High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism.

PloS One
Raymond J KelleherDavid Margulies

Abstract

Identification of common molecular pathways affected by genetic variation in autism is important for understanding disease pathogenesis and devising effective therapies. Here, we test the hypothesis that rare genetic variation in the metabotropic glutamate-receptor (mGluR) signaling pathway contributes to autism susceptibility. Single-nucleotide variants in genes encoding components of the mGluR signaling pathway were identified by high-throughput multiplex sequencing of pooled samples from 290 non-syndromic autism cases and 300 ethnically matched controls on two independent next-generation platforms. This analysis revealed significant enrichment of rare functional variants in the mGluR pathway in autism cases. Higher burdens of rare, potentially deleterious variants were identified in autism cases for three pathway genes previously implicated in syndromic autism spectrum disorder, TSC1, TSC2, and SHANK3, suggesting that genetic variation in these genes also contributes to risk for non-syndromic autism. In addition, our analysis identified HOMER1, which encodes a postsynaptic density-localized scaffolding protein that interacts with Shank3 to regulate mGluR activity, as a novel autism-risk gene. Rare, potentially deleterious HO...Continue Reading

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Methods Mentioned

BETA
sample pooling
PCR
genotyping
exome sequencing

Software Mentioned

HeliScope
PolyPhen2
SNP
MutPred
SNPsniffer
miRanda
MOSAIK
GAII
Sequence Scanner
SIFT

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