High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population
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info:eu-repo/semantics/embargoedAccessTarih
2021Yazar
Mitani, TadahiroIşıkay, Sedat
Gezdirici, Alper
Yılmaz Güleç, Elif
Punetha, Jaya
Fatih, Jawid M.
Herman, Isabella
Akay, Gülşen
Du, Haowei
Calame, Daniel G.
Ayaz, Akif
Tos, Tülay
Yeşil, Gözde
Aydın, Hatip
Geçkinli, Bilgen
Elçioğlu, Nursel
Candan, Şükrü
Sezer, Özlem
Bağış Erdem, Haktan
Gül, Davut
Demiral, Emine
Elmas, Muhsin
Yesilbaş, Osman
Kılıç, Betül
Güngör, Serdal
Ceylan, Ahmet C.
Bozdoğan, Sevcan
Özalp, Özge
Çiçek, Salih
Aslan, Hüseyin
Yalçıntepe, Sinem
Topçu, Vehap
Bayram, Yavuz
Grochowski, Christopher M.
Jolly, Angad
Dawood, Moez
Duan, Ruizhi
Jhangiani, Shalini N.
Doddapaneni, Harsha
Hu, Jianhong
Muzny, Donna M.
Marafi, Dana
Çoban Akdemir, Zeynep
Karaca, Ender
Carvalho, Claudia M. B.
Gibbs, Richard A.
Posey, Jennifer E.
Lupski, James R.
Pehlivan, Davut
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Mitani, T., Işıkay, S., Gezdirici, A., Yılmaz Güleç, E., Punetha, J., Fatih, J. M. ... Pehlivan, D. (2021). High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population. American Journal of Human Genetics, 108(10), 1981-2005. https://dx.doi.org/10.1016/j.ajhg.2021.08.009Özet
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.
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American Journal of Human GeneticsCilt
108Sayı
10Koleksiyonlar
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