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PLoS Genet. 2012;8(4):e1002635. doi: 10.1371/journal.pgen.1002635. Epub 2012 Apr 12.

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

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1
Division of Genetics, Department of Medicine, Children's Hospital Boston, Boston, Massachusetts, United States of America.

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.

PMID:
22511880
PMCID:
PMC3325173
DOI:
10.1371/journal.pgen.1002635
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors have declared that no competing interests exist.

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