Details

Autor(en) / Beteiligte

• 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
• Geschwind, Daniel H.

Titel

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

Ist Teil von

• PLoS genetics, 2012-04, Vol.8 (4), p.e1002635-e1002635

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.