Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.

TitleGenes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.
Publication TypeJournal Article
Year of Publication2015
AuthorsKaraca, E, Harel, T, Pehlivan, D, Jhangiani, SN, Gambin, T, Akdemir, ZCoban, Gonzaga-Jauregui, C, Erdin, S, Bayram, Y, Campbell, IM, Hunter, JV, Atik, MM, Van Esch, H, Yuan, B, Wiszniewski, W, Isikay, S, Yesil, G, Yuregir, OO, Bozdogan, STug, Aslan, H, Aydin, H, Tos, T, Aksoy, A, De Vivo, DC, Jain, P, B Geckinli, B, Sezer, O, Gul, D, Durmaz, B, Cogulu, O, Ozkinay, F, Topcu, V, Candan, S, Cebi, AHan, Ikbal, M, Gulec, EYilmaz, Gezdirici, A, Koparir, E, Ekici, F, Coskun, S, Cicek, S, Karaer, K, Koparir, A, Duz, MBugrahan, Kirat, E, Fenercioglu, E, Ulucan, H, Seven, M, Guran, T, Elcioglu, N, Yildirim, MSelman, Aktas, D, Alikaşifoğlu, M, Ture, M, Yakut, T, Overton, JD, Yuksel, A, Ozen, M, Muzny, DM, Adams, DR, Boerwinkle, E, Chung, WK, Gibbs, RA, Lupski, JR
JournalNeuron
Volume88
Issue3
Pagination499-513
Date Published2015 Nov 4
ISSN0896-6273
KeywordsBrain, Cohort Studies, Databases, Genetic, Female, Gene Regulatory Networks, Genetic Association Studies, Genetic Variation, Humans, Male, Mendelian Randomization Analysis, Nervous System Diseases, Pedigree
Abstract

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.

DOI10.1016/j.neuron.2015.09.048
Alternate JournalNeuron
PubMed ID26539891
PubMed Central IDPMC4824012
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
5U54HG003273 / HG / NHGRI NIH HHS / United States
T32 GM007526 / GM / NIGMS NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
K23 NS078056 / NS / NINDS NIH HHS / United States
T32 GM07526 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
K23NS078056 / NS / NINDS NIH HHS / United States