experiences [ 32 , 38 ], also affecting the parent–child relationship. Difficulties were especially challenging when the child could not express his or her own needs, making it very difficult for the parents to know whether their child was in pain or was in need of something [ 48 ]. During adolescence and early adulthood, parents mentioned how adherence issues to treatment could reduce the child’s long-term independence, and rise concerns about their child's ability to manage their own medical needs [ 33 ], possibly also affecting the child-parent relationship. In social settings, parents felt the need to shield their child from other people’s attitudes, fearing that the child’s self-perceptions could be negatively affected if people reacted to the child’s behaviour or the rare disease [ 50 , 57 ].

Demands associated with the rare condition led parents to feel torn between caring for their child and work obligations [ 27 , 47 , 49 , 55 ]. They felt that they had to inform the work place about their situation [ 57 ] or seek a different work situation [ 29 , 45 , 54 , 59 ], when the child’s care was described as a part-time job in itself [ 27 , 59 ]. Additional care needs also led parents to struggle with finding time for personal and/or social activities [ 30 , 46 , 48 , 55 ], and complicated the preservation of social relations outside the family [ 32 , 39 , 54 , 56 ]. Plans were difficult to make or had to be adjusted to the situation because of the many insecurities associated with daily care and/or treatment demands [ 41 , 51 , 55 ].

Due to medical or psychological problems related to the child’s diagnosis, caregivers experienced difficulties in looking after their child and provide the best upbringing [ 39 ]. Hence, in-home caregivers were necessary in some families. Still, finding suitable in-home caregivers that parents felt they could trust, and welcoming them into their private home could feel challenging and invading [ 31 , 59 ].

Parents as coordinators, advocates, and experts

Due to the lack of knowledge within the health care system, parents were the ones finding out whether support was existing and available, requesting care, social aid or benefits, or other resources they in some cases did not manage to receive, and took on the arduous and demanding responsibility of coordinating the follow-up of their child [ 27 , 29 , 30 , 31 , 32 , 37 , 39 , 41 , 42 , 46 , 48 , 49 , 55 ].

Several studies shed light on parents’ struggle to get what they believed should be proper care, being the ones noticing or bringing up that something was wrong with their child, being perceived as difficult and demanding, or having the feeling that health care providers did not believe them or even blamed them for the child’s symptoms [ 27 , 29 , 30 , 31 , 32 , 35 , 37 , 38 , 40 , 41 , 42 , 46 , 47 , 49 , 51 , 53 ]. Being dependent upon referrals and access to other necessary aids created a feeling of disempowerment in some parents, if such help was not provided [ 27 ]. Caregivers also felt they took on the responsibility for medical care they did not have any competence for in the first place, such as handling nutritional adjustments, educational needs, and/or managing other problems related to the diagnosis [ 47 , 50 ].

Due to a lack of dialogue between health care professionals, parents experienced medical appointments as repetitive in nature, and the need to tell their child's and family's story repeatedly across consultations [ 30 , 53 ]. Parents described spending energy and time looking for medical treatment that could alleviate their child’s symptoms [ 47 ], hoping to regain some control by taking on the responsibility of researching their child’s health care needs [ 32 ]. Some parents, or the larger family, also took the responsibility of finding and trying out treatment alternatives, in the hope of alleviating their child’s suffering [ 46 , 52 ].

Parents also felt responsible for special arrangements in school, social activities, interpersonal relationships, general life adjustments and assistance from psychological support teams, in addition to the family’s financial security [ 28 , 42 , 44 , 45 , 46 , 47 , 52 ]. One study described how school and health care settings also relied on parents’ knowledge and information to coordinate the child’s needs [ 42 ].

Parents labelled themselves as fighters, saviours, and navigators for their child, in their efforts to be heard [ 31 , 37 , 53 ] and described the paramount need to stand up for the child, intervene, negotiate, or act on the child's behalf, which could sometimes mean less time for caring for the sick child [ 44 , 45 ].

The lack of knowledge about the child’s rare condition led parents to search for information on the internet, but missed guidance from health care providers on this search [ 27 , 34 , 35 , 44 ]. They tried to be critical of the information they found and looked for what they considered to be reputable sources, such as scientific journals, and also connected with health care providers with specialized knowledge [ 27 ]. As a consequence of this extensive and ongoing search for information, in addition to their lived experiences, parents became experts on their child’s rare condition and felt they had acquired more knowledge about the rare condition than the health care providers [ 29 , 30 , 35 , 36 , 37 , 51 , 52 , 55 ]. Parents could feel that care providers’ knowledge was based on outdated information, whereas they had read more recent studies and were more updated on relevant research [ 30 ]. Nevertheless, several studies revealed that some parents did not feel that their experience was valued, acknowledged, or sought by health care providers [ 31 , 35 , 36 , 53 ]. This reversal of traditional parent–professional roles was experienced as difficult and an additional responsibility for some parents [ 28 ], who frequently felt they needed to be the expert “home doctors” [ 28 , 35 , 45 , 50 , 51 ]. Other studies showed that some parents treasured feeling as experts in their child’s care, and that understanding complex medical information could increase parents’ self-confidence [ 29 , 32 , 35 ].

Caregivers described how they had to monitor whether or not symptoms were developing in their child, for example whether their child was gaining weight or whether problems were related to the diagnosis or the child’s personality development [ 39 ], and in some cases also felt they were responsible for treatment decisions [ 28 ].

Emotional reactions

Parents described a wide range of emotional reactions, such as feelings of shock, anxiety and fear, lack of control, defencelessness, depression or loss, denial, self-blame and guilt, helplessness, and distress [ 28 , 29 , 32 , 33 , 34 , 35 , 36 , 38 , 41 , 42 , 44 , 45 , 46 , 47 , 49 , 51 , 52 , 53 , 55 ]. Uncertainty, unpredictability, and ambiguity characterized everyday life for many parents, or they felt trapped in a box or square that they could not get out of [ 43 , 44 , 46 , 53 ]. Feelings such as disbelief, displacement, anger, frustration, or pain were also described [ 29 , 31 , 35 , 37 , 40 , 44 , 45 , 54 ], eventually followed by feelings of acceptance [ 47 , 53 ]. In cases of genetically inheritable disorders, parents also felt guilt or fear of passing on the disorder to their children [ 36 , 41 ]. Life was described as a rollercoaster or a constant battle [ 37 , 38 , 44 ]. In one study, parents described how they felt they were in a movie, watching something they struggled with understanding was their own life, being centre stage and managing complications and disease manifestations, they had never imagined [ 49 ]. Having to cope with their child’s pain, fear of death, or the child’s own grief over the rare condition acted as an additional worry for parents [ 38 , 43 , 44 , 52 , 53 ].

Parents suffer because, firstly, their child’s illness requires so much attention, time, and energy that the physical and emotional wear and tear sooner or later takes its toll [ 36 ]. The many emotional reactions, such as powerlessness, threatened the parents’ belief in their own parenting skills [ 32 , 38 ]. Several studies also shed light on physical symptoms of exhaustion, physical burnout, insomnia, or illness in parents of children with a rare condition [ 30 , 32 , 36 , 42 , 47 , 59 ].

The concern regarding potential social reactions was a reality for many parents [ 28 , 43 , 46 , 47 ]. Informing others was associated with feelings of depression and anxiety [ 48 ]. Fear or experiences of bullying was also a prominent aspect for several parents [ 41 , 46 ]. Parents also described the immense emotional cost of shielding or defending their child against social misconceptions and reactions, due to the social or physical visibility of the condition, sometimes leading to social avoidance [ 28 , 32 , 37 , 38 , 41 , 43 , 44 , 49 ].

Having to cope with many unanswered questions regarding the child’s future care and treatment options caused feelings of loneliness, helplessness and insecurity [ 27 , 28 , 29 , 32 , 34 , 36 , 37 , 38 , 39 , 40 , 44 , 47 , 49 , 52 , 54 , 55 , 56 ]. Fragmented care delivery increased families’ emotional load [ 30 , 37 , 44 , 50 ]. The overall lack of understanding and knowledge about the rare genetic disorder and its treatment led to anger, frustration, sorrow, and feelings of isolation [ 28 , 42 , 44 ], or a sense of loneliness [ 36 , 50 ], due to the lack of strategies or tools needed to deal with the situation. Parents could find it difficult to share their experiences and what they went through, which led to feelings of isolation [ 31 , 34 , 48 , 49 ]. Feeling isolated could also be triggered by a lack of understanding from close friends or family [ 49 , 58 ], or from health care providers [ 27 , 29 , 30 , 41 , 52 ]. In contrast, social support and normalising everyday life, such as going to work, reduced feelings of isolation [ 48 , 56 ]. Parents were also concerned over how the impact of illness affected their child's quality of life and/or daily life [ 28 , 33 , 43 ].

Theme 3: Factors promoting positive experiences in parents

All studies except two presented findings related to positive adjustment in parents of children with a rare condition. The third theme was categorised into three sub-themes: Engaged and understanding health care professionals, Benefits of social support, and Protective factors and coping mechanisms.

Engaged and understanding health care professionals

Parents shared how relieving it was to be treated with respect and knowledge from the health care professionals in charge of treatment and feel that their problems were taken seriously [ 41 ]. Care professionals honouring the families' knowledge and recognising that parents had first-hand experience with the condition was important [ 30 , 31 ]. The development of self-reliance and trust in their ability to cope with problems could be enhanced when parents’ perception of subjective vulnerability was counterbalanced by support from professionals [ 35 , 53 ].

The importance of professional caregivers’ personal characteristics was underlined, so that a trusting relationship could be built between parents and helpers [ 53 ]. Respect, compassion and empathy, emotional support and involvement, being treated with sensitivity, tact, and kindness, continuity, knowledge and availability, and boosting parents’ knowledge were described to be ideal characteristics in health care professionals [ 34 , 36 , 48 , 53 , 54 ]. Personal and direct communication was also central when information was provided [ 44 ]. Connection with care professionals was achieved when they were experienced to be kind, caring, present, understanding and listening, while also being real and truthful about the situation [ 30 , 37 , 42 , 48 , 53 , 54 ]. Trust depended on the degree to which professionals managed to be honest about their lack of knowledge and managed to show that they understood the emotional impact of the rare condition on the families’ lives [ 36 , 48 , 51 ].

Benefits of social support

Social support was experienced as hugely important, protected against emotional distress [ 35 , 48 , 56 , 58 ], and provided parents with much necessary support when the child’s help needs exceeded the parents’ available resources [ 36 ]. Daily life, such as being at work, normalised parents’ situation and enabled them to have social interactions, which could have a protective social function [ 48 , 54 , 59 ]. Social and emotional support could also be found in faith communities and helped parents coping with their situation [ 56 ]. Specific and practical support, on the other hand, was complicated by parents’ fear that others could not correctly understand their child’s care needs and they therefore could not trust support to be given [ 45 ]. In one study, fathers did not want social support, since handling things alone or within the nuclear family acted as a protective strategy and a buffer against exposure to the courtesy stigma that could be triggered if help was sought or received [ 57 ].

The larger family may normally provide additional support, which was confirmed in one study [ 58 ]. However, cultural or societal frameworks could lead the larger family, such as older family members and grandparents, to blame the child’s parents for the rare condition [ 47 , 52 ], or feel shame about their grandchildren, which led to a lack of support within the larger family [ 52 ]. In yet other families, the genetic aspects of the condition meant that several family members were affected; reducing the opportunities for support, and/or caregivers could find it difficult to ask for help [ 28 ].

Other people’s level of understanding and positive attitude was described as central for parents to feel supported by friends and others [ 45 ]. Therefore, the emotional, practical, and social benefits of talking to others with similar experiences was highlighted as important by parents in several studies [ 27 , 28 , 29 , 35 , 36 , 39 , 40 , 41 , 45 , 47 , 48 , 50 ]. Being active members of patient associations where parents could discuss challenges, share experiences, and provide each other with information and advice, was described as a main source of social support [ 27 , 29 , 44 , 45 , 50 ], and a necessary asset for reducing feelings of isolation [ 27 , 29 , 33 , 35 , 39 , 48 , 50 ]. Nevertheless, some parents felt that attending support conferences and meeting other parents had increased their worries for the child’s future [ 45 ].

The lack of knowledge within the health care system and society as a whole, leading to an absence of clear, understandable and accessible public information, strengthened the importance of searching for information on the Internet and seek support and feel connected to other parents who had undergone the same situation [ 27 , 34 , 35 , 40 , 42 , 45 , 55 ]. The asset of online peer support was described to be its flexibility and availability, with easy access to other parents’ experiences and recommendations on a daily basis or whenever needed [ 27 , 35 , 44 ]. Parents were, however, well aware that the Internet also could be an anxiety provoking and frightening tool [ 35 , 44 ].

Protective factors and coping mechanisms

Several studies mentioned individual characteristics that had strengthened parents’ coping mechanisms. Willpower, perseverance, and courage seemed particularly important, as well as the ability to adjust and plan everyday life so that it matched the child’s needs [ 35 , 37 , 42 , 45 , 47 , 48 , 52 ]. A sense of agency and self-reliance also strengthened parents’ ability to cope and trust in their ability to help and care for their child when problems arised [ 32 , 33 , 35 , 37 , 38 , 53 , 57 ]. High levels of health literacy was also explicitly described as helpful in one study [ 35 ]. Parents also aimed at increasing their child’s sense of agency, encouraging the child in participating in treatment decisions or defending him-/herself from negative social reactions [ 52 , 57 ]. Parents had also experienced that demanding experiences had strengthened their self-confidence, changed their outlook on life, and increased their empathy skills and understanding of other’s challenges [ 32 ].

Families described a process of normality reconstruction, incorporating the child’s condition with its consequences, and a re-organizing of family life based on the needs of the child, which appeared to give parents a sense of control over their situation [ 50 ]. Having the same condition as their child was also described as enhancing parents’ coping skills, as they had previous experience with the disease [ 41 ]. Normalization and acceptance was facilitated if the parents felt the child’s situation was stable. Nevertheless, the lack of knowledge regarding the condition’s progress and outcome created a fragile sense of control, and could be easily shattered in case of unexpected events [ 44 , 50 ].

Parents developed strategies and knowledge themselves, learning by doing [ 42 ]. Focusing on daily tasks and everyday life was a way of coping with grief and loss [ 28 , 52 ]. Religious beliefs, or mindfulness practice and yoga, were described as helping caregivers revisit life's challenges, accept trials and tribulations, and find strength to cope [ 45 , 47 , 52 , 56 ]. Parents described the importance of identifying activities or daily routines that could strengthen their own and the family’s emotional coping [ 45 , 59 ]. The importance of focusing on positive aspects of being a parent of a child with a rare condition [ 44 ], as well as feelings of gratitude and hope also strengthened parents’ adjustment to the rare condition [ 38 ].

Parents’ experiences of having a child with a rare genetic disorder have previously not been systematically reviewed. The present review examined the qualitative literature methodically, in order to identify parents’ experiences of having a child with a rare genetic disorder. Findings were categorized according to three main themes: Parents’ experiences with health care, Responsibilities and challenges, and Factors promoting positive experiences in parents. This systematic review demonstrates that parents of children with rare genetic disorders share many common challenges, such as a lack of knowledge in the health care system as well as in society in general, a lack of coordinated care, and lack of available information about rare disorders. Consequently, parents experience that they have to be experts on their child’s rare disorder, coordinators in the health care system, and act as advocates for their child. Many parents felt isolated and alone, and experienced a change in their social situation when they became parents to a child with a rare disorder; especially mothers described challenges with working fulltime and having a child with a rare disorder. Few articles focused primarily on protective factors or parents’ coping mechanisms. However, the synthesis of the results demonstrated that all but two studies presented findings that shed light on factors promoting positive experiences in parents, such as engaged and understanding health care professionals, benefits of contact with others in a similar situation and social contacts in general, and the use of personal coping mechanisms such as educating themselves, focusing on daily activities, religious beliefs and feelings of gratitude and hope.

Parents’ experiences with the health care system

Parents mentioned health care professionals’ lack of knowledge and lack of experience about rare disorders in the majority of the studies. Lack of knowledge, and its negative consequences such as delays in obtaining an accurate diagnosis and maltreatment [ 60 , 61 ], is not novel news. Lack of knowledge is indeed a major barrier for people with rare disorders [ 62 ], and our systematic review demonstrates that this also is true for parents to children with rare disorders.

In 2009, the European commission requested that all European countries should elaborate and adopt plans and national strategies for rare diseases. Sadly, this seems to be easier said than done [ 63 ]. Collecting and sharing knowledge across different countries, and for different rare disorders, are important methods to increase knowledge. Unfortunately, the small number of available individuals to include in the research on rare disorders adds an extra challenge to this task. The readers of published literature may also be few, giving this research low prestige and more difficult to fund [ 64 ]. International collaboration is therefore of major importance, and research programs for rare disorders across countries, such as projects promoted by the European Joint Programme on Rare Diseases (EJP RD) [ 65 ], should be encouraged. European Reference Networks (ERN) were founded on the principle that experts and specialists need to communicate and collaborate across countries if we are to solve challenges related to rare conditions [ 66 ]. However, the effect these ERN’s have on individuals’, families’ and health care professionals’ experiences on access to knowledge and treatment of rare disorders remains unanswered and should be prioritized in future research.

Some individuals live with an undiagnosed condition and the International Rare Diseases Research Consortium (IRDiRC) suggest that this group of individuals should enter a globally coordinated diagnostic and research pipeline [ 67 ]. Until such a pipeline is up and running, existing international collaboration is of immeasurable value. The importance of national and international networks, and databases such as DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) [ 68 ] and GeneMatcher [ 69 ], to identify other ultra-rare patients and researchers interested in the gene or disease cannot be overestimated.

Health care professionals and patient support organizations must continue to work together as they already do in the North American National Organization for rare disorders (NORD) and European Organization for rare diseases (EURORDIS). Although the awareness about rare disorders is increasing in Asia [ 70 ], there is room for improvement, especially in Africa [ 71 ]. Results from the current study demonstrate clear unmet medical needs, lack of knowledge on a societal level, with corresponding psychological consequences for parents of children with a rare disorder, problems that may be exacerbated in countries with less available resources. Hence, European and North-American actions, such as the organization of ERNs or NORD, could possibly have the potential to address some of the unmet needs revealed in the present study, and inspire similar actions in regions with fewer resources world-wide.

Several of the studies mentioned that the children had to see several different specialists before the diagnosis was set. Challenges continued also after the diagnosis, since far from all questions parents had had been resolved. For rare disorders, and especially for ultra-rare disorders, the current study confirms that parents face many unknowns, just to mention a few: What is the prognosis? Will there be treatment available? Will my child get access to treatment? For more well-known chronic disorders, parents will not need to ask most of these questions, because answers are obvious and health care professionals may provide them immediately. In contrast, parents of children with rare disorders often continue to search for knowledge about the disorder and possible treatment. Lack of coordinated care was identified as a major challenge for the parents in the present review. When parents of children with spinal muscular atrophy were asked to provide advice that could improve the follow-up of their child, they suggested health care professionals to designate a coordinator for every family [ 72 ]. Future research should investigate whether this is a solution that could improve parents’ health care experiences when the child has a rare condition.

Responsibilities and challenges

In addition to health care professionals’ lack of knowledge, many parents described a lack of available information about their child’s rare disorder, and a general lack of knowledge in society. The parents described how they became the experts on the rare disorder, acted as coordinators for their children’s follow-up, and became advocates for their child. A review on adults with a rare disorder also revealed that people affected by a rare condition considered themselves as “expert patients”; They educated themselves and became experts on their condition, because of health care professionals’ lack of knowledge and experience with the condition [ 62 ]. Health care professionals should see this gained expertise as a value [ 73 ]. However, research may indicate that some health care providers feel challenged by lay knowledge [ 74 ]. Instead, health care professionals should use the expert knowledge parents of children with rare disorders have as a valued resource that may optimize care. Previous research has shown that the parents’ voices are vital to influence and guide service development [ 75 ], and a critical element in creating responsive, meaningful, and widely accepted policies [ 76 ].

Several studies demonstrated how care needs and consequences of the rare disorder had forced parents to make changes in their social life, such as cutting down work-hours or quitting their job, and seeing friends and family less. For some, this had promoted a sense of isolation and almost all studies described how parents had to cope with a range of emotional reactions in their daily lives that could potentially affect their psychological adjustment. Parents of children with a rare condition have additional stressors, including balancing work and family, time constraints, stress, and feelings of “doing it all” [ 77 ]. Research on rare craniofacial conditions has demonstrated that parental distress has the potential to impact the child’s own emotional development [ 78 ]. In contrast, parents who feel they have managed to adjust positively to their child’s condition will probably be better equipped to help their child to develop a positive and strong self-image [ 79 ], in line with research showing that parents’ sense of self-efficacy in their ability to care for their child is central for the development of the child’s well-being [ 80 ].

Although parents of children with congenital genetic disorders may have heritable concerns regarding their child’s genetic status, this was not a prominent theme in the studies included in this review. One reason may be that the issue of heritability was not specifically addressed in these studies. Concerns regarding heritability may be sensitive for parents to share, and thus may be missed unless specifically addressed.

Factors promoting positive experiences in parents

Studies focusing primarily on factors and coping mechanisms that have a positive effect on parents of children with rare disorders are lacking. None of the included studies systematically investigated protective factors that could promote coping. Nevertheless, most studies revealed positive factors and parental coping mechanisms. As many of the negative factors, such as lack of knowledge and lack of treatment, may not be solved immediately, a focus on factors promoting positive experiences may be clinically helpful. Interestingly, in all but two of the studies, parents mentioned factors important to them as positive. Parents described the importance of having a social network and to be able to work outside of home in order to get some normalcy in life. It may therefore be important to encourage parents to continue in their jobs, and for society and employers to facilitate the work situation in an optimal way for parents [ 81 ], as well as encourage the parents to find ways to keep up their social life and contact with family and friends.

The parents considered it very beneficial to be in contact with others in a similar situation, i.e. parents of other children with the same diagnosis as their own child. For some rare disorders, there may be national or international patient support groups. For most rare disorders, this is missing, and parents may find support groups in social media such as Facebook. Information shared on support groups on Internet may be valuable to families with a member with a rare disorder [ 82 ]. A recent study demonstrated that most of the support groups on Facebook are private groups [ 83 ]. For many parents, these groups are the only place where they find others in a similar situation, as well as information about the disease and possible treatment options. A lack of professional involvement in these private groups may challenge the scientific quality of its content. Researchers and health care professionals could be more involved in such groups, as it could be of benefit to both parties. However, Facebook, or other similar web-sites on the Internet, are not secure platforms to share sensitive data, and parents and health care professionals should therefore be careful with their use.

An engaged and understanding doctor was also of high value to the parents, and these qualities in a health care professional seemed to be more important than the health care professional’s actual level of knowledge. Although health care workers’ lack of knowledge may be frustrating to parents, a lack of interest or a lack of respect for the parents’ knowledge may be even more damaging, and lead to a deterioration of the relationship between parents and health care professionals, which could be followed by less optimal health care for the child as a consequence. Though the lack of knowledge is disturbing, it is important to know that for some disorders, such as for example many ultra-rare disorders or disorders of N -of-1, little knowledge is available, and will perhaps be lacking for many years. It is therefore very important for health care professionals to show engagement, sensitivity, and understanding irrespective of the level of knowledge about the rare condition [ 72 , 84 ]. Research on how health care professionals can provide optimal care for parents of children with rare disorders, despite a lack of competence and knowledge, should be prioritized, as well as research to minimize the gap of lack of knowledge. Health care professionals should be trained to handle situations where they do not have the necessary knowledge, and where information may be replaced by uncertainties. Meeting the parents with confidence, interest and respect will not act as a substitute to a lack of knowledge; however, it may still be of help to the parents. Less use of the health care system and poorer health may be the result of parents’ mistrust to health care professionals [ 85 ].

The majority of participants in the included studies were mothers. This could reflect that mothers take more responsibility for being the child’s primary caregiver. Indeed, several studies demonstrated that the father was the primary caretaker and provider of the family’s economy, by keeping a full time job. However, more research on fathers’ experiences is warranted.

Strengths and limitations

The strengths of this literature review lie in the methodological and systematic approach, investigating the lived experiences of being a parent or primary caregiver of a child with a rare genetic disorder from a qualitative perspective. It is, however, also important to acknowledge some limitations with the present review. First, some methodological challenges were encountered. Given the many thousands different rare conditions, identifying a good search strategy was important, and the search strategy was therefore discussed in detail with a specialist librarian before conducting the search. A different methodological approach could have been to specifically include some more “common” rare congenital genetic disorders within the search process. However, choosing which diagnoses to include would have been a methodological challenge, and this method was therefore not chosen in the present review.

Articles on specific rare diagnoses in which “rare disease”, or its synonyms, were not included in the title, abstract or keywords, could therefore have been missed. Hence, chances were possibly higher not identifying rare conditions with higher prevalence rates, compared to very rare or ultra-rare conditions, and may have influenced results. However, in order to counterbalance this limitation, we used the search words rare, orphan, diseases, disorder*, diagnosis*.

Another methodological challenge was that some studies presented quotes without the context they were a part of, or presented some results very shortly, complicating the synthesis of the results in the present review. One paper presented their results as part of the discussion, also complicating the extraction of data for this review. Further, few studies explicitly explored the potential uniqueness of the rarity of a condition, investigating whether challenges that are identified have a similar or differential impact on individuals, depending of the specificity of the condition.

A strength of this study is that we are three authors with different backgrounds. CVDL and KBF both have experience in qualitative research. CVDL is a clinical geneticist with several years of experience of working with families with rare disorders. KBF is a psychologist and has vast knowledge about rare disorders and the psychosocial consequences of living with a rare disorder. IN is a doctor in training in pediatrics with less knowledge about rare disorders, which was seen as a strength, since IN could challenge CVDL and KBF’s potential pre-conceptions about rare disorders when discussing the synthesis of the results, reducing the risk of bias.

The current review demonstrates that parents of children with a rare genetic disorder face many common challenges across different conditions. Health care professionals’ lack of knowledge seems to be a major obstacle for parent’s ability to care for their child, and they should be trained to handle and optimize meetings with the families in spite of uncertainties and lack knowledge. Parents also described the importance of having social networks and the benefit of being in contact with parents of children with similar challenges as themselves, which could possibly counteract the negative impact of a lack of knowledge in health care services and society in general. There is a need for more coordinated care for children with rare disorders, and a more holistic approach in the follow up of the children and the parents. The expertise of the parents should be valued. The development of more international collaboration on research, diagnostics, creating and making available scientific correct information understandable for health care professionals and lay people should be prioritized. Unmet medical needs and the lack of knowledge have clear psychological consequences for the parents, and therefore need to be addressed by health care policies.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

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We thank Marie Susanne Isachsen, librarian at the medical library at Oslo University Hospital, Rikshospitalet, Norway, for assistance in the search process.

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von der Lippe, C., Neteland, I. & Feragen, K.B. Children with a rare congenital genetic disorder: a systematic review of parent experiences. Orphanet J Rare Dis 17 , 375 (2022). https://doi.org/10.1186/s13023-022-02525-0

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Orphanet Journal of Rare Diseases

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The Face of a Rare Genetic Disease

By Karobi Moitra

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This case study is designed to teach basic concepts of genetics by focusing on a rare disease, pseudoxanthoma elasticum (PXE).  Chromosome 16 is the narrator at the beginning of the case and introduces students to genes, chromosomes and mutations. The focus then shifts to the patient and his mother as she finds out about her son’s disease and her subsequent efforts to connect with patient advocacy groups for support. The case concludes with students watching a TED talk given by Sharon Terry, the real-life mother on whom this story is loosely based, so that students can connect on an emotional and human level with someone who has intimate experience as a parent of children with a rare genetic disease. The case is suitable for high school general biology classes, but it can also be used by biology major or non-major undergraduates in a lower-division biology class, or in any lower-division non-major class focused on human disease.

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• Explain the basic structure and function of chromosomes.
• Explain the relationship between genes, chromosomes, nucleus and the cell.
• Describe the genetic disease PXE.
• Explain the basic concepts of genetics.
• Understand mutations and their role in disease.
• Learn how to locate information about a particular disease or gene.
• Read and understand scientific articles and resources.
• Understand patient advocacy.
• Connect with the human face of genetic diseases.

Genetics; pseudoxanthoma elasticum; PXE; Sharon Terry; disease; advocacy; genetics; chromosomes; genes; mutation

Subject Headings

EDUCATIONAL LEVEL

High school, Undergraduate lower division

TOPICAL AREAS

Social issues

TYPE/METHODS

Teaching Notes & Answer Key

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Case teaching notes are protected and access to them is limited to paid subscribed instructors. To become a paid subscriber, purchase a subscription here .

Teaching notes are intended to help teachers select and adopt a case. They typically include a summary of the case, teaching objectives, information about the intended audience, details about how the case may be taught, and a list of references and resources.

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Materials & Media

Supplemental materials.

• Science Didn’t Understand My Kid’s Rare Disease Until I Decided to Study It Sharon Terry talks about her children's rare disease PXE and how she decided to study it. This is a personal and true story of a mother who decided to do something to help her kids and other kids suffering from the rare disease PXE. Running time: 14:54 min. Produced by TEDMED, 2016.
• Mutation This video explains the concept of genetic mutations and how they relate to the central dogma of molecular biology. Running time: 7:02 min. Produced by Bozemanscience, 2012.

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8.1: Case Study: Genes and Inheritance

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• Page ID 16760

• Suzanne Wakim & Mandeep Grewal
• Butte College

Case Study: Cancer in the Family

People tend to look similar to their biological parents, as illustrated by the family tree in Figure \(\PageIndex{1}\). But, you can also inherit traits from your parents that you can’t see. Rebecca becomes very aware of this fact when she visits her new doctor for a physical exam. Her doctor asks several questions about her family's medical history, including whether Rebecca has or had relatives with cancer. Rebecca tells her that her grandmother, aunt, and uncle, who have all passed away, all had cancer. They all had breast cancer, including her uncle, and her aunt additionally had ovarian cancer. Her doctor asks how old they were when they were diagnosed with cancer. Rebecca is not sure exactly, but she knows that her grandmother was fairly young at the time, probably in her forties.

Rebecca’s doctor explains that while the vast majority of cancers are not due to inherited factors, a cluster of cancers within a family may indicate that there are mutations in certain genes that increase the risk of getting certain types of cancer, particularly breast and ovarian cancer. Some signs that cancers may be due to these genetic factors are present in Rebecca’s family, such as cancer with an early age of onset (e.g. breast cancer before age 50), breast cancer in men, and breast cancer and ovarian cancer within the same person or family.

Based on her family medical history, Rebecca’s doctor recommends that she see a genetic counselor because these professionals can help determine whether the high incidence of cancers in her family could be due to inherited mutations in their genes. If so, they can test Rebecca to find out whether she has the particular variations of these genes that would increase her risk of getting cancer.

When Rebecca sees the genetic counselor, he asks how her grandmother, aunt, and uncle with cancer are related to her. She says that these relatives are all on her mother’s side — they are her mother’s mother and siblings. The genetic counselor records this information in the form of a specific type of family tree, called a pedigree, indicating which relatives had which type of cancer and how they are related to each other and to Rebecca. He also asks her ethnicity. Rebecca says that her family, on both sides, are Ashkenazi Jews, meaning Jews whose ancestors came from central and eastern Europe. “But what does that have to do with anything?” she asks. The counselor tells Rebecca that mutations in two tumor-suppressor genes called BRCA1 and BRCA2, located on chromosome 17 and 13, respectively, are particularly prevalent in people of Ashkenazi Jewish descent and greatly increase the risk of getting cancer. About 1 in 40 Ashkenazi Jewish people have one of these mutations, compared to about 1 in 800 in the general population. Her ethnicity, along with the types of cancer, age of onset, and the specific relationships between her family members who had cancer indicate to the counselor that she is a good candidate for genetic testing for the presence of these mutations.

Rebecca says that her 72-year-old mother never had cancer, and nor had many other relatives on that side of the family, so how could the cancers be genetic? The genetic counselor explains that the mutations in the BRCA1 and BRCA2 genes, although dominant, are not inherited by everyone in a family. Also, even people with mutations in these genes do not necessarily get cancer — the mutations simply increase their risk of getting cancer. For instance, 55 to 65% of women with a harmful mutation in the BRCA1 gene will get breast cancer before age 70, compared to 12% of women in the general population who will get breast cancer sometime over the course of their lives.

Rebecca is not sure she wants to know whether she has a higher risk of cancer. The genetic counselor understands her apprehension but explains that if she knows that she has harmful mutations in either of these genes, her doctor will screen her for cancer more often and at earlier ages. Therefore, any cancers she may develop are likely to be caught earlier when they are often much more treatable. Rebecca decides to go through with the testing, which involves taking a blood sample, and nervously waits for her results.

Chapter Overview: Genetics

At the end of this chapter, you will find out Rebecca ’s test results. By then, you will have learned how mutations in genes such as BRCA1 and BRCA2 can be passed down and cause disease. Especially, you will learn about:

• How Gregor Mendel discovered the laws of inheritance for certain types of traits.
• The science of heredity, known as genetics, and the relationship between genes and traits.
• Simple and more complex inheritance of some human traits.
• Genetic Disorders.

As you read this chapter, keep Rebecca’s situation in mind and think about the following questions:

• What do the BRCA1 and BRCA2 genes normally do? How can they cause cancer?
• Are BRCA1 and BRCA2 considered linked genes? And are they on autosomes or sex chromosomes?
• After learning more about pedigrees, draw the pedigree for cancer in Rebecca’s family. Use the pedigree to help you think about why it is possible that her mother does not have one of the BRCA gene mutations, even if her grandmother, aunt, and uncle did have it.
• Why do you think certain gene mutations are prevalent in certain ethnic groups?

Attributions

• Caelius and Valerius family tree by Ann Martin , licensed CC BY 2.0 via Flickr
• Text adapted from Human Biology by CK-12 licensed CC BY-NC 3.0

Human Genetics and Disease

We are in the midst of a genomics revolution with new technologies enabling discoveries in human genetics with unprecedented speed and scope. Faculty in the Department of Genetics and Genome Sciences are working to apply these cutting-edge techniques to identify new genetic causes of disease and better understand how an individual’s genetic makeup contributes to their disease susceptibility.

Studies of both rare and common diseases can lead to new mechanistic understanding of disease pathology, the discovery of gene functions, the improvement of disease prediction modeling, and the identification of new therapeutic targets. In our department, David Buchner identifies new genetic causes of rare pediatric endocrine disorders including infertility, growth, and skeletal disorders. Anthony Wynshaw-Boris and Ashleigh Schaffer study human brain development, with Professor Wynshaw-Boris focused on autism and brain overgrowth and Professor Schaffer focused on rare pediatric neurological disease. 

One disease that is a particular focus of research in our department is cystic fibrosis. Ann Harris utilizes genomic approaches to understand what controls the expression of the cystic fibrosis gene and also other genetic factors that modify disease severity. Craig Hodges specializes in making and studying new animal models of cystic fibrosis. Shih-Hsing Leir researches the causes of infertility in men with cystic fibrosis. Mitch Drumm is focused on applying our molecular knowledge of the cystic fibrosis gene and other modifier genes to the development of new therapeutics targeted for the treatment of cystic fibrosis.

Cancer genetics is another area of active research in our department, with the promise of improving individual cancer risk predictions and tailoring treatments to individual patients based on their genetic profile. Charis Eng works to identify and characterize genes that cause susceptibility to inherited cancer syndromes, with a particular focus on PTEN in breast, thyroid, and endometrial, among other cancers. Peter Scacheri studies how enhancers alter gene expression to influence cancer risk and progression. Anna Mitchell seeks to identify novel inherited mutations that contribute to familial cancers and related syndromes. 

Anne Matthews directs the department’s genetic counseling program that trains the next generation of counselors to understand our rapidly progressing knowledge of how genetics influences disease risk and to effectively communicate this information to patients.   

• Case report
• Open access
• Published: 23 April 2024

Genetic exploration of Dravet syndrome: two case report

• Agung Triono 1 ,
• Elisabeth Siti Herini   ORCID: orcid.org/0000-0003-2571-8310 1 &

Journal of Medical Case Reports volume  18 , Article number:  215 ( 2024 ) Cite this article

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Dravet syndrome is an infantile-onset developmental and epileptic encephalopathy (DEE) characterized by drug resistance, intractable seizures, and developmental comorbidities. This article focuses on manifestations in two Indonesian children with Javanese ethnicity who experienced Dravet syndrome with an SCN1A gene mutation, presenting genetic analysis findings using next-generation sequencing.

Case presentation

We present a case series involving two Indonesian children with Javanese ethnicity whom had their first febrile seizure at the age of 3 months, triggered after immunization. Both patients had global developmental delay and intractable seizures. We observed distinct genetic findings in both our cases. The first patient revealed heterozygous deletion mutation in three genes ( TTC21B , SCN1A , and SCN9A ). In our second patient, previously unreported mutation was discovered at canonical splice site upstream of exon 24 of the SCN1A gene. Our patient’s outcomes improved after therapeutic evaluation based on mutation findings When comparing clinical manifestations in our first and second patients, we found that the more severe the genetic mutation discovered, the more severe the patient’s clinical manifestations.

These findings emphasize the importance of comprehensive genetic testing beyond SCN1A , providing valuable insights for personalized management and tailored therapeutic interventions in patients with Dravet syndrome. Our study underscores the potential of next-generation sequencing in advancing genotype–phenotype correlations and enhancing diagnostic precision for effective disease management.

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Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy (SMEI), is an infantile-onset developmental and epileptic encephalopathy (DEE) characterized by drug resistance, intractable seizures, and comorbidities including intellectual disability, behavioral problems, sleep disturbances, gait disturbances, and an increased risk of sudden unexpected death in epilepsy [ 1 , 2 ]. The incidence of DS is approximately 1 in every 15,700 births [ 3 ]. The first symptom of DS is seizures in the first year of life, followed by developmental delay [ 1 ]. This first seizure is either generalized tonic–clonic or focal (occasionally hemiclonic) clonic, and in more than half of the cases, it is a febrile seizure, making it difficult to distinguish from a self-limiting febrile seizure. Infection, hot environment, exhaust, sunlight, or exercise can initiate an attack of DS [ 4 , 5 ]. Approximately 80% of patients with DS carry a pathogenic variant of the sodium channel alpha 1 subunit ( SCN1A ) gene resulting in haploinsufficiency Nav1.1, the alpha-1 subunit of the sodium channel. PCDH19, SCN2A, SCN8A, SCN1B, GABRA1, GABRB3, GABRG2, KCNA2, CHD2, CPLX1, HCN1A, and STXBP1 variants may also be involved in DS or DS-like phenotypes. Accordingly, genetic testing is required to identify other genes that play a role in the DS phenotype and to expand genotype-DS phenotype correlations to enhance the future management of this disease [ 6 ]. In the last decade, next-generation sequencing (NGS) technology has been able to analyze a set of genes (targeted panel sequencing), exome [(whole exome sequencing (WES)], or genome [whole genome sequencing (WGS)] in a single sequencing process, making it possible to diagnose rare diseases such as early childhood epilepsy [ 7 ]. Identification of the genetic basis of DS can provide additional information regarding pathophysiology, prognosis, and individual drug therapy options according to the patient’s condition.

We present a case series involving two children, one aged 11 years and 2 months, and the other aged 1 year and 4 months. Both children were diagnosed with DS, exhibiting symptoms of intractable seizures, global developmental delay, and seizures triggered by postimmunization fever. Despite displaying similar symptoms, the two individuals possess different genetic variants of the SCN1A gene and also possible novel mutation in DS. We also discuss the main clinical characteristics, treatment course, and management of DS at tertiary referral hospitals in Indonesia.

A boy with Javanese ethnicity aged 11 years and 2 months with uncontrollable seizures regularly visits our hospital. The patient had his first seizure at the age of 3 months with a duration of 15 min, and it was triggered after receiving diphtheria–pertussis–tetanus (DPT) immunization, which was accompanied by fever. The patient has about six to seven seizures per day for 1 min in the form of generalized tonic–clonic and absence seizures. He was the first child of nonconsanguineous healthy parents with normal prenatal and birth history. He has a younger sister with normal development. There is no history of family members with febrile seizure. The patient was born at 40 weeks of gestation, with a birth weight of 4000 g, length of 52 cm, and head circumference of 33 cm. The patient is currently experiencing global developmental delay and is still in kindergarten. He had learning difficulties and was unable to speak words at an age-appropriate level. He had delayed motor development and was unable to perform age-appropriate motor activities. Head circumference was 46.5 cm (microcephaly). There were no signs of meningeal irritation nor Babinski response. The motor examination revealed no increased tone in the upper and lower limb. Other systemic examinations revealed no abnormalities. Interictal electroencephalography (EEG) showed diffuse epileptiform irritative abnormality on a normal background (Fig.  1 ). Magnetic resonance imaging (MRI) of the brain showed cerebral atrophy, bilateral frontal subarachnoid enlargement, bilateral occipital lobe and polymicrogyria, and a neuroglial cyst in the right temporal lobe (Fig.  2 ). He was recommended to get genetic testing done since he was suspected of having DS.

Electroencephalography (EEG) shows diffuse epileptiform irritative abnormality on a normal background

Axial brain magnetic resonance imagery shows cerebral atrophy, bilateral frontal subarachnoid enlargement, bilateral occipital lobe polymicrogyria, and a neuroglial cyst in the right temporal lobe

Whole genome sequencing (WGS), whole exome sequencing (WES), and Sanger sequencing were performed at 3Billion (Seoul, Korea). The WGS and WES procedures were conducted according to the protocols of Richards et al . [ 8 ] and Seo et al . [ 9 ], respectively. Both WES and WGS are comprised of four main parts: (1) high-quality sequencing; (2) sequencing data analysis including alignment to the genome reference consortium human 37 (GRCh37)/hg19 for WES, also alignment to the genome reference consortium human 38 (GRCh38) and revised Cambridge reference sequence (rCRS) of the mitochondrial genome for WGS; (3) variant annotation and prioritization by EVIDENCE [a software that was developed in house to prioritize variants based on the American College of Medical Genetics and Genomics (ACMG) guidelines [ 10 ]]; and (4) variant interpretation in the context of the patient’s symptoms and reporting of disease-causing variants. Once EVIDENCE prioritizes the top candidate variants/genes, 3Billion’s highly-trained clinical/medical geneticists manually curate each variant to identify the disease-causing variant for reporting.

In our initial examination, we performed WES on patient 1 and subsequently identified a copy number variant (CNV), prompting us to proceed with WGS. The WGS analysis revealed a heterozygous pathogenic 552.9 Kb deletion variant in 2q24.3. The heterozygous deletion NC_000002.12:g.165811316_166364199delinsTGTACACTA at 2q24.3 spans across three genes ( TTC21B , SCN1A , and SCN9A ). The variant is not observed in the gnomAD SVs v2.1.1 dataset. SCN1A is subject to haploinsufficiency. Other pathogenic variants have been reported in this region. There are multiple similarly affected individuals reported with similar likely pathogenic copy–number–loss overlapping this region [ 11 , 12 ]. Therefore, this variant was classified as pathogenic. Due to region-spanning mutation in SCN1A, which suitable with clinical manifestation, the patient was diagnosed with DS (OMIM 607208: since we were unable to perform a Sanger sequencing study on both of the parents, the pattern of inheritance is still uncertain.

The arents were counseled about their child’s condition and agreed to undergo multipronged therapy. Before the patient was diagnosed with DS, he had received valproic acid (30 mg/kg per day), phenobarbital (2.5 mg/kg per day), and oxcarbazepine (5 mg/kg per day), also physio, occupation, and speech therapy but had not shown significant improvement. He was seizure-free for 3 months after oxcarbazepine was changed to levetiracetam (27 mg/kg per day). However, the patient then had another episodes of less than 5 minutes general tonic–clonic seizure (GTCS)-induced by fever. Interictal EEG was performed to evaluate his condition, and we found that the diffuse epileptiform irritative abnormality persisted.

A 1 year and 4 month-old-girl with Javanese ethnicity was referred to our hospital due experiencing myoclonic seizure followed by 20 minute GTCS at 3 months, after fever following DPT immunization. She then continued to experience generalized tonic–clonic seizures one to two times per day for 10–15 seconds. At 9 months of age, the patient received a second DPT immunization, and on the same day, she had another generalized tonic–clonic seizure that lasted > 30 minutes, resulting in her admission to the pediatric intensive care unit. Before the first seizure, the patient could lift her head, grasp a toy and make eye contact, but after that, she could neither lift her head nor grasp an object. The patient has no previous history of trauma.

She had a normal head circumference increased physiological reflexes in all extremities. Other systemic examinations revealed no abnormalities. Computed tomography (CT) scan examination of the head showed a subdural hygroma in the right and left frontoparietal region, without any other abnormalities (Fig.  3 ). Electroencephalography (EEG) at the beginning of the seizure did not show any abnormalities, but the EEG follow-up 7 months after the onset of the seizure showed an abnormal epileptiform (spike wave) with a normal background (Fig.  4 ). Thus, she was suspected of having DS and was recommended to undergo genetic examination.

Axial brain computed tomography scan shows a subdural hygroma in the right and left frontoparietal region, without any other abnormalities

Electroencephalography shows abnormal irritative epileptiform with a normal background

Whole exome sequencing (WES) showed a likely pathogenic variant identified as a heterozygous mutation of the SCN1A gene with genomic position 2-166859265-T-C (GRCh37), [NM_001165963.4:C.4003-2A > G [NP_001159435.1:p.?]. The variant is located in the canonical splice site upstream of exon 24 of SCN1A gene (NM_001165963.4 transcript). Since this variant is an essential splicing variant, the protein consequence is uncertain and therefore represented as (p.?). In this patient’s genetic mutation, the canonical junction site occurs which is expected to alter the junction and result in loss or disruption of normal protein function. However, using an in silico predictor, spliceAI ( https://spliceailookup.broadinstitute.org/ ), the variant is predicted to result in a loss of 22 base pairs at end of exon 24. This loss is expected to create a frameshift at the Gly1342 position. Sanger sequencing confirmed the patient’s genotype (Fig.  5 A), but the mother’s Sanger analysis was negative (Fig.  5 B). Due to familial issues, Sanger sequencing was not performed on the father, leaving the inheritance pattern unresolved.

A Sanger sequencing result of patient 2 showed a heterozygous mutation of the SCN1A gene with the genomic position 2-166859265-T-C (GRCh37), [NM_001165963.4:C.4003-2A >G [NP_001159435.1:p.?] (red arrow); and B Sanger sequencing result of patient 2’s mother showed normal sequence

The parents were counseled about their child’s condition and agreed to undergo multipronged therapy. Before patient was diagnosed with DS, she received clonazepam (0.01 mg/kg per day), valproic acid (29 mg/kg per day), and phenytoin (5 mg/kg per day), but seizure persisted. When phenytoin was stopped, with valproic acid (30 mg/kg per day) and clonazepam (0.04 mg/kg per day) adjusted, seizures were greatly decreased. Later, patient only experienced one seizure per year. The patient routinely received physio, speech, and occupational therapy.

When comparing the clinical features and outcomes of the two patients (Table  1 ), we found that our first patient, who had three medications, was still having a generalized seizure induced by fever with duration less than 5 minutes after they had been seizure-free for 3 months (at the age 11 years and 8 months. Our second patient, however, only experienced one seizure annually after receiving two medications (at the age 1 year and 10 months). This difference implies that the clinical state of the first patient was worse than that of the second.

Research on the identification of DS genetic mutations using NGS has never been done in Indonesia. In 2010, we conducted a study to identify pathogenic variants of the SCN1A gene using the Sanger sequencing method and successfully reported cases of novel SCN1A mutations in Indonesia in patients with severe myoclonic epilepsy in infancy (SMEI) and borderline SMEI (SMEB). The first boy identified with SMEI experienced a variety of seizures, including his first febrile seizure and general tonic–clonic seizure at 7 months of age, and later suffered from myoclonic seizures, left-sided hemiconvulsions, also focal convulsions without fever, along with delayed speech development. The second patient with SMEB had his first febrile seizures with GTCS after immunization at 3 months old, then later on experienced status epilepticus, GTCS, and atonic convulsions without fever [ 13 ]. We also conducted another research on the spectrum of generalized epilepsy with febrile seizure plus (GEFS+) focusing on clinical manifestations and SCN1A gene mutations. That study analyzed a total of 34 patients who suffered from SMEI (7 patients), SMEB (7 patients), febrile seizure plus (FS+) and absence/myoclonic/atonic/partial seizures (11 patients), and FS+ (9 patients) [ 14 ].

However, the research that we have done uses the Sanger sequencing genetic examination, which is expensive and takes considerable time. Additionally, it is unable to find any other gene besides SCN1A in patients with DS. A study by Djémié et al . in Belgium reported the discovery of 28 pathogenic variants of the SCN1A gene using the NGS method which were previously missed or undiagnosed using Sanger sequencing [ 7 ]. To link DS cases more effectively, we are attempting to conduct NGS genetic tests, specifically WES and WGS.

Dravet syndrome (DS) was infrequently reported in Indonesia due to its difficulty in diagnosis, misdiagnosis as febrile seizures or other epilepsy syndromes, or lack of follow-up and genetic testing in our country. According to the to the International League Against Epilepsy (ILAE) [ 15 ], the diagnostic criteria for this condition should consist of a number of the following symptoms: (1) a family history of epilepsy or febrile seizures; (2) normal development before seizures onset; (3) seizure before 1 year of age; (4) EEG with generalized spike and polyspike waves; (5) pleomorphic epilepsy (myoclonic, focal, clonic, absence, and generalized seizures); (6) focal abnormalities or early photosensitivity; (7) psychomotor retardation after 24 months; (8) exacerbation of seizures with increased body temperature; and (9) the appearance of subsequent ataxia, pyramidal signs or interictal myoclonus after the beginning of psychomotor slowing. Both of our patients had seizures beginning with increased body temperature and regression of development after seizure onset, which were resistant to the majority of anticonvulsant medications. The seizures began as generalized tonic–clonic seizures, followed by absence seizures. Both of our patients also experienced subsequent ataxia and pyramidal signs. Thus, they were suspected of having DS and were advised to undergo genetic testing.

Infants with DS have normal physical and psychomotor development at the time of their first seizure, which typically occurs between the ages of 5 and 8 months. In our case series, both of our patients experienced their first seizure at the age of 3 months [ 16 , 17 ]. In the first year of life, the most common form of seizure is febrile tonic–clonic. Some patients may experience myoclonic and dyscognitive seizures infrequently. Frequently, protracted seizures result in status epilepticus. In the first year of life, seizures are precipitated by fever/illness, immunization, and cleansing [ 16 ]. As the infant develops, he or she will experience a variety of seizure types, as well as fever and emotional stress, flashes of light, and overexertion being seizure triggers. The child with DS will develop hypotonia, ataxia, incoordination, and pyramidal signs, dysautonomia events, cognitive impairment, and behavioral disturbances such as attention deficit, hyperactivity, or autistic characteristics [ 15 ]. Some of the conditions above are very consistent with what happened to our patients.

The EEG performed during the early phases of the disease is normal. However, as the child grows, generalized spike waves with isolated or brief discharges of fast polyspike waves may be present [ 15 , 18 ]. In the first case, we found diffuse epileptiform irritative abnormality with a normal background, whereas in the second case, initially it was found normal, then a few months later it became abnormal irritative epileptiform with a normal background.

Genetic testing is developing rapidly and playing a significant role in the specific diagnosis and management of epilepsy [ 19 , 20 ]. Several genes with pathogenic mutations produce DS or DS-like phenotypes, which inevitably require different drug therapy approaches. Genes that cause DS can be grouped based on how they work: specifically, three sodium channel-related genes ( SCN2A, SCN8A , and SCN1B ), one potassium channel-related gene ( KCNA2 ), three gamma-aminobutyric acid receptors ( GABAR ) genes ( GABRA2, GABRB3 , and GABRG2 ), a cyclic nucleotide gated cation channel gene ( HCN1 ), and other functional genes including CHD2, CPLX1 , and STXBP1 . Approximately 80% of patients with DS have a pathogenic variant of the SCN1A gene, from which the majority of SCN1A variants are de novo, but 10% of people inherit the SCNA1 mutation from one or both parents [ 6 ]. Both of our patients had a mutation in the SCN1A gene, which is the most common mutation seen in DS.

Furthermore, TTC21B and SCN9A mutations were also found in our first patient. A study conducted by Suls et al . also reported a four generation Bulgarian family with epilepsy, revealing a heterozygous 400 kb deletion on chromosome 2q24 that included the SCN1A and TTC21B genes [ 21 ]. The patients exhibited variable phenotypes, but all experienced generalized tonic–clonic seizures around the first year of life, with some presenting myoclonic or absence seizures. Febrile seizures occurred in three of the four patients during infancy. Notably, one patient had mild mental retardation, another had psychomotor slowing, and a third had mental retardation from early infancy; all showed reduced seizures on medication. The findings in that study parallel the situation observed in our initial patient case. Meanwhile, a study by Singh et al . identified a heterozygous mutation in the SCN9A gene in two patients diagnosed with DS [ 22 ]. One of these patients also exhibited a mutation in the SCN1A gene. The study provided evidence suggesting that the SCN9A gene on chromosome 2q24 could potentially serve as a modifier for DS. Among 109 patients with DS, 8% were found to have an SCN9A mutation. This included six patients with double heterozygosity for SCN9A and SCN1A mutations and three patients with only heterozygous SCN9A mutations, supporting the notion of a multifactorial inheritance pattern [ 22 ]. The previous research confirmed the severity of clinical symptoms in our first patient, whom we identified mutations in the SCN1A, SCN9A , and TTC21B genes.

In the last decade, there has been a very rapid development of neurogenetic science and diagnostic technology. NGS is the latest method of genetic examination that allows for the discovery of causal mutations, including de novo, novel, and familial mutations related to epilepsy syndromes that have variable phenotypic features [ 23 ]. The first generation of DNA sequencing using the Sanger method could only examine one gene at a time and had limitations especially when examining large genomic regions, so the NGS method is more widely used today [ 7 , 23 ]. A study conducted by Kim et al . in Seoul reported an increase in diagnostic yield using WES after targeted panel sequencing with negative results in infantile onset epilepsy by 8%. This result suggests that WES assays increase the opportunity to search for new epilepsy genes and uncover less well-known epileptic phenotypes from known neurological diseases [ 24 ]. The WES examination also allows for the discovery of de novo or inherited mutations if the patient and both parents are examined [ 25 ].

According to the recommendations of the North American consensus panel, clobazam and valproic acid are the first-line therapies for antiepileptic drugs, followed by stiripentol, topiramate and levetiracetam. Patients with a suboptimal response to clobazam and valproic acid have been advised to consider the ketogenic diet as a second-line treatment [ 17 ]. SCN1A is a gene that codes for sodium channel channels, so drugs that work as sodium channel blockers, such as lamotrigine, phenytoin, carbamazepine, oxcarbazepine, lacosamide, and rufinamide, are contraindicated in patients with DS because they can increase the frequency of seizures [ 4 ]. After the failure of first- and second-line therapy, surgical therapies, such as vagus nerve stimulation (VNS), were moderately agreed upon and should be considered [ 17 ]. Besides medication, controlling infections and body temperature variations also showed to decrease the frequency of seizures and severity of the disease [ 18 ]. Initially, the first patient received oxcarbazepine and the second patient got phenytoin, which had been contraindicated to patients with DS. Futhermore, after eliminating medications that were contraindicated, both patients’ outcome improved.

In this study, we discovered unique mutations that have never been documented before, particularly in Indonesia, where NGS analysis of DS genetic variants has never been done. However, the limitation of this study, is that the information comes from two cases only. Further research is needed to explore more cases from Indonesia population.

In summary, our case series utilizing next-generation sequencing (NGS) unveils the intricate genetic landscape of Dravet syndrome (DS) in two Indonesian pediatric cases. By using WGS and WES, we identified distinct mutations in the SCN1A gene, as well as contributions from genes, such as TTC21B and SCN9A . The power of WGS lies in its ability to uncover rare pathogenic variants, including a 552.9 Kb deletion in the 2q24.3 region. These findings emphasize the importance of comprehensive genetic testing beyond SCN1A , providing valuable insights for personalized management and tailored therapeutic interventions in patients with DS. Our study underscores the potential of NGS in advancing genotype–phenotype correlations and enhancing diagnostic precision for effective disease management. Furthermore, we found that the clinical condition of the first patient was worse than that experienced by the second patient. This difference suggests that the more severe the genetic mutation detected, the more severe the clinical manifestations of the patient.

Availability of data and materials

The dataset used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

American College Of Medical Genetics

Copy number variant

Computed tomography

• Dravet syndrome

Developmental and epileptic encephalopathy

Electroencephalography

Febrile seizure plus

Generalized epilepsy with febrile seizure plus

Genome reference consortium human 37

Genome reference consortium human 38

General tonic clonic seizure

International league against epilepsy

Magnetic resonance imaging

• Next-generation sequencing

Revised Cambridge reference sequence

Sodium channel alpha 1 subunit

Severe myoclonic epilepsy of infancy-borderline

Severe myoclonic epilepsy in infancy

Vagus nerve stimulation

Whole-exome sequencing

Whole-genome sequencing

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Acknowledgements

The authors express their gratitude to the patient and their families for their cooperation, as well as to all the staff and nurses who provided care for the patient. We are also thankful for the Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada for funding this research and providing English editing services for assistance in the editing and proofreading process. Additionally, we appreciate the assistance of Kristy Iskandar, Marissa Leviani Hadiyanto and Khansadhia Hasmaradana Mooiindie during the data collection and editing phases.

This study was supported by the Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, (Dana Masyarakat to ESH). The funding body did not influence the study design, data analysis, data interpretation, nor manuscript writing.

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Agung Triono & Elisabeth Siti Herini

Pediatric Surgery Division, Department of Surgery/Genetics Working Group/Translational Research Unit, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr. Sardjito Hospital, Yogyakarta, 55281, Indonesia

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ESH, AG, and G made substantial contributions to the conception and design of the work. AG contributed to data acquisition. ESH, AG, and G performed the data analyses and the interpretation of the data. ESH and AG drafted the text and prepared the figures. ESH, AG, and G revised, read, and approved the final manuscript. All authors approve the present version for publication, and are accountable for all aspects related to the study.

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Triono, A., Herini, E.S. & Gunadi Genetic exploration of Dravet syndrome: two case report. J Med Case Reports 18 , 215 (2024). https://doi.org/10.1186/s13256-024-04514-2

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EDITORIAL article

Editorial: the genetics and epigenetics of mental health.

• 1 Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil
• 2 Faculdades Pequeno Príncipe, Curitiba, Brazil
• 3 Department of Genetics, Federal University of Parana, Post-graduation Program in Genetics, Curitiba, Brazil
• 4 Translational Research in Respiratory Medicine, Hospital Universitari Arnau de Vilanova-Santa Maria, Biomedical Research Institute of Lleida (IRBLleida), Lleida, Spain
• 5 CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain

Editorial on the Research Topic The genetics and epigenetics of mental health

Mental health conditions cover a broad spectrum of disturbances, including neurological and substance use disorders, suicide risk, and associated psychosocial, cognitive, and intellectual disabilities (WHO, 2022). Despite a substantial amount of evidence, the interaction of genetic variants, epigenetic mechanisms, and environmental risk factors involved in mental health is poorly understood. Through distinct perspectives and different experimental approaches, the genetics and epigenetics of mental health were addressed in seven relevant articles included in this Research Topic, briefly summarized below.

Stress has severe consequences on the epigenome, but the timing of its occurrence, as well as the intensity and number of events, are critical for the severity of mental health symptoms. In particular, Serpeloni et al. demonstrated that stress generated in the form of intimate partner violence (IPV) during and/or after pregnancy impacts the offspring’s epigenome, shaping its resilience. They observed that individuals exposed to maternal IPV after birth presented psychiatric issues similar to their mothers, with different outcomes if the exposure to maternal IPV occurred both prenatally and postnatally. Prenatal IPV was associated with differential methylation in CpG sites in the genes encoding the glucocorticoid receptor ( NR3C1 ) and its repressor FKBP51 ( FKBP5 ), associated with the ability to terminate hormonal stress responses. Also considering early-life experiences and data from 2008 to 2016 of the Health and Retirement Study, Shin et al. concluded that early life experiences and relationships have a significant influence, attenuating or exacerbating the risk of suffering from mental health problems among individuals with a higher polygenic risk score predisposing to autism.

Environmental and developmental factors are also strongly linked to obsessive-compulsive disorder (OCD). They may explain the apparent discrepancy between the relatively high heritability scores and the inconsistent results found in genetic association studies, owing to their impact on gene expression and regulation. Based on this, Deng et al. stratified OCD patients by the age of disease onset. The findings revealed associations between the early onset and variants of genes whose products play a role in neural development, corroborating the age-associated genetic heterogeneity of OCD.

Further exploring environmental and genetic etiological clues, Li et al. used genome-wide association study (GWAS) data to calculate polygenic risk scores for salivary and tongue dorsum microbiomes associated with anxiety and depression. Additionally, causal relationships between the oral microbiome, anxiety, and depression were detected through Mendelian randomization, unraveling potential pathogenic mechanisms and interventional targets. Constructing a similar line of evidence, Becerra et al. found associations between the epigenetic regulation of inflammatory processes, the composition of gut microbiome, and modified Rosenberg self-esteem scores in samples from the Native Hawaiian and other Pacific Islander (NHPI) populations, which present a high prevalence and mortality from chronic and immunometabolic diseases, as well as mental health problems. This warrants further investigation into the relationship of microbiota to brain activity and mental health.

There is a lot of debate regarding suicidal behavior and its relationship with psychiatric disorders, but the extent to which they share the same genetic architecture is unknown. This Research Topic was investigated by Kootbodien et al. through the use of genomic structural equation modeling and Mendelian randomization with a large genomic dataset. The authors observed a strong genetic correlation between suicidal ideation, attempts, and self-harm, as well as a moderate to strong genetic correlation between suicidal behavioral traits and a range of psychiatric disorders, most notably major depressive disorder, involving pathways related to developmental biology, signal transduction, and RNA degradation. In conclusion, the study provided evidence of a shared etiology between suicidal behavior and psychiatric disorders, with overlapping pathophysiological pathways.

Malekpour et al. , in their investigation of psychogenic non-epileptic seizures (PNES), also uncovered shared pathways with psychiatric conditions. PNES, the most prevalent non-epileptic disorder among patients referring to epilepsy centers, carries a mortality rate akin to drug-resistant epilepsy. Employing a systems biology approach, the authors pinpointed several key components influencing the disease pathogenesis network. These include brain-derived neurotrophic factor (BDNF), cortisol, norepinephrine, proopiomelanocortin (POMC), neuropeptide Y (NPY), the growth hormone receptor signaling pathway, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, and the neurotrophin signaling pathway.

In general, these studies have some limitations: small sample sizes, leading to low statistical power in some cases, environmental confounding factors (such as diet and physical activity), which were not considered in the microbiome studies, incomplete phenotype descriptions, and partial coverages of human genetic diversity. Childhood adversities and adult comorbidities are among the variables that were not controlled for as possible causes of the investigated psychiatric and neurological disorders, and some results still claim for functional studies to be validated. Thus, the findings brought more elaborated questions, each of which shed some light on knowledge gaps that remain very difficult to fill. How do early-life epigenetic processes regulate our mental health resilience and disease resistance? What is the role of the microbiome in this process and how do genetic variants influence its composition? How does the impact of all these elements shape the resistance of human populations to psychiatric and neurological diseases and, most importantly, translate into public health measures in the future? We hope to engage more researchers in the pursuit of these answers.

Author contributions

GCK: Conceptualization, Data curation, Writing–original draft, Writing–review and editing. ABWB: Writing–original draft, Writing–review and editing. ADST: Conceptualization, Data curation, Writing–original draft, Writing–review and editing.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Empresa Brasileira de Serviços Hospitalares (Ebserh) grant numbers 423317/2021-0 and 313741/2021-2 (8520137521584230), Research for the United Health SUS System (PPSUS-MS), CNPq, Fundação Araucária and SESA-PR, Protocol N°: SUS2020131000106. ABWB receives CNPq research productivity scholarships (protocols 313741/2021). ADST receives financial support from Instituto de Salud Carlos III (Miguel Servet, 2023: CP23/00095), co-funded by Fondo Social Europeo Plus (FSE+).

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: methylation, GWAS-genome-wide association study, microbiome & dysbiosis, poligenic risk score, neurological conditions, epigenome, genome

Citation: Kretzschmar GC, Boldt ABW and Targa ADS (2024) Editorial: The genetics and epigenetics of mental health. Front. Genet. 15:1402495. doi: 10.3389/fgene.2024.1402495

Received: 17 March 2024; Accepted: 26 March 2024; Published: 09 April 2024.

Edited and reviewed by:

Copyright © 2024 Kretzschmar, Boldt and Targa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Gabriela Canalli Kretzschmar, [email protected] ; Angelica Beate Winter Boldt, [email protected] ; Adriano D. S. Targa, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Crimean-Congo hemorrhagic fever (CCHF), caused by CCHF virus, is a tickborne disease that can cause a range of illness outcomes, from asymptomatic infection to fatal viral hemorrhagic fever; the disease has been described in >30 countries. We conducted a literature review to provide an overview of the virology, pathogenesis, and pathology of CCHF for clinicians. The virus life cycle and molecular interactions are complex and not fully described. Although pathogenesis and immunobiology are not yet fully understood, it is clear that multiple processes contribute to viral entry, replication, and pathological damage. Limited autopsy reports describe multiorgan involvement with extravasation and hemorrhages. Advanced understanding of CCHF virus pathogenesis and immunology will improve patient care and accelerate the development of medical countermeasures for CCHF.

Crimean-Congo hemorrhagic fever (CCHF) is a tickborne infection that can range from asymptomatic to fatal and has been described in >30 countries. Early identification and isolation of patients with suspected or confirmed CCHF and the use of appropriate prevention and control measures are essential for preventing human-to-human transmission. Here, we provide an overview of the epidemiology, clinical features, and prevention and control of CCHF. CCHF poses a continued public health threat given its wide geographic distribution, potential to spread to new regions, propensity for genetic variability, and potential for severe and fatal illness, in addition to the limited medical countermeasures for prophylaxis and treatment. A high index of suspicion, comprehensive travel and epidemiologic history, and clinical evaluation are essential for prompt diagnosis. Infection control measures can be effective in reducing the risk for transmission but require correct and consistent application.

Crimean-Congo hemorrhagic fever virus (CCHFV) is the most geographically widespread tickborne viral infection worldwide and has a fatality rate of up to 62%. Despite its widespread range and high fatality rate, no vaccines or treatments are currently approved by regulatory agencies in the United States or Europe. Supportive treatment remains the standard of care, but the use of antiviral medications developed for other viral infections have been considered. We reviewed published literature to summarize the main aspects of CCHFV infection in humans. We provide an overview of diagnostic testing and management and medical countermeasures, including investigational vaccines and limited therapeutics. CCHFV continues to pose a public health threat because of its wide geographic distribution, potential to spread to new regions, propensity for genetic variability, potential for severe and fatal illness, and limited medical countermeasures for prophylaxis and treatment. Clinicians should become familiar with available diagnostic and management tools for CCHFV infections in humans.

Jamestown Canyon virus (JCV) is a mosquitoborne orthobunyavirus in the California serogroup that circulates throughout Canada and the United States. Most JCV exposures result in asymptomatic infection or a mild febrile illness, but JCV can also cause neurologic diseases, such as meningitis and encephalitis. We describe a case series of confirmed JCV-mediated neuroinvasive disease among persons from the provinces of British Columbia, Alberta, Quebec, and Nova Scotia, Canada, during 2011–2016. We highlight the case definitions, epidemiology, unique features and clinical manifestations, disease seasonality, and outcomes for those cases. Two of the patients (from Quebec and Nova Scotia) might have acquired JCV infections during travel to the northeastern region of the United States. This case series collectively demonstrates JCV’s wide distribution and indicates the need for increased awareness of JCV as the underlying cause of meningitis/meningoencephalitis during mosquito season.

We analyzed hospital discharge records of patients with coccidioidomycosis-related codes from the International Classification of Diseases, 10th revision, Clinical Modification, to estimate the prevalence of hospital visits associated with the disease in Texas, USA. Using Texas Health Care Information Collection data for 2016–2021, we investigated the demographic characteristics and geographic distribution of the affected population, assessed prevalence of hospital visits for coccidioidomycosis, and examined how prevalence varied by demographic and geographic factors. In Texas, 709 coccidioidomycosis-related inpatient and outpatient hospital visits occurred in 2021; prevalence was 3.17 cases per 100,000 total hospital visits in 2020. Geographic location, patient sex, and race/ethnicity were associated with increases in coccidioidomycosis-related hospital visits; male, non-Hispanic Black, and Hispanic patients had the highest prevalence of coccidioidomycosis compared with other groups. Increased surveillance and healthcare provider education and outreach are needed to ensure timely and accurate diagnosis and treatment of coccidioidomycosis in Texas and elsewhere.

High incidences of congenital syphilis have been reported in areas along the Pacific coast of Colombia. In this retrospective study, conducted during 2018–2022 at a public hospital in Buenaventura, Colombia, we analyzed data from 3,378 pregnant women. The opportunity to prevent congenital syphilis was missed in 53.1% of mothers because of the lack of syphilis screening. Characteristics of higher maternal social vulnerability and late access to prenatal care decreased the probability of having > 1 syphilis screening test, thereby increasing the probability of having newborns with congenital syphilis. In addition, the opportunity to prevent congenital syphilis was missed in 41.5% of patients with syphilis because of the lack of treatment, which also increased the probability of having newborns with congenital syphilis. We demonstrate the urgent need to improve screening and treatment capabilities for maternal syphilis, particularly among pregnant women who are more socially vulnerable.

Understanding SARS-CoV-2 infection in populations at increased risk for poor health is critical to reducing disease. We describe the epidemiology of SARS-CoV-2 infection in Kakuma Refugee Camp Complex, Kenya. We performed descriptive analyses of SARS-CoV-2 infection in the camp and surrounding community during March 16, 2020‒December 31, 2021. We identified cases in accordance with national guidelines.We estimated fatality ratios and attack rates over time using locally weighted scatterplot smoothing for refugees, host community members, and national population. Of the 18,864 SARS-CoV-2 tests performed, 1,024 were positive, collected from 664 refugees and 360 host community members. Attack rates were 325.0/100,000 population (CFR 2.9%) for refugees,150.2/100,000 population (CFR 1.11%) for community, and 628.8/100,000 population (CFR 1.83%) nationwide. During 2020–2021, refugees experienced a lower attack rate but higher CFR than the national population, underscoring the need to prioritize SARS-CoV-2 mitigation measures, including vaccination.

Considering patient room shortages and prevalence of other communicable diseases, reassessing the isolation of patients with Clostridioides difficile infection (CDI) is imperative. We conducted a retrospective study to investigate the secondary CDI transmission rate in a hospital in South Korea, where patients with CDI were not isolated. Using data from a real-time locating system and electronic medical records, we investigated patients who had both direct and indirect contact with CDI index patients. The primary outcome was secondary CDI transmission, identified by whole-genome sequencing. Among 909 direct and 2,711 indirect contact cases, 2 instances of secondary transmission were observed (2 [0.05%] of 3,620 cases), 1 transmission via direct contact and 1 via environmental sources. A low level of direct contact (113 minutes) was required for secondary CDI transmission. Our findings support the adoption of exhaustive standard preventive measures, including environmental decontamination, rather than contact isolation of CDI patients in nonoutbreak settings.

During the 2022 multicountry mpox outbreak, the United Kingdom identified cases beginning in May. UK cases increased in June, peaked in July, then rapidly declined after September 2022. Public health responses included community-supported messaging and targeted mpox vaccination among eligible gay, bisexual, and other men who have sex with men (GBMSM). Using data from an online survey of GBMSM during November–December 2022, we examined self-reported mpox diagnoses, behavioral risk modification, and mpox vaccination offer and uptake. Among 1,333 participants, only 35 (2.6%) ever tested mpox-positive, but 707 (53%) reported behavior modification to avoid mpox. Among vaccine-eligible GBMSM, uptake was 69% (95% CI 65%–72%; 601/875) and was 92% (95% CI 89%–94%; 601/655) among those offered vaccine. GBMSM self-identifying as bisexual, reporting lower educational qualifications, or identifying as unemployed were less likely to be vaccinated. Equitable offer and provision of mpox vaccine are needed to minimize the risk for future outbreaks and mpox-related health inequalities.

We investigated clinically suspected measles cases that had discrepant real-time reverse transcription PCR (rRT-PCR) and measles-specific IgM test results to determine diagnoses. We performed rRT-PCR and measles-specific IgM testing on samples from 541 suspected measles cases. Of the 24 IgM-positive and rRT-PCR­–negative cases, 20 were among children who received a measles-containing vaccine within the previous 6 months; most had low IgG relative avidity indexes (RAIs). The other 4 cases were among adults who had an unknown previous measles history, unknown vaccination status, and high RAIs. We detected viral nucleic acid for viruses other than measles in 15 (62.5%) of the 24 cases with discrepant rRT-PCR and IgM test results. Measles vaccination, measles history, and contact history should be considered in suspected measles cases with discrepant rRT-PCR and IgM test results. If in doubt, measles IgG avidity and PCR testing for other febrile exanthematous viruses can help confirm or refute the diagnosis.

To determine the kinetics of hepatitis E virus (HEV) in asymptomatic persons and to evaluate viral load doubling time and half-life, we retrospectively tested samples retained from 32 HEV RNA-positive asymptomatic blood donors in Germany. Close-meshed monitoring of viral load and seroconversion in intervals of ≈4 days provided more information about the kinetics of asymptomatic HEV infections. We determined that a typical median infection began with PCR-detectable viremia at 36 days and a maximum viral load of 2.0 × 10 4 IU/mL. Viremia doubled in 2.4 days and had a half-life of 1.6 days. HEV IgM started to rise on about day 33 and peaked on day 36; IgG started to rise on about day 32 and peaked on day 53 . Although HEV IgG titers remained stable, IgM titers became undetectable in 40% of donors. Knowledge of the dynamics of HEV viremia is useful for assessing the risk for transfusion-transmitted hepatitis E.

We evaluated Q fever prevalence in blood donors and assessed the epidemiologic features of the disease in Israel in 2021. We tested serum samples for Coxeilla burnetii phase I and II IgG using immunofluorescent assay, defining a result of > 200 as seropositive. We compared geographic and demographic data. We included 1,473 participants; 188 (12.7%) were seropositive. The calculated sex- and age-adjusted national seroprevalence was 13.9% (95% CI 12.2%–15.7%). Male sex and age were independently associated with seropositivity (odds ratio [OR] 1.6, 95% CI 1.1–2.2; p = 0.005 for male sex; OR 1.2, 95% CI 1.01–1.03; p<0.001 for age). Residence in the coastal plain was independently associated with seropositivity for Q fever (OR 1.6, 95% CI 1.2–2.3; p<0.001); residence in rural and farming regions was not. Q fever is highly prevalent in Israel. The unexpected spatial distribution in the nonrural coastal plain suggests an unrecognized mode of transmission.

During December 11, 2020–March 29, 2022, the US government delivered ≈700 million doses of COVID-19 vaccine to vaccination sites, resulting in vaccination of ≈75% of US adults during that period. We evaluated accessibility of vaccination sites. Sites were accessible by walking within 15 minutes by 46.6% of persons, 30 minutes by 74.8%, 45 minutes by 82.8%, and 60 minutes by 86.7%. When limited to populations in counties with high social vulnerability, accessibility by walking was 55.3%, 81.1%, 86.7%, and 89.4%, respectively. By driving, lowest accessibility was 96.5% at 15 minutes. For urban/rural categories, the 15-minute walking accessibility between noncore and large central metropolitan areas ranged from 27.2% to 65.1%; driving accessibility was 79.9% to 99.5%. By 30 minutes driving accessibility for all urban/rural categories was >95.9%. Walking time variations across jurisdictions and between urban/rural areas indicate that potential gains could have been made by improving walkability or making transportation more readily available.

We estimated COVID-19 transmission potential and case burden by variant type in Alberta, British Columbia, and Ontario, Canada, during January 23, 2020–January 27, 2022; we also estimated the effectiveness of public health interventions to reduce transmission. We estimated time-varying reproduction number (R t ) over 7-day sliding windows and nonoverlapping time-windows determined by timing of policy changes. We calculated incidence rate ratios (IRRs) for each variant and compared rates to determine differences in burden among provinces. R t corresponding with emergence of the Delta variant increased in all 3 provinces; British Columbia had the largest increase, 43.85% (95% credible interval [CrI] 40.71%–46.84%). Across the study period, IRR was highest for Omicron (8.74 [95% CrI 8.71–8.77]) and burden highest in Alberta (IRR 1.80 [95% CrI 1.79–1.81]). Initiating public health interventions was associated with lower R t and relaxing restrictions and emergence of new variants associated with increases in R t .

We conducted a large surveillance study among members of an integrated healthcare delivery system in Pacific Northwest of the United States to estimate medical costs attributable to medically attended acute gastroenteritis (MAAGE) on the day care was sought and during 30-day follow-up. We used multivariable regression to compare costs of MAAGE and non-MAAGE cases matched on age, gender, and index time. Differences accounted for confounders, including race, ethnicity, and history of chronic underlying conditions. Analyses included 73,140 MAAGE episodes from adults and 18,617 from children who were Kaiser Permanente Northwest members during 2014–2016. Total costs were higher for MAAGE cases relative to non-MAAGE comparators as were costs on the day care was sought and costs during follow-up. Costs of MAAGE are substantial relative to the cost of usual-care medical services, and much of the burden accrues during short-term follow-up.

We investigated links between antimicrobial resistance in community-onset bacteremia and 1-year bacteremia recurrence by using the clinical data warehouse of Europe’s largest university hospital group in France. We included adult patients hospitalized with an incident community-onset Staphylococcus aureus , Escherichia coli , or Klebsiella spp. bacteremia during 2017–2019. We assessed risk factors of 1-year recurrence using Fine–Gray regression models. Of the 3,617 patients included, 291 (8.0%) had > 1 recurrence episode. Third-generation cephalosporin (3GC)-resistance was significantly associated with increased recurrence risk after incident Klebsiella spp. (hazard ratio 3.91 [95% CI 2.32–6.59]) or E. coli (hazard ratio 2.35 [95% CI 1.50–3.68]) bacteremia. Methicillin resistance in S. aureus bacteremia had no effect on recurrence risk. Although several underlying conditions and infection sources increased recurrence risk, 3GC-resistant Klebsiella spp. was associated with the greatest increase. These results demonstrate a new facet to illness induced by 3GC-resistant Klebsiella spp. and E. coli in the community setting.

We conducted a cross-sectional study in wild boar and extensively managed Iberian pig populations in a hotspot area of Crimean-Congo hemorrhagic fever virus (CCHFV) in Spain. We tested for antibodies against CCHFV by using 2 ELISAs in parallel. We assessed the presence of CCHFV RNA by means of reverse transcription quantitative PCR protocol, which detects all genotypes. A total of 113 (21.8%) of 518 suids sampled showed antibodies against CCHFV by ELISA. By species, 106 (39.7%) of 267 wild boars and 7 (2.8%) of 251 Iberian pigs analyzed were seropositive. Of the 231 Iberian pigs and 231 wild boars analyzed, none tested positive for CCHFV RNA. These findings indicate high CCHFV exposure in wild boar populations in endemic areas and confirm the susceptibility of extensively reared pigs to CCHFV, even though they may only play a limited role in the enzootic cycle.

African swine fever virus (ASFV) genotype II is endemic to Vietnam. We detected recombinant ASFV genotypes I and II (rASFV I/II) strains in domestic pigs from 6 northern provinces in Vietnam. The introduction of rASFV I/II strains could complicate ongoing ASFV control measures in the region.

In a representative sample of female children and adolescents in Germany, Toxoplasma gondii seroprevalence was 6.3% (95% CI 4.7%–8.0%). With each year of life, the chance of being seropositive increased by 1.2, indicating a strong force of infection. Social status and municipality size were found to be associated with seropositivity.

We describe the detection of Paranannizziopsis sp. fungus in a wild population of vipers in Europe. Fungal infections were severe, and 1 animal likely died from infection. Surveillance efforts are needed to better understand the threat of this pathogen to snake conservation.

We evaluated the in vitro effects of lyophilization for 2 vesicular stomatitis virus–based vaccines by using 3 stabilizing formulations and demonstrated protective immunity of lyophilized/reconstituted vaccine in guinea pigs. Lyophilization increased stability of the vaccines, but specific vesicular stomatitis virus–based vaccines will each require extensive analysis to optimize stabilizing formulations.

We report a cluster of serogroup B invasive meningococcal disease identified via genomic surveillance in older adults in England and describe the public health responses. Genomic surveillance is critical for supporting public health investigations and detecting the growing threat of serogroup B Neisseria meningitidis infections in older adults.

We detected Mayaro virus (MAYV) in 3.4% (28/822) of febrile patients tested during 2018–2021 from Roraima State, Brazil. We also isolated MAYV strains and confirmed that these cases were caused by genotype D. Improved surveillance is needed to better determine the burden of MAYV in the Amazon Region.

Across 133 confirmed mpox zoonotic index cases reported during 1970–2021 in Africa, cases occurred year-round near the equator, where climate is consistent. However, in tropical regions of the northern hemisphere under a dry/wet season cycle, cases occurred seasonally. Our findings further support the seasonality of mpox zoonotic transmission risk.

We investigated molecular evolution and spatiotemporal dynamics of atypical Legionella pneumophila serogroup 1 sequence type 1905 and determined its long-term persistence and linkage to human disease in dispersed locations, far beyond the large 2014 outbreak epicenter in Portugal. Our finding highlights the need for public health interventions to prevent further disease spread.

Norovirus is a major cause of acute gastroenteritis; GII.4 is the predominant strain in humans. Recently, 2 new GII.4 variants, Hong Kong 2019 and San Francisco 2017, were reported. Characterization using GII.4 monoclonal antibodies and serum demonstrated different antigenic profiles for the new variants compared with historical variants.

Cruise ships carrying COVID-19–vaccinated populations applied near-identical nonpharmaceutical measures during July–November 2021; passenger masking was not applied on 2 ships. Infection risk for masked passengers was 14.58 times lower than for unmasked passengers and 19.61 times lower than in the community. Unmasked passengers’ risk was slightly lower than community risk.

During a 2023 outbreak of Mycoplasma pneumoniae –associated community-acquired pneumonia among children in northern Vietnam, we analyzed M. pneumoniae isolated from nasopharyngeal samples. In almost half (6 of 13) of samples tested, we found known A2063G mutations (macrolide resistance) and a novel C2353T variant on the 23S rRNA gene.

We report the detection of Crimean-Congo hemorrhagic fever virus (CCHFV) in Corsica, France. We identified CCHFV African genotype I in ticks collected from cattle at 2 different sites in southeastern and central-western Corsica, indicating an established CCHFV circulation. Healthcare professionals and at-risk groups should be alerted to CCHFV circulation in Corsica.

In Latin America, rabies virus has persisted in a cycle between Desmodus rotundus vampire bats and cattle, potentially enhanced by deforestation. We modeled bovine rabies virus outbreaks in Costa Rica relative to land-use indicators and found spatial-temporal relationships among rabies virus outbreaks with deforestation as a predictor.

With the use of metagenomic next-generation sequencing, patients diagnosed with Whipple pneumonia are being increasingly correctly diagnosed. We report a series of 3 cases in China that showed a novel pattern of movable infiltrates and upper lung micronodules. After treatment, the 3 patients recovered, and lung infiltrates resolved.

Dogs are known to be susceptible to influenza A viruses, although information on influenza D virus (IDV) is limited. We investigated the seroprevalence of IDV in 426 dogs in the Apulia region of Italy during 2016 and 2023. A total of 14 samples were positive for IDV antibodies, suggesting exposure to IDV in dogs.

We report the detection of OXA-181 carbapenemase in an azithromycin-resistant Shigella spp. bacteria in an immunocompromised patient. The emergence of OXA-181 in Shigella spp. bacteria raises concerns about the global dissemination of carbapenem resistance in Enterobacterales and its implications for the treatment of infections caused by Shigella bacteria.

Although a vaccine against SARS-CoV-2 Omicron-XBB.1.5 variant is available worldwide and recent infection is protective, the lack of recorded infection data highlights the need to assess variant-specific antibody neutralization levels. We analyzed IgG levels against receptor-binding domain–specific SARS-CoV-2 ancestral strain as a correlate for high neutralizing titers against XBB variants.

We describe a feline sporotrichosis cluster and zoonotic transmission between one of the affected cats and a technician at a veterinary clinic in Kansas, USA. Increased awareness of sporotrichosis and the potential for zoonotic transmission could help veterinary professionals manage feline cases and take precautions to prevent human acquisition.

We report a clinical isolate of Burkholderia thailandensis 2022DZh obtained from a patient with an infected wound in southwest China. Genomic analysis indicates that this isolate clusters with B. thailandensis BPM, a human isolate from Chongqing, China. We recommend enhancing monitoring and surveillance for B. thailandensis infection in both humans and livestock.

To determine changes in Bordetella pertussis and B. parapertussis detection rates, we analyzed 1.43 million respiratory multiplex PCR test results from US facilities from 2019 through mid-2023. From mid-2022 through mid-2023, Bordetella spp. detection increased 8.5-fold; 95% of detections were B. parapertussis. While B. parapertussis rates increased, B. pertussis rates decreased.

We report a case of Sphingobium yanoikuyae bacteremia in an 89-year-old patient in Japan. No standard antimicrobial regimen has been established for S. yanoikuyae infections. However, ceftriaxone and ceftazidime treatments were effective in this case. Increased antimicrobial susceptibility data are needed to establish appropriate treatments for S. yanoikuyae .

Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released.

Volume 30, Number 6—June 2024

Perspective.

• Decolonization and Pathogen Reduction to Prevent Antimicrobial Resistance and Healthcare-Associated Infections M. R. Mangalea et al.
• Deciphering Unexpected Vascular Locations of Scedosporium spp. and Lomentospora prolificans Fungal Infections, France C. Vignals et al.
• An Electronic Health Record–Based Algorithm for Respiratory Virus–like Illness N. M. Cocoros et al.
• Severe Human Parainfluenza Virus Community- and Healthcare-Acquired Pneumonia in Adults at Tertiary Hospital in Seoul, South Korea, 2010–2019 J. H. Park et al.
• SARS-CoV-2 Disease Severity in Children during Pre-Delta, Delta, and Omicron Periods, Colorado L. Bankers et al.
• Effectiveness of 23-Valent Pneumococcal Polysaccharide Vaccine Against Invasive Pneumococcal Disease in Follow-Up Study, Denmark K. Nielsen et al.
• Chest Radiograph Screening for Detection of Subclinical Tuberculosis in Asymptomatic Household Contacts, Peru Q. Tan et al.
• Outbreak of Highly Pathogenic Avian Influenza Virus H5N1 in Seals in the St. Lawrence Estuary, Quebec, Canada S. Lair et al.
• Carbapenem-Resistant and Extended-Spectrum β-Lactamase–Producing Enterobacterales Cases among Children, United States, 2016–2020 H. N. Grome et al.
• Antibodies to H5N1 Influenza A Virus in Retrieving Hunting Dogs, Washington State, USA J. D. Brown et al.

We characterized the evolution and molecular characteristics of avian influenza A(H7N9) viruses isolated in China during 2021–2023. We systematically analyzed the 10-year evolution of the hemagglutinin gene to determine the evolutionary branch. Our results showed recent antigenic drift, providing crucial clues for updating the H7N9 vaccine and disease prevention and control.

• Burkholderia semiarida as Cause of Recurrent Pulmonary Infection in Immunocompetent Patient, China D. Kuang et al.
• SARS-CoV-2 in Captive Nonhuman Primates, Spain, 2020–2023 D. Cano-Terriza et al.
• Infection- and Vaccine-Induced SARS-CoV-2 Seroprevalence in Persons 0–101 Years of Age, Japan, 2023 R. Kinoshita et al.
• Zoonotic Ancylostoma ceylanicum Infection in Coyotes from the Guanacaste Conservation Area, Costa Rica, 2021 P. A. Zendejas-Heredia et al.
• Detection of Encephalitozoon cuniculi in Cerebrospinal Fluid from Immunocompetent Patients, Czech Republic B. Sak et al.
• Emergence of Group B Streptococcus Disease in Pigs and Porcupines, Italy C. Garbarino et al.
• Molecular Identification of Fonsecaea monophora , Novel Agent of Fungal Brain Abscess S. Gourav et al.

During May–July 2023, a cluster of 7 patients at local hospitals in Florida, USA, received a diagnosis of Plasmodium vivax malaria. Whole-genome sequencing of the organism from 4 patients and phylogenetic analysis with worldwide representative P. vivax genomes indicated probable single parasite introduction from Central/South America.

Because novel SARS-CoV-2 variants continue to emerge, immunogenicity of XBB.1.5 monovalent vaccines against live clinical isolates needs to be evaluated. We report boosting of IgG (2.1×), IgA (1.5×), and total IgG/A/M (1.7×) targeting the spike receptor-binding domain and neutralizing titers against WA1 (2.2×), XBB.1.5 (7.4×), EG.5.1 (10.5×), and JN.1 (4.7×) variants.

Using the GISAID EpiCoV database, we identified 256 COVID-19 patients in Japan during March 31–December 31, 2023, who had mutations in the SARS-CoV-2 nonstructural protein 5 conferring ensitrelvir resistance. Ongoing genomic surveillance is required to monitor emergence of SARS-CoV-2 mutations that are resistant to anticoronaviral drugs.

• Novel Avian Influenza A(H5N6) in Wild Birds, South Korea, 2023 A. Cho et al.

Volume 30, Number 7—July 2024

We report highly pathogenic avian influenza A(H5N1) virus in dairy cattle and cats in Kansas and Texas, United States, which reflects the continued spread of clade 2.3.4.4b viruses that entered the country in late 2021. Infected cattle experienced nonspecific illness, reduced feed intake and rumination, and an abrupt drop in milk production, but fatal systemic influenza infection developed in domestic cats fed raw (unpasteurized) colostrum and milk from affected cows. Cow-to-cow transmission appears to have occurred because infections were observed in cattle on Michigan, Idaho, and Ohio farms where avian influenza virus–infected cows were transported. Although the US Food and Drug Administration has indicated the commercial milk supply remains safe, the detection of influenza virus in unpasteurized bovine milk is a concern because of potential cross-species transmission. Continued surveillance of highly pathogenic avian influenza viruses in domestic production animals is needed to prevent cross-species and mammal-to-mammal transmission.

• Borrelia miyamotoi -associated Acute Meningoencephalitis, Minnesota, United States J. M. Kubiak et al.

Research Letter

• Pasteurella bettyae Infections in Men Who Have Sex With Men, France A. Li et al.

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Active CME Articles

During October 2021–June 2023, a total of 392 cases of acute hepatitis of unknown etiology in children in the United States were reported to Centers for Disease Control and Prevention as part of national surveillance. We describe demographic and clinical characteristics, including potential involvement of adenovirus in development of acute hepatitis, of 8 fatally ill children who met reporting criteria. The children had diverse courses of illness. Two children were immunocompromised when initially brought for care. Four children tested positive for adenovirus in multiple specimen types, including 2 for whom typing was completed. One adenovirus-positive child had no known underlying conditions, supporting a potential relationship between adenovirus and acute hepatitis in previously healthy children. Our findings emphasize the importance of continued investigation to determine the mechanism of liver injury and appropriate treatment. Testing for adenovirus in similar cases could elucidate the role of the virus.

In 2022, concurrent outbreaks of hepatitis A, invasive meningococcal disease (IMD), and mpox were identified in Florida, USA, primarily among men who have sex with men. The hepatitis A outbreak (153 cases) was associated with hepatitis A virus genotype IA. The IMD outbreak (44 cases) was associated with Neisseria meningitidis serogroup C, sequence type 11, clonal complex 11. The mpox outbreak in Florida (2,845 cases) was part of a global epidemic. The hepatitis A and IMD outbreaks were concentrated in Central Florida and peaked during March–­June, whereas mpox cases were more heavily concentrated in South Florida and had peak incidence in August. HIV infection was more common (52%) among mpox cases than among hepatitis A (21%) or IMD (34%) cases. Where feasible, vaccination against hepatitis A, meningococcal disease, and mpox should be encouraged among at-risk groups and offered along with program services that target those groups.

Disseminated leishmaniasis (DL) is an emergent severe disease manifesting with multiple lesions. To determine the relationship between immune response and clinical and therapeutic outcomes, we studied 101 DL and 101 cutaneous leishmaniasis (CL) cases and determined cytokines and chemokines in supernatants of mononuclear cells stimulated with leishmania antigen. Patients were treated with meglumine antimoniate (20 mg/kg) for 20 days (CL) or 30 days (DL); 19 DL patients were instead treated with amphotericin B, miltefosine, or miltefosine and meglumine antimoniate. High levels of chemokine ligand 9 were associated with more severe DL. The cure rate for meglumine antimoniate was low for both DL (44%) and CL (60%), but healing time was longer in DL (p = 0.003). The lowest cure rate (22%) was found in DL patients with >100 lesions. However, meglumine antimoniate/miltefosine treatment cured all DL patients who received it; therefore, that combination should be considered as first choice therapy.

Streptococcus suis , a zoonotic bacterial pathogen circulated through swine, can cause severe infections in humans. Because human S. suis infections are not notifiable in most countries, incidence is underestimated. We aimed to increase insight into the molecular epidemiology of human S. suis infections in Europe. To procure data, we surveyed 7 reference laboratories and performed a systematic review of the scientific literature. We identified 236 cases of human S. suis infection from those sources and an additional 87 by scanning gray literature. We performed whole-genome sequencing to type 46 zoonotic S. suis isolates and combined them with 28 publicly available genomes in a core-genome phylogeny. Clonal complex (CC) 1 isolates accounted for 87% of typed human infections; CC20, CC25, CC87, and CC94 also caused infections. Emergence of diverse zoonotic clades and notable severity of illness in humans support classifying S. suis infection as a notifiable condition.

During January–August 2021, the Community Prevalence of SARS-CoV-2 Study used time/location sampling to recruit a cross-sectional, population-based cohort to estimate SARS-CoV-2 seroprevalence and nasal swab sample PCR positivity across 15 US communities. Survey-weighted estimates of SARS-CoV-2 infection and vaccine willingness among participants at each site were compared within demographic groups by using linear regression models with inverse variance weighting. Among 22,284 persons > 2 months of age and older, median prevalence of infection (prior, active, or both) was 12.9% across sites and similar across age groups. Within each site, average prevalence of infection was 3 percentage points higher for Black than White persons and average vaccine willingness was 10 percentage points lower for Black than White persons and 7 percentage points lower for Black persons than for persons in other racial groups. The higher prevalence of SARS-CoV-2 infection among groups with lower vaccine willingness highlights the disparate effect of COVID-19 and its complications.

Invasive fusariosis can be life-threatening, especially in immunocompromised patients who require intensive care unit (ICU) admission. We conducted a multicenter retrospective study to describe clinical and biologic characteristics, patient outcomes, and factors associated with death and response to antifungal therapy. We identified 55 patients with invasive fusariosis from 16 ICUs in France during 2002­–­­2020. The mortality rate was high (56%). Fusariosis-related pneumonia occurred in 76% of patients, often leading to acute respiratory failure. Factors associated with death included elevated sequential organ failure assessment score at ICU admission or history of allogeneic hematopoietic stem cell transplantation or hematologic malignancies. Neither voriconazole treatment nor disseminated fusariosis were strongly associated with response to therapy. Invasive fusariosis can lead to multiorgan failure and is associated with high mortality rates in ICUs. Clinicians should closely monitor ICU patients with a history of hematologic malignancies or stem cell transplantation because of higher risk for death.

Using whole-genome sequencing, we characterized Escherichia coli strains causing early-onset sepsis (EOS) in 32 neonatal cases from a 2019–2021 prospective multicenter study in France and compared them to E. coli strains collected from vaginal swab specimens from women in third-trimester gestation. We observed no major differences in phylogenetic groups or virulence profiles between the 2 collections. However, sequence type (ST) analysis showed the presence of 6/32 (19%) ST1193 strains causing EOS, the same frequency as in the highly virulent clonal group ST95. Three ST1193 strains caused meningitis, and 3 harbored extended-spectrum β-lactamase. No ST1193 strains were isolated from vaginal swab specimens. Emerging ST1193 appears to be highly prevalent, virulent, and antimicrobial resistant in neonates. However, the physiopathology of EOS caused by ST1193 has not yet been elucidated. Clinicians should be aware of the possible presence of E. coli ST1193 in prenatal and neonatal contexts and provide appropriate monitoring and treatment.

We describe detection of the previously rarely reported gram-positive bacterium Auritidibacter ignavus in 3 cases of chronic ear infections in Germany. In all 3 cases, the patients had refractory otorrhea. Although their additional symptoms varied, all patients had an ear canal stenosis and A. ignavus detected in microbiologic swab specimens. A correct identification of A. ignavus in the clinical microbiology laboratory is hampered by the inability to identify it by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Also, the bacterium might easily be overlooked because of its morphologic similarity to bacterial species of the resident skin flora. We conclude that a high index of suspicion is warranted to identify A. ignavus and that it should be particularly considered in patients with chronic external otitis who do not respond clinically to quinolone ear drop therapy.

We reviewed invasive Nocardia infections in 3 noncontiguous geographic areas in the United States during 2011–2018. Among 268 patients with invasive nocardiosis, 48.2% were from Minnesota, 32.4% from Arizona, and 19.4% from Florida. Predominant species were N. nova complex in Minnesota (33.4%), N. cyriacigeorgica in Arizona (41.4%), and N. brasiliensis in Florida (17.3%). Transplant recipients accounted for 82/268 (30.6%) patients overall: 14 (10.9%) in Minnesota, 35 (40.2%) in Arizona, and 33 (63.5%) in Florida. Manifestations included isolated pulmonary nocardiosis among 73.2% of transplant and 84.4% of non–transplant patients and central nervous system involvement among 12.2% of transplant and 3.2% of non–transplant patients. N. farcinica (20.7%) and N. cyriacigeorgica (19.5%) were the most common isolates among transplant recipients and N. cyriacigeorgica (38.0%), N. nova complex (23.7%), and N. farcinica (16.1%) among non–transplant patients. Overall antimicrobial susceptibilities were similar across the 3 study sites.

We collected stool from school-age children from 352 households living in the Black Belt region of Alabama, USA, where sanitation infrastructure is lacking. We used quantitative reverse transcription PCR to measure key pathogens in stool that may be associated with water and sanitation, as an indicator of exposure. We detected genes associated with > 1 targets in 26% of specimens, most frequently Clostridioides difficile (6.6%), atypical enteropathogenic Escherichia coli (6.1%), and enteroaggregative E. coli (3.9%). We used generalized estimating equations to assess reported risk factors for detecting > 1 pathogen in stool. We found no association between lack of sanitation and pathogen detection (adjusted risk ratio 0.95 [95% CI 0.55–1.7]) compared with specimens from children served by sewerage. However, we did observe an increased risk for pathogen detection among children living in homes with well water (adjusted risk ratio 1.7 [95% CI 1.1–2.5]) over those reporting water utility service.

Campylobacter fetus accounts for 1% of Campylobacter spp. infections, but prevalence of bacteremia and risk for death are high. To determine clinical features of C. fetus infections and risks for death, we conducted a retrospective observational study of all adult inpatients with a confirmed C. fetus infection in Nord Franche-Comté Hospital, Trevenans, France, during January 2000–December 2021. Among 991 patients with isolated Campylobacter spp. strains, we identified 39 (4%) with culture-positive C. fetus infections, of which 33 had complete records and underwent further analysis; 21 had documented bacteremia and 12 did not. Secondary localizations were reported for 7 (33%) patients with C. fetus bacteremia, of which 5 exhibited a predilection for vascular infections (including 3 with mycotic aneurysm). Another 7 (33%) patients with C. fetus bacteremia died within 30 days. Significant risk factors associated with death within 30 days were dyspnea, quick sequential organ failure assessment score > 2 at admission, and septic shock.

Group A Streptococcus (GAS) primary peritonitis is a rare cause of pediatric acute abdomen (sudden onset of severe abdominal pain); only 26 pediatric cases have been reported in the English language literature since 1980. We discuss 20 additional cases of pediatric primary peritonitis caused by GAS among patients at Starship Children’s Hospital, Auckland, New Zealand, during 2010–2022. We compare identified cases of GAS primary peritonitis to cases described in the existing pediatric literature. As rates of rates of invasive GAS increase globally, clinicians should be aware of this cause of unexplained pediatric acute abdomen.

In Mississippi, USA, infant hospitalization with congenital syphilis (CS) spiked by 1,000%, from 10 in 2016 to 110 in 2022. To determine the causes of this alarming development, we analyzed Mississippi hospital discharge data to evaluate trends, demographics, outcomes, and risk factors for infants diagnosed with CS hospitalized during 2016–2022. Of the 367 infants hospitalized with a CS diagnosis, 97.6% were newborn, 92.6% were covered by Medicaid, 71.1% were African American, and 58.0% were nonurban residents. Newborns with CS had higher odds of being affected by maternal illicit drug use, being born prematurely (<37 weeks), and having very low birthweight (<1,500 g) than those without CS. Mean length of hospital stay (14.5 days vs. 3.8 days) and mean charges ($56,802 vs. $13,945) were also higher for infants with CS than for those without. To address escalation of CS, Mississippi should invest in comprehensive prenatal care and early treatment of vulnerable populations.

Ongoing surveillance after pneumococcal conjugate vaccination (PCV) deployment is essential to inform policy decisions and monitor serotype replacement. We report serotype and disease severity trends in 3,719 adults hospitalized for pneumococcal disease in Bristol and Bath, United Kingdom, during 2006–2022. Of those cases, 1,686 were invasive pneumococcal disease (IPD); 1,501 (89.0%) had a known serotype. IPD decreased during the early COVID-19 pandemic but during 2022 gradually returned to prepandemic levels. Disease severity changed throughout this period: CURB65 severity scores and inpatient deaths decreased and ICU admissions increased. PCV7 and PCV13 serotype IPD decreased from 2006–2009 to 2021–2022. However, residual PCV13 serotype IPD remained, representing 21.7% of 2021–2022 cases, indicating that major adult PCV serotype disease still occurs despite 17 years of pediatric PCV use. Percentages of serotype 3 and 8 IPD increased, and 19F and 19A reemerged. In 2020–2022, a total of 68.2% IPD cases were potentially covered by PCV20.

Borrelia miyamotoi , transmitted by Ixodes spp. ticks, was recognized as an agent of hard tick relapsing fever in the United States in 2013. Nine state health departments in the Northeast and Midwest have conducted public health surveillance for this emerging condition by using a shared, working surveillance case definition. During 2013–2019, a total of 300 cases were identified through surveillance; 166 (55%) were classified as confirmed and 134 (45%) as possible. Median age of case-patients was 52 years (range 1–86 years); 52% were male. Most cases (70%) occurred during June–September, with a peak in August. Fever and headache were common symptoms; 28% of case-patients reported recurring fevers, 55% had arthralgia, and 16% had a rash. Thirteen percent of patients were hospitalized, and no deaths were reported. Ongoing surveillance will improve understanding of the incidence and clinical severity of this emerging disease.

During 2006–2021, Canada had 55 laboratory-confirmed outbreaks of foodborne botulism, involving 67 cases. The mean annual incidence was 0.01 case/100,000 population. Foodborne botulism in Indigenous communities accounted for 46% of all cases, which is down from 85% of all cases during 1990–2005. Among all cases, 52% were caused by botulinum neurotoxin type E, but types A (24%), B (16%), F (3%), and AB (1%) also occurred; 3% were caused by undetermined serotypes. Four outbreaks resulted from commercial products, including a 2006 international outbreak caused by carrot juice. Hospital data indicated that 78% of patients were transferred to special care units and 70% required mechanical ventilation; 7 deaths were reported. Botulinum neurotoxin type A was associated with much longer hospital stays and more time spent in special care than types B or E. Foodborne botulism often is misdiagnosed. Increased clinician awareness can improve diagnosis, which can aid epidemiologic investigations and patient treatment.

Corynebacterium ulcerans is a closely related bacterium to the diphtheria bacterium C. diphtheriae , and some C. ulcerans strains produce toxins that are similar to diphtheria toxin. C. ulcerans is widely distributed in the environment and is considered one of the most harmful pathogens to livestock and wildlife. Infection with C. ulcerans can cause respiratory or nonrespiratory symptoms in patients. Recently, the microorganism has been increasingly recognized as an emerging zoonotic agent of diphtheria-like illness in Japan. To clarify the overall clinical characteristics, treatment-related factors, and outcomes of C. ulcerans infection, we analyzed 34 cases of C. ulcerans that occurred in Japan during 2001–2020. During 2010–2020, the incidence rate of C. ulcerans infection increased markedly, and the overall mortality rate was 5.9%. It is recommended that adults be vaccinated with diphtheria toxoid vaccine to prevent the spread of this infection.

Mycolicibacterium neoaurum is a rapidly growing mycobacterium and an emerging cause of human infections. M. neoaurum infections are uncommon but likely underreported, and our understanding of the disease spectrum and optimum management is incomplete. We summarize demographic and clinical characteristics of a case of catheter-related M. neoaurum bacteremia in a child with leukemia and those of 36 previously reported episodes of M. neoaurum infection. Most infections occurred in young to middle-aged adults with serious underlying medical conditions and commonly involved medical devices. Overall, infections were not associated with severe illness or death. In contrast to other mycobacteria species, M. neoaurum was generally susceptible to multiple antimicrobial drugs and responded promptly to treatment, and infections were associated with good outcomes after relatively short therapy duration and device removal. Delays in identification and susceptibility testing were common. We recommend using combination antimicrobial drug therapy and removal of infected devices to eradicate infection.

We retrospectively reviewed consecutive cases of mucormycosis reported from a tertiary-care center in India to determine the clinical and mycologic characteristics of emerging Rhizopus homothallicus fungus. The objectives were ascertaining the proportion of R. homothallicus infection and the 30-day mortality rate in rhino-orbital mucormycosis attributable to R. homothallicus compared with R. arrhizus. R. homothallicus accounted for 43 (6.8%) of the 631 cases of mucormycosis. R. homothallicus infection was independently associated with better survival (odds ratio [OR] 0.08 [95% CI 0.02–0.36]; p = 0.001) than for R. arrhizus infection (4/41 [9.8%] vs. 104/266 [39.1%]) after adjusting for age, intracranial involvement, and surgery. We also performed antifungal-susceptibility testing, which indicated a low range of MICs for R. homothallicus against the commonly used antifungals (amphotericin B [0.03–16], itraconazole [0.03–16], posaconazole [0.03–8], and isavuconazole [0.03–16]). 18S gene sequencing and amplified length polymorphism analysis revealed distinct clustering of R. homothallicus .

Zoonotic outbreaks of sporotrichosis are increasing in Brazil. We examined and described the emergence of cat-transmitted sporotrichosis (CTS) caused by the fungal pathogen Sporothrix brasiliensis . We calculated incidence and mapped geographic distribution of cases in Curitiba, Brazil, by reviewing medical records from 216 sporotrichosis cases diagnosed during 2011–May 2022. Proven sporotrichosis was established in 84 (39%) patients and probable sporotrichosis in 132 (61%). Incidence increased from 0.3 cases/100,000 outpatient visit-years in 2011 to 21.4 cases/100,000 outpatient visit-years in 2021; of the 216 cases, 58% (n = 126) were diagnosed during 2019–2021. The main clinical form of sporotrichosis was lymphocutaneous (63%), followed by localized cutaneous (24%), ocular (10%), multisite infections (3%), and cutaneous disseminated (<0.5%). Since the first report of CTS in Curitiba in 2011, sporotrichosis has increased substantially, indicating continuous disease transmission. Clinician and public awareness of CTS and efforts to prevent transmission are needed.

Babesiosis is a globally distributed parasitic infection caused by intraerythrocytic protozoa. The full spectrum of neurologic symptoms, the underlying neuropathophysiology, and neurologic risk factors are poorly understood. Our study sought to describe the type and frequency of neurologic complications of babesiosis in a group of hospitalized patients and assess risk factors that might predispose patients to neurologic complications. We reviewed medical records of adult patients who were admitted to Yale-New Haven Hospital, New Haven, Connecticut, USA, during January 2011–October 2021 with laboratory-confirmed babesiosis. More than half of the 163 patients experienced > 1 neurologic symptoms during their hospital admissions. The most frequent symptoms were headache, confusion/delirium, and impaired consciousness. Neurologic symptoms were associated with high-grade parasitemia, renal failure, and history of diabetes mellitus. Clinicians working in endemic areas should recognize the range of symptoms associated with babesiosis, including neurologic.

Tularemia is a zoonotic infection caused by Francisella tularensis . Its most typical manifestations in humans are ulceroglandular and glandular; infections in prosthetic joints are rare. We report 3 cases of F. tularensis subspecies holarctica –related prosthetic joint infection that occurred in France during 2016–2019. We also reviewed relevant literature and found only 5 other cases of Francisella -related prosthetic joint infections worldwide, which we summarized. Among those 8 patients, clinical symptoms appeared 7 days to 19 years after the joint placement and were nonspecific to tularemia. Although positive cultures are typically obtained in only 10% of tularemia cases, strains grew in all 8 of the patients. F. tularensis was initially identified in 2 patients by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; molecular methods were used for 6 patients. Surgical treatment in conjunction with long-term antimicrobial treatment resulted in favorable outcomes; no relapses were seen after 6 months of follow-up.

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• Published: 24 April 2024

Three patterns link brain organization to genes in health and disease

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Gene expression in the human cortex is shown to exhibit a generalizable three-component architecture that reflects neuronal, metabolic, and immune programmes of healthy brain development. The three components have distinct associations with autism spectrum disorder and schizophrenia, revealing connections between previously unrelated results from studies of case–control neuroimaging, differential gene expression, and genetic risk.

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Hawrylycz, M. J. et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489 , 391–399 (2012). The original paper presenting the AHBA, in which principal components of cortical gene expression were suggested to reflect brain organization.

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Burt, J. B. et al. Hierarchy of transcriptomic specialization across human cortex captured by structural neuroimaging topography. Nat. Neurosci. 21 , 1251–1259 (2018). This paper characterizes the first component of cortical gene expression, C1, as reflecting a neuronal hierarchy defined by tract-tracing and indexed by structural neuroimaging.

Sydnor, V. J. et al. Neurodevelopment of the association cortices: patterns, mechanisms, and implications for psychopathology. Neuron 109 , 2820–2846 (2021). This review proposes that neurodevelopment involves a ‘sensorimotor–association axis’ defined by ten brain maps, of which one is the cortical gene expression component C1.

Merikangas, A. K. et al. What genes are differentially expressed in individuals with schizophrenia? A systematic review. Mol. Psychiatry 27 , 1373–1383 (2022). This review demonstrates the lack of consistency in genes linked to schizophrenia across differential expression studies, which are also inconsistent with GWAS.

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Johnson, M. B. & Hyman, S. E. A critical perspective on the synaptic pruning hypothesis of schizophrenia pathogenesis. Biol. Psychiatry 92 , 440–442 (2022). This commentary calls for an understanding of synaptic pruning in schizophrenia compared with healthy adolescent neurodevelopment.

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This is a summary of: Dear, R. et al. Cortical gene expression architecture links healthy neurodevelopment to the imaging, transcriptomics and genetics of autism and schizophrenia. Nat. Neurosci . https://doi.org/10.1038/s41593-024-01624-4 (2024).

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Three patterns link brain organization to genes in health and disease. Nat Neurosci (2024). https://doi.org/10.1038/s41593-024-01625-3

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Published : 24 April 2024

DOI : https://doi.org/10.1038/s41593-024-01625-3

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