Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes
Year: 2013
Type: article
Study design: Observational Study
Abstract: 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.
Source: Human Molecular Genetics
DOI: 10.1093/hmg/ddt669
Authors: A. C. Lionel, K. Tammimies, A. K. Vaags, J. A. Rosenfeld, J. W. Ahn, D. Merico, A. Noor, C. K. Runke, V. K. Pillalamarri, M. T. Carter, M. J. Gazzellone, B. Thiruvahindrapuram, C. Fagerberg, L. W. Laulund, G. Pellecchia, S. Lamoureux, C. Deshpande, J. Clayton-Smith, A. C. White, S. Leather, J. Trounce, H. Melanie Bedford, E. Hatchwell, P. S. Eis, R. K. C. Yuen, S. Walker, M. Uddin, M. T. Geraghty, S. M. Nikkel, E. M. Tomiak, B. A. Fernandez, N. Soreni, J. Crosbie, P. D. Arnold, R. J. Schachar, W. Roberts, A. D. Paterson, J. So, P. Szatmari, C. Chrysler, M. Woodbury-Smith, R. Brian Lowry, L. Zwaigenbaum, D. Mandyam, J. Wei, J. R. MacDonald, J. L. Howe, T. Nalpathamkalam, Z. Wang, D. Tolson, D. S. Cobb, T. M. Wilks, M. J. Sorensen, P. I. Bader, Y. An, B.-L. Wu, S. A. Musumeci, C. Romano, D. Postorivo, A. M. Nardone, M. D. Monica, G. Scarano, L. Zoccante, F. Novara, O. Zuffardi, R. Ciccone, V. Antona, M. Carella, L. Zelante, P. Cavalli, C. Poggiani, U. Cavallari, B. Argiropoulos, J. Chernos, C. Brasch-Andersen, M. Speevak, M. Fichera, C. M. Ogilvie, Y. Shen, J. C. Hodge, M. E. Talkowski, D. J. Stavropoulos, C. R. Marshall, S. W. Scherer
Institutions: University of Toronto, Centre for Applied Genomics, Karolinska Institutet, Alberta Health Services, Calgary Laboratory Services, Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, Hospital for Sick Children, Mayo Clinic, Harvard University, Massachusetts General Hospital, Odense University Hospital, Manchester Academic Health Science Centre, St Mary's Hospital, Brighton General Hospital, Brighton and Sussex University Hospitals NHS Trust, North York General Hospital, University of Ottawa, Children's Hospital of Eastern Ontario, Memorial University of Newfoundland, St. Joseph’s Healthcare Hamilton, Bloorview Research Institute, Centre for Addiction and Mental Health, McMaster University, Alberta Children's Hospital, University of Alberta, Madigan Army Medical Center, Kalispell Regional Medical Center, Fudan University, Children's Hospital of Fudan University, Boston Children's Hospital, University of Rome Tor Vergata, Azienda Ospedaliera G.Rummo, University of Verona, University of Pavia, Fondazione Istituto Neurologico Nazionale Casimiro Mondino, University of Palermo, Casa Sollievo della Sofferenza, Istituti Ospitalieri di Cremona, University of Calgary, Alberta Children's Hospital Research Institute, Trillium Health Centre, Credit Valley Hospital, University of Catania, Oasi Maria SS, I.R.C.C.S. Oasi Maria SS, Shanghai Jiao Tong University, Shanghai Children's Medical Center
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,390
Funders: U.S. Department of Defense, Autism Speaks, GlaxoSmithKline, Canadian Institute for Advanced Research, Genome Canada, Ontario Genomics, Broad Institute, Government of Ontario, Ontario Genomics Institute, Sick Kids Foundation, University of Toronto, Vetenskapsrådet, Hospital for Sick Children, National Institutes of Health, U.S. Navy, Canadian Institutes of Health Research, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1271251741, G132635143, G1327305488, G198446568, G2750880407, Genes and Environment Initiatives in Type 2 Diabetes, G2888548701, G3047652723, G3428241583, G3799582765, Dietary and Hormonal Determinants of Cancer in Women, Genome Wide Association Coordinating Center, G83951392, G9000031451, G9000144374, G9000158339, G9000190097, G9000216934, G948540326
OpenAlex ID: W2155294359