Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism

Maria H. Chahrour, Timothy W. Yu, Elaine T. Lim, Bulent Ataman, Michael E. Coulter, R. Sean Hill, Christine R. Stevens, Christian R. Schubert, Michael E. Greenberg, Stacey B. Gabriel, Christopher A. Walsh

Research output: Contribution to journalArticle

126 Scopus citations

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.

Original languageEnglish (US)
Article numbere1002635
JournalPLoS genetics
Volume8
Issue number4
DOIs
StatePublished - Apr 1 2012

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Chahrour, M. H., Yu, T. W., Lim, E. T., Ataman, B., Coulter, M. E., Hill, R. S., Stevens, C. R., Schubert, C. R., Greenberg, M. E., Gabriel, S. B., & Walsh, C. A. (2012). Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS genetics, 8(4), [e1002635]. https://doi.org/10.1371/journal.pgen.1002635