TY - JOUR
T1 - Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism
AU - Chahrour, Maria H.
AU - Yu, Timothy W.
AU - Lim, Elaine T.
AU - Ataman, Bulent
AU - Coulter, Michael E.
AU - Hill, R. Sean
AU - Stevens, Christine R.
AU - Schubert, Christian R.
AU - Greenberg, Michael E.
AU - Gabriel, Stacey B.
AU - Walsh, Christopher A.
PY - 2012/4
Y1 - 2012/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84860564877&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84860564877&partnerID=8YFLogxK
U2 - 10.1371/journal.pgen.1002635
DO - 10.1371/journal.pgen.1002635
M3 - Article
C2 - 22511880
AN - SCOPUS:84860564877
SN - 1553-7390
VL - 8
JO - PLoS genetics
JF - PLoS genetics
IS - 4
M1 - e1002635
ER -