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

Anath C Lionel, Kristiina Tammimies, Andrea K Vaags, Jill A Rosenfeld, Joo Wook Ahn, Daniele Merico, Abdul Noor, Cassandra K Runke, Vamsee K Pillalamarri, Melissa T Carter, Matthew J Gazzellone, Bhooma Thiruvahindrapuram, Christina Ringmann Fagerberg, Lone W Laulund, Giovanna Pellecchia, Sylvia Lamoureux, Charu Deshpande, Jill Clayton-Smith, Ann C White, Susan LeatherJohn Trounce, H Melanie Bedford, Eli Hatchwell, Peggy S Eis, Ryan K C Yuen, Susan Walker, Mohammed Uddin, Michael T Geraghty, Sarah M Nikkel, Eva M Tomiak, Bridget A Fernandez, Noam Soreni, Jennifer Crosbie, Paul D Arnold, Russell J Schachar, Wendy Roberts, Andrew D Paterson, Joyce So, Peter Szatmari, Christina Chrysler, Marc Woodbury-Smith, R Brian Lowry, Lonnie Zwaigenbaum, Divya Mandyam, John Wei, Jeffrey R Macdonald, Jennifer L Howe, Thomas Nalpathamkalam, Zhuozhi Wang, Daniel Tolson, David S Cobb, Timothy M Wilks, Mark J Sorensen, Patricia I Bader, Yu An, Bai-Lin Wu, Sebastiano Antonino Musumeci, Corrado Romano, Diana Postorivo, Anna M Nardone, Matteo Della Monica, Gioacchino Scarano, Leonardo Zoccante, Francesca Novara, Orsetta Zuffardi, Roberto Ciccone, Vincenzo Antona, Massimo Carella, Leopoldo Zelante, Pietro Cavalli, Carlo Poggiani, Ugo Cavallari, Bob Argiropoulos, Judy Chernos, Charlotte Brasch-Andersen, Marsha Speevak, Marco Fichera, Caroline Mackie Ogilvie, Yiping Shen, Jennelle C Hodge, Michael E Talkowski, Dimitri J Stavropoulos, Christian R Marshall, Stephen W Scherer

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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. 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 neurodevelopmental disorder 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 neurodevelopmental disorder subjects (p=0.002) compared with 44,085 population-based controls. Frequent phenotypes observed in individuals with such deletions included Autism Spectrum Disorders (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 neurodevelopmental disorders, 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.
TidsskriftHuman Molecular Genetics
Udgave nummer10
Sider (fra-til)2752-2768
StatusUdgivet - 14. jan. 2014

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