Yu, Timothy W.Lim, Elaine T.Stevens, Christine R.Gabriel, Stacey B.Chahrour, Maria H.Ataman, BulentCoulter, Michael EdwardHill, RobertSchubert, ChristianGreenberg, MichaelWalsh, Christopher2012-12-112012Chahrour, 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): e1002635.1553-7390http://nrs.harvard.edu/urn-3:HUL.InstRepos:10029445Although 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.en-USbiologygeneticsgenomicsgenome sequencingJournal Article2012-12-1110.1371/journal.pgen.1002635