Journal
HUMAN MOLECULAR GENETICS
Volume 23, Issue 10, Pages 2752-2768Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddt669
Keywords
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Funding
- University of Toronto McLaughlin Centre
- NeuroDevNet
- Genome Canada
- Ontario Genomics Institute
- Canadian Institutes for Health Research (CIHR)
- National Institutes of Health [MH095867]
- Canadian Institute for Advanced Research
- Canada Foundation for Innovation
- Government of Ontario
- Autism Speaks
- The Hospital for Sick Children Foundation
- NeuroDevNet doctoral fellowship
- Swedish Research Council
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
- NIDDK Central Repositories
- NIH Genes, Environment and Health Initiative [GEI] [U01HG004399]
- National Institutes of Health (NIH) [CA87969, CA55075, DK58845]
- NIH GEI [U01HG004424]
- Division of Aging Biology, National Institute on Aging
- Division of Geriatrics and Clinical Gerontology, National Institute on Aging
- National Eye Institute
- Center for Inherited Disease Research (CIDR) [1 X01 HG005274-01]
- Gene Environment Association Studies (GENEVA) Coordinating Center [U01HG004446]
- Collaborative Genetic Study of Nicotine Dependence (COGEND) [P01 CA089392]
- University of Wisconsin Transdisciplinary Tobacco Use Research Center [P50 DA019706, P50 CA084724]
- National Institute of Diabetes
- Endocrinology and Metabolic Diseases of the NIDDK
- NIH
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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 neuronalmigration 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.
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