Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism

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Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism

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Title: Whole-Exome Sequencing and Homozygosity Analysis Implicate Depolarization-Regulated Neuronal Genes in Autism
Author: Yu, Timothy W.; Lim, Elaine T.; Stevens, Christine R.; Gabriel, Stacey B.; Chahrour, Maria H.; Ataman, Bulent; Coulter, Michael Edward; Hill, Robert Sean; Schubert, Christian R.; Greenberg, Michael Eldon; Walsh, Christopher A.

Note: Order does not necessarily reflect citation order of authors.

Citation: Chahrour, Maria H., Timothy W. Yu, Elaine T. Lim, Bulent Ataman, Michael E. Coulter, R. Sean Hill, Christine R. Stevens, et al. 2012. Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genetics 8(4): e1002635.
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Abstract: 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.
Published Version: doi:10.1371/journal.pgen.1002635
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3325173/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10029445

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