High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.

TitleHigh prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population.
Publication TypeJournal Article
Year of Publication2021
AuthorsMitani, T, Isikay, S, Gezdirici, A, Gulec, EYilmaz, Punetha, J, Fatih, JM, Herman, I, Akay, G, Du, H, Calame, DG, Ayaz, A, Tos, T, Yesil, G, Aydin, H, Geckinli, B, Elcioglu, N, Candan, S, Sezer, O, Erdem, HBagis, Gul, D, Demiral, E, Elmas, M, Yesilbas, O, Kilic, B, Gungor, S, Ceylan, AC, Bozdogan, S, Ozalp, O, Cicek, S, Aslan, H, Yalcintepe, S, Topcu, V, Bayram, Y, Grochowski, CM, Jolly, A, Dawood, M, Duan, R, Jhangiani, SN, Doddapaneni, H, Hu, J, Muzny, DM, Marafi, D, Akdemir, ZCoban, Karaca, E, Carvalho, CMB, Gibbs, RA, Posey, JE, Lupski, JR, Pehlivan, D
Corporate AuthorsBaylor-Hopkins Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2021 Oct 07
KeywordsAdolescent, Adult, Child, Child, Preschool, Cohort Studies, Exome Sequencing, Female, Genomics, Humans, Infant, Infant, Newborn, Male, Middle Aged, Mutation, Neurodevelopmental Disorders, Pedigree, Phenotype, Prevalence, Turkey, Young Adult

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.

Alternate JournalAm J Hum Genet
PubMed ID34582790
PubMed Central IDPMC8546040
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
R01 GM132589 / GM / NIGMS NIH HHS / United States

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