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

Ender Karaca, Tamar Harel, Davut Pehlivan, Shalini N. Jhangiani, Tomasz Gambin, Zeynep Coban Akdemir, Claudia Gonzaga-Jauregui, Serkan Erdin, Yavuz Bayram, Ian M. Campbell, Jill V. Hunter, Mehmed M. Atik, Hilde Van Esch, Bo Yuan, Wojciech Wiszniewski, Sedat Isikay, Gozde Yesil, Ozge O. Yuregir, Sevcan Tug Bozdogan, Huseyin AslanHatip Aydin, Tulay Tos, Ayse Aksoy, Darryl C. De Vivo, Preti Jain, B. Bilge Geckinli, Ozlem Sezer, Davut Gul, Burak Durmaz, Ozgur Cogulu, Ferda Ozkinay, Vehap Topcu, Sukru Candan, Alper Han Cebi, Mevlit Ikbal, Elif Yilmaz Gulec, Alper Gezdirici, Erkan Koparir, Fatma Ekici, Salih Coskun, Salih Cicek, Kadri Karaer, Asuman Koparir, Mehmet Bugrahan Duz, Emre Kirat, Elif Fenercioglu, Hakan Ulucan, Mehmet Seven, Tulay Guran, Nursel Elcioglu, Mahmut Selman Yildirim, Dilek Aktas, Mehmet Alikaşifoğlu, Mehmet Ture, Tahsin Yakut, John D. Overton, Adnan Yuksel, Mustafa Ozen, Donna M. Muzny, David R. Adams, Eric Boerwinkle, Wendy K. Chung, Richard A. Gibbs, James R. Lupski

Research output: Contribution to journalArticle

92 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)499-513
Number of pages15
JournalNeuron
Volume88
Issue number3
DOIs
StatePublished - Nov 4 2015

ASJC Scopus subject areas

  • Neuroscience(all)

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    Karaca, E., Harel, T., Pehlivan, D., Jhangiani, S. N., Gambin, T., Coban Akdemir, Z., Gonzaga-Jauregui, C., Erdin, S., Bayram, Y., Campbell, I. M., Hunter, J. V., Atik, M. M., Van Esch, H., Yuan, B., Wiszniewski, W., Isikay, S., Yesil, G., Yuregir, O. O., Tug Bozdogan, S., ... Lupski, J. R. (2015). Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Neuron, 88(3), 499-513. https://doi.org/10.1016/j.neuron.2015.09.048