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

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dc.authoridDu, Haowei/0000-0001-9052-1587
dc.authoridYilmaz Gulec, Elif/0000-0003-0872-3898
dc.authoridSezer, Ozlem turkeli/0000-0001-5727-7965
dc.authoridTopçu, Vehap/0000-0001-7224-5697
dc.authoridGeckinli, Bilge/0000-0003-0317-5677
dc.authoridErdem, Haktan Bağış/0000-0002-4391-1387
dc.authoridCeylan, Ahmet Cevdet/0000-0003-4938-3420
dc.authorwosidOzalp Yuregir, Ozge/JCF-2622-2023
dc.authorwosidDu, Haowei/HHN-1823-2022
dc.authorwosidGezdirici, Alper/W-8459-2018
dc.authorwosidYilmaz Gulec, Elif/X-2778-2018
dc.authorwosidSezer, Ozlem turkeli/AAT-4372-2020
dc.authorwosidTopçu, Vehap/E-5545-2015
dc.authorwosidGeckinli, Bilge/AGY-3825-2022
dc.contributor.authorMitani, Tadahiro
dc.contributor.authorIsikay, Sedat
dc.contributor.authorGezdirici, Alper
dc.contributor.authorGulec, Elif Yilmaz
dc.contributor.authorPunetha, Jaya
dc.contributor.authorFatih, Jawid M.
dc.contributor.authorHerman, Isabella
dc.date.accessioned2024-08-04T20:50:42Z
dc.date.available2024-08-04T20:50:42Z
dc.date.issued2021
dc.departmentİnönü Üniversitesien_US
dc.description.abstractNeurodevelopmental 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.en_US
dc.description.sponsorshipU.S. National Human Genome Research Institute (NHGRI); National Heart Lung and Blood Institute (NHBLI) [UM1 HG006542]; NHGRI [U01 HG011758, U54HG003273, K08 HG008986]; U.S. National Institute of General Medical Sciences [R01 GM132589]; U.S. National Institute of Neurological Disorders and Stroke (NINDS) [R35NS105078]; Uehara Memorial Foundation; United States National Institute of Health [T32 GM007526-42]; International Rett Syndrome Foundation (IRSF [3701-1]; National Human Genome Research Institute [K08HG008986] Funding Source: NIH RePORTERen_US
dc.description.sponsorshipWe thank all the families for their participation in this research. This study was supported in part by the U.S. National Human Genome Research Institute (NHGRI) and National Heart Lung and Blood Institute (NHBLI) to the Baylor-Hopkins Center for Mendelian Genomics (BHCMG; UM1 HG006542 to J.R.L), an NHGRI grant to Baylor College of Medicine (BCM)-Genomics Research Elucidates the Genetics of Rare (GREGoR) (U01 HG011758 to J.E.P.), an NHGRI grant to BCM Human Genome Sequencing Center (U54HG003273 to R.A.G.), the U.S. National Institute of General Medical Sciences (R01 GM132589 to C.M.B.C.), and the U.S. National Institute of Neurological Disorders and Stroke (NINDS; R35NS105078 to J.R.L.). T.M. is supported by the Uehara Memorial Foundation. D.M. is supported by a Medical Genetics Research Fellowship Program through the United States National Institute of Health (T32 GM007526-42). D.P. is supported by the International Rett Syndrome Foundation (IRSF grant #3701-1). J.E.P. was supported by NHGRI K08 HG008986.en_US
dc.identifier.doi10.1016/j.ajhg.2021.08.009
dc.identifier.endpage2005en_US
dc.identifier.issn0002-9297
dc.identifier.issn1537-6605
dc.identifier.issue10en_US
dc.identifier.pmid34582790en_US
dc.identifier.scopus2-s2.0-85115954722en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1981en_US
dc.identifier.urihttps://doi.org/10.1016/j.ajhg.2021.08.009
dc.identifier.urihttps://hdl.handle.net/11616/100229
dc.identifier.volume108en_US
dc.identifier.wosWOS:000705304300013en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherCell Pressen_US
dc.relation.ispartofAmerican Journal of Human Geneticsen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectCopy-Number Variationen_US
dc.subjectGene-Discoveryen_US
dc.subjectIntellectual Disabilityen_US
dc.subjectPhenotypic Expansionen_US
dc.subjectStructural Variantsen_US
dc.subjectJoubert Syndromeen_US
dc.subjectDisease Geneen_US
dc.subjectMutationsen_US
dc.subjectIdentificationen_US
dc.subjectTransporten_US
dc.titleHigh prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish populationen_US
dc.typeArticleen_US

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