Disruption of theASTN2/TRIM32locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes

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Rare copy number variants (CNVs) disruptingASTN2or bothASTN2andTRIM32have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins,ASTN2and its paralogASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screenedASTN2/TRIM32andASTN1(1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affectingASTN2. Deletions ofASTN1were much rarer. Deletions near the 3′ terminus ofASTN2, which would disrupt all transcript isoforms (a subset of these deletions also includedTRIM32), were significantly enriched in the NDD subjects (P= 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3′-terminalASTN2deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifyingASTN2human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3′ end. Spatiotemporal expression profiling in the human brain revealed consistently highASTN1expression whileASTN2expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

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