The burden of pathogenic variants in clinically actionable genes in a founder population

Lynch, Megan; Maloney, Kristin A.; Pollin, Toni I.; Streeten, Elizabeth A.; Xu, Huichun; Shuldiner, Alan R.; Hout, Cristopher V. Van; Gonzaga‐Jauregui, Claudia; Mitchell, Braxton D.

doi:10.1002/ajmg.a.62472

Cited by 7 publications

(3 citation statements)

References 41 publications

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“…The observed yield of SFs, 2.7% (7/261), corresponds to an expected rate of < 3% of individuals who are commonly identified as carriers of at least one reportable SF in one of those genes defined by the ACMG. The proportion of SFs in ES/GS may vary depending on the occurrence of specific variants in founder populations [ 33 ]. Referring the SF variants to clinicians is crucial to provide an early intervention and to reduce the life-threatening effects.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders

Wayhelova,

Vallova,

Broz

et al. 2024

Orphanet J Rare Dis

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Background Neurodevelopmental disorders (NDDs) and/or associated multiple congenital abnormalities (MCAs) represent a genetically heterogeneous group of conditions with an adverse prognosis for the quality of intellectual and social abilities and common daily functioning. The rapid development of exome sequencing (ES) techniques, together with trio-based analysis, nowadays leads to up to 50% diagnostic yield. Therefore, it is considered as the state-of-the-art approach in these diagnoses. Results In our study, we present the results of ES in a cohort of 85 families with 90 children with severe NDDs and MCAs. The interconnection of the in-house bioinformatic pipeline and a unique algorithm for variant prioritization resulted in a diagnostic yield of up to 48.9% (44/90), including rare and novel causative variants (41/90) and intragenic copy-number variations (CNVs) (3/90). Of the total number of 47 causative variants, 53.2% (25/47) were novel, highlighting the clinical benefit of ES for unexplained NDDs. Moreover, trio-based ES was verified as a reliable tool for the detection of rare CNVs, ranging from intragenic exon deletions (GRIN2A, ZC4H2 genes) to a 6-Mb duplication. The functional analysis using PANTHER Gene Ontology confirmed the involvement of genes with causative variants in a wide spectrum of developmental processes and molecular pathways, which form essential structural and functional components of the central nervous system. Conclusion Taken together, we present one of the first ES studies of this scale from the central European region. Based on the high diagnostic yield for paediatric NDDs in this study, 48.9%, we confirm trio-based ES as an effective and reliable first-tier diagnostic test in the genetic evaluation of children with NDDs.

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Section: Discussionmentioning

confidence: 99%

Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders

Wayhelova,

Vallova,

Broz

et al. 2024

Orphanet J Rare Dis

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“…The findings of PVs in the isolated populations reported herein are in line with previous reports [ 12 , 13 ]. Specifically, Khayat et al [ 13 ] reported 48 PVs in the AR genes (24 novel PVs) in an isolated community of Muslim Arabs in Israel ( n = 50) based on the results of WES in that population [ 14 ]. The Israeli population genetic carrier screening program is included in the health basket and hence is covered by the health maintenance organizations (HMOs) [ 15 ].…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Genetic Analysis of Druze Provides Insights into Carrier Screening

Avnat

Shapira

Shoval

et al. 2023

Genes

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Background: Druze individuals, like many genetically homogeneous and isolated populations, harbor recurring pathogenic variants (PV) in autosomal recessive (AR) disorders. Methods: Variant calling of whole-genome sequencing (WGS) of 40 Druze from the Human Genome Diversity Project (HGDP) was performed (HGDP-cohort). Additionally, we performed whole exome sequencing (WES) of 118 Druze individuals: 38 trios and 2 couples, representing geographically distinct clans (WES-cohort). Rates of validated PV were compared with rates in worldwide and Middle Eastern populations, from the gnomAD and dbSNP datasets. Results: Overall, 34 PVs were identified: 30 PVs in genes underlying AR disorders, 3 additional PVs were associated with autosomal dominant (AD) disorders, and 1 PV with X-linked-dominant inherited disorder in the WES cohort. Conclusions: The newly identified PVs associated with AR conditions should be considered for incorporation into prenatal-screening options offered to Druze individuals after an extension and validation of the results in a larger study.

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“…Rare variants that are common in at least one population should be thoroughly evaluated for pathogenicity. While there are documented examples of disease alleles with elevated allele frequencies in population-specific founder variants, [68][69][70][71] detailed phenotypic and functional characterization of variants is critical for variant curation efforts.…”

Section: Interpretation Of Rare Variants For Clinical Diagnosticsmentioning

confidence: 99%

A deep catalog of protein-coding variation in 985,830 individuals

Sun,

Bai,

Chen

et al. 2023

Preprint

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Coding variants that have significant impact on function can provide insights into the biology of a gene but are typically rare in the population. Identifying and ascertaining the frequency of such rare variants requires very large sample sizes. Here, we present the largest catalog of human protein-coding variation to date, derived from exome sequencing of 985,830 individuals of diverse ancestry to serve as a rich resource for studying rare coding variants. Individuals of African, Admixed American, East Asian, Middle Eastern, and South Asian ancestry account for 20% of this Exome dataset. Our catalog of variants includes approximately 10.5 million missense (54% novel) and 1.1 million predicted loss-of-function (pLOF) variants (65% novel, 53% observed only once). We identified individuals with rare homozygous pLOF variants in 4,874 genes, and for 1,838 of these this work is the first to document at least one pLOF homozygote. Additional insights from the RGC-ME dataset include 1) improved estimates of selection against heterozygous loss-of-function and identification of 3,459 genes intolerant to loss-of-function, 83 of which were previously assessed as tolerant to loss-of-function and 1,241 that lack disease annotations; 2) identification of regions depleted of missense variation in 457 genes that are tolerant to loss-of-function; 3) functional interpretation for 10,708 variants of unknown or conflicting significance reported in ClinVar as cryptic splice sites using splicing score thresholds based on empirical variant deleteriousness scores derived from RGC-ME; and 4) an observation that approximately 3% of sequenced individuals carry a clinically actionable genetic variant in the ACMG SF 3.1 list of genes. We make this important resource of coding variation available to the public through a variant allele frequency browser. We anticipate that this report and the RGC-ME dataset will serve as a valuable reference for understanding rare coding variation and help advance precision medicine efforts.

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The burden of pathogenic variants in clinically actionable genes in a founder population

Cited by 7 publications

References 41 publications

Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders

Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders

Comprehensive Genetic Analysis of Druze Provides Insights into Carrier Screening

A deep catalog of protein-coding variation in 985,830 individuals

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