High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.
Alu-Alu mediated rearrangement (AAMR)
exome reanalysis
identity-by-descent (IBD)
multilocus pathogenic variation
neurodevelopmental disorders
runs of homozygosity (ROH)
whole-genome sequencing
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
07 10 2021
07 10 2021
Historique:
received:
09
03
2021
accepted:
20
08
2021
pubmed:
29
9
2021
medline:
16
11
2021
entrez:
28
9
2021
Statut:
ppublish
Résumé
Neurodevelopmental disorders (NDDs) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDDs is > 3%, resulting in significant sociocultural and economic challenges to society. With recent advances in family-based genomics, rare-variant analyses, and further exploration of the Clan Genomics hypothesis, there has been a logarithmic explosion in neurogenetic "disease-associated genes" molecular etiology and biology of NDDs; however, the majority of NDDs remain molecularly undiagnosed. We applied genome-wide screening technologies, including exome sequencing (ES) and whole-genome sequencing (WGS), to identify the molecular etiology of 234 newly enrolled subjects and 20 previously unsolved Turkish NDD families. In 176 of the 234 studied families (75.2%), a plausible and genetically parsimonious molecular etiology was identified. Out of 176 solved families, deleterious variants were identified in 218 distinct genes, further documenting the enormous genetic heterogeneity and diverse perturbations in human biology underlying NDDs. We propose 86 candidate disease-trait-associated genes for an NDD phenotype. Importantly, on the basis of objective and internally established variant prioritization criteria, we identified 51 families (51/176 = 28.9%) with multilocus pathogenic variation (MPV), mostly driven by runs of homozygosity (ROHs) - reflecting genomic segments/haplotypes that are identical-by-descent. Furthermore, with the use of additional bioinformatic tools and expansion of ES to additional family members, we established a molecular diagnosis in 5 out of 20 families (25%) who remained undiagnosed in our previously studied NDD cohort emanating from Turkey.
Identifiants
pubmed: 34582790
pii: S0002-9297(21)00308-6
doi: 10.1016/j.ajhg.2021.08.009
pmc: PMC8546040
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1981-2005Subventions
Organisme : NIGMS NIH HHS
ID : T32 GM007526
Pays : United States
Organisme : NHGRI NIH HHS
ID : K08 HG008986
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG011758
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : NHGRI NIH HHS
ID : U54 HG003273
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS105078
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM132589
Pays : United States
Informations de copyright
Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. J.R.L. serves on the Scientific Advisory Board of BG. Other authors have no potential conflicts to report.
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