Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism
Author(s)
Chahrour, Maria H.; Yu, Timothy W.; Lim, Elaine T.; Ataman, Bulent; Coulter, Michael E.; Hill, R. Sean; Stevens, Christine R.; Schubert, Christian R.; Greenberg, Michael E.; Gabriel, Stacey B.; Walsh, Christopher A.; ... Show more Show less
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Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recessive mutations. Whole-exome sequencing of 16 probands revealed validated homozygous, potentially pathogenic recessive mutations that segregated perfectly with disease in 4/16 families. The candidate genes (UBE3B, CLTCL1, NCKAP5L, ZNF18) encode proteins involved in proteolysis, GTPase-mediated signaling, cytoskeletal organization, and other pathways. Furthermore, neuronal depolarization regulated the transcription of these genes, suggesting potential activity-dependent roles in neurons. We present a multidimensional strategy for filtering whole-exome sequence data to find candidate recessive mutations in autism, which may have broader applicability to other complex, heterogeneous disorders.
Date issued
2012-04Department
Massachusetts Institute of Technology. Research Laboratory of ElectronicsJournal
PLoS Genetics
Publisher
Public Library of Science
Citation
Chahrour, Maria H. et al. “Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism.” Ed. Daniel H. Geschwind. PLoS Genetics 8.4 (2012): e1002635.
Version: Final published version
ISSN
1553-7390
1553-7404