%0 Journal Article %J Am J Hum Genet %D 2021 %T High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population. %A Mitani, Tadahiro %A Isikay, Sedat %A Gezdirici, Alper %A Gulec, Elif Yilmaz %A Punetha, Jaya %A Fatih, Jawid M %A Herman, Isabella %A Akay, Gulsen %A Du, Haowei %A Calame, Daniel G %A Ayaz, Akif %A Tos, Tulay %A Yesil, Gozde %A Aydin, Hatip %A Geckinli, Bilgen %A Elcioglu, Nursel %A Candan, Sukru %A Sezer, Ozlem %A Erdem, Haktan Bagis %A Gul, Davut %A Demiral, Emine %A Elmas, Muhsin %A Yesilbas, Osman %A Kilic, Betul %A Gungor, Serdal %A Ceylan, Ahmet C %A Bozdogan, Sevcan %A Ozalp, Ozge %A Cicek, Salih %A Aslan, Huseyin %A Yalcintepe, Sinem %A Topcu, Vehap %A Bayram, Yavuz %A Grochowski, Christopher M %A Jolly, Angad %A Dawood, Moez %A Duan, Ruizhi %A Jhangiani, Shalini N %A Harshavardhan Doddapaneni %A Jianhong Hu %A Donna M Muzny %A Marafi, Dana %A Akdemir, Zeynep Coban %A Karaca, Ender %A Carvalho, Claudia M B %A Richard A Gibbs %A Posey, Jennifer E %A James R Lupski %A Pehlivan, Davut %K Adolescent %K Adult %K Child %K Child, Preschool %K Cohort Studies %K Exome Sequencing %K Female %K Genomics %K Humans %K Infant %K Infant, Newborn %K Male %K Middle Aged %K Mutation %K Neurodevelopmental Disorders %K Pedigree %K Phenotype %K Prevalence %K Turkey %K Young Adult %X

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.

%B Am J Hum Genet %V 108 %P 1981-2005 %8 2021 Oct 07 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/34582790?dopt=Abstract %R 10.1016/j.ajhg.2021.08.009 %0 Journal Article %J Neuron %D 2015 %T Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. %A Karaca, Ender %A Harel, Tamar %A Pehlivan, Davut %A Jhangiani, Shalini N %A Gambin, Tomasz %A Coban Akdemir, Zeynep %A Gonzaga-Jauregui, Claudia %A Erdin, Serkan %A Bayram, Yavuz %A Campbell, Ian M %A Hunter, Jill V %A Atik, Mehmed M %A Van Esch, Hilde %A Yuan, Bo %A Wiszniewski, Wojciech %A Isikay, Sedat %A Yesil, Gozde %A Yuregir, Ozge O %A Tug Bozdogan, Sevcan %A Aslan, Huseyin %A Aydin, Hatip %A Tos, Tulay %A Aksoy, Ayse %A De Vivo, Darryl C %A Jain, Preti %A Geckinli, B Bilge %A Sezer, Ozlem %A Gul, Davut %A Durmaz, Burak %A Cogulu, Ozgur %A Ozkinay, Ferda %A Topcu, Vehap %A Candan, Sukru %A Cebi, Alper Han %A Ikbal, Mevlit %A Yilmaz Gulec, Elif %A Gezdirici, Alper %A Koparir, Erkan %A Ekici, Fatma %A Coskun, Salih %A Cicek, Salih %A Karaer, Kadri %A Koparir, Asuman %A Duz, Mehmet Bugrahan %A Kirat, Emre %A Fenercioglu, Elif %A Ulucan, Hakan %A Seven, Mehmet %A Guran, Tulay %A Elcioglu, Nursel %A Yildirim, Mahmut Selman %A Aktas, Dilek %A Alikaşifoğlu, Mehmet %A Ture, Mehmet %A Yakut, Tahsin %A Overton, John D %A Yuksel, Adnan %A Ozen, Mustafa %A Muzny, Donna M %A Adams, David R %A Boerwinkle, Eric %A Chung, Wendy K %A Gibbs, Richard A %A Lupski, James R %K Brain %K Cohort Studies %K Databases, Genetic %K Female %K Gene Regulatory Networks %K Genetic Association Studies %K Genetic Variation %K Humans %K Male %K Mendelian Randomization Analysis %K Nervous System Diseases %K Pedigree %X

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.

%B Neuron %V 88 %P 499-513 %8 2015 Nov 04 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/26539891?dopt=Abstract %R 10.1016/j.neuron.2015.09.048 %0 Journal Article %J Clin Dysmorphol %D 2014 %T Fibular aplasia, tibial campomelia, and oligosyndactyly: a further patient with a 2-year follow-up. %A Sezer, Ozlem %A Gebesoglu, Ismet %A Bo Yuan %A Karaca, Ender %A Gokce, Erkan %A Gunes, Sezgin %K Adolescent %K Adult %K Campomelic Dysplasia %K Child, Preschool %K Female %K Fibula %K Fingers %K Follow-Up Studies %K Foot Deformities, Congenital %K Hand Deformities, Congenital %K Humans %K Infant %K Infant, Newborn %K Male %K Pregnancy %K Radiography %K Syndactyly %K Tibia %K Toes %B Clin Dysmorphol %V 23 %P 121-6 %8 2014 Oct %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/25144151?dopt=Abstract %R 10.1097/MCD.0000000000000051