High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population
| Autor: | Sevcan Tug Bozdogan, Ahmet C. Ceylan, Alper Gezdirici, Sukru Candan, Harsha Doddapaneni, Daniel G. Calame, Muhsin Elmas, Özlem Sezer, Shalini N. Jhangiani, Osman Yeşilbaş, Davut Gul, Sinem Yalcintepe, Nursel Elcioglu, Akif Ayaz, Jennifer E. Posey, Ozge Ozalp, Haowei Du, Yavuz Bayram, Betül Kılıç, Moez Dawood, Hatip Aydin, Serdal Güngör, Angad Jolly, Ender Karaca, Haktan Bağış Erdem, Vehap Topcu, Christopher M. Grochowski, Sedat Işıkay, Elif Yilmaz Gulec, Richard A. Gibbs, Ruizhi Duan, Emine Demiral, Donna M. Muzny, Jianhong Hu, Jaya Punetha, Tadahiro Mitani, Tulay Tos, Davut Pehlivan, Huseyin Aslan, Jawid M Fatih, Isabella Herman, Gozde Yesil, Salih Cicek, Zeynep Coban Akdemir, Bilgen Bilge Geçkinli, James R. Lupski, Claudia M.B. Carvalho, Gulsen Akay, Dana Marafi |
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| Rok vydání: | 2021 |
| Předmět: |
Adult
Male Turkish population Adolescent Turkey Alu-Alu Mediated Rearrangement (AAMR) Identity-By-Descent (IBD) Genomics Runs of Homozygosity Biology Article Cohort Studies Young Adult Exome Reanalysis Exome Sequencing Prevalence Genetics Humans Child Genetics (clinical) Exome sequencing Whole genome sequencing Multilocus Pathogenic Variation Genetic heterogeneity Haplotype Infant Newborn Infant Middle Aged Runs of Homozygosity (ROH) Pedigree Phenotype Neurodevelopmental Disorders Child Preschool Mutation Whole-Genome Sequencing Etiology Female |
| Zdroj: | Am J Hum Genet |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2021.08.009 |
| Popis: | Neurodevelopmental disorders (NDD5) are clinically and genetically heterogenous; many such disorders are secondary to perturbation in brain development and/or function. The prevalence of NDD5 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 NDD5; however, the majority of NDD5 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 NDD5. 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 (ROH5) - 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. United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Human Genome Research Institute (NHGRI) ; United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) ; International Rett Syndrome Foundation (IRSF |
| Databáze: | OpenAIRE |
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