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Rare copy number variants (CNVs) disrupting  ASTN2  or both  ASTN2  and  TRIM32  have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins,  ASTN2  and its paralog  ASTN1 , 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 screened  ASTN2/TRIM32  and  ASTN1  (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 affecting  ASTN2 . Deletions of  ASTN1  were much rarer. Deletions near the 3′ terminus of  ASTN2 , which would disrupt all transcript isoforms (a subset of these deletions also included  TRIM32 ), 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′-terminal  ASTN2  deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying  ASTN2  human 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 high  ASTN1  expression while  ASTN2  expression 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.

human molecular genetics

Disruption of the  ASTN2 / TRIM32  locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes