Lionel, Anath C3; Tammimies, Kristiina4; Vaags, Andrea K4; Rosenfeld, Jill A4; Ahn, Joo Wook4; Merico, Daniele4; Noor, Abdul4; Runke, Cassandra K4; Pillalamarri, Vamsee K4; Carter, Melissa T4; Gazzellone, Matthew J4; Thiruvahindrapuram, Bhooma4; Fagerberg, Christina Ringmann5; Laulund, Lone W6; Pellecchia, Giovanna4; Lamoureux, Sylvia4; Deshpande, Charu4; Clayton-Smith, Jill4; White, Ann C4; Leather, Susan4; Trounce, John4; Bedford, H Melanie4; Hatchwell, Eli4; Eis, Peggy S4; Yuen, Ryan K C4; Walker, Susan4; Uddin, Mohammed4; Geraghty, Michael T4; Nikkel, Sarah M4; Tomiak, Eva M4; Fernandez, Bridget A4; Soreni, Noam4; Crosbie, Jennifer4; Arnold, Paul D4; Schachar, Russell J4; Roberts, Wendy4; Paterson, Andrew D4; So, Joyce4; Szatmari, Peter4; Chrysler, Christina4; Woodbury-Smith, Marc4; Lowry, R Brian4; Zwaigenbaum, Lonnie4; Mandyam, Divya4; Wei, John4; Macdonald, Jeffrey R4; Howe, Jennifer L4; Nalpathamkalam, Thomas4; Wang, Zhuozhi4; Tolson, Daniel4; Cobb, David S4; Wilks, Timothy M4; Sorensen, Mark J4; Bader, Patricia I4; An, Yu4; Wu, Bai-Lin4; Musumeci, Sebastiano Antonino4; Romano, Corrado4; Postorivo, Diana4; Nardone, Anna M4; Della Monica, Matteo4; Scarano, Gioacchino4; Zoccante, Leonardo4; Novara, Francesca4; Zuffardi, Orsetta4; Ciccone, Roberto4; Antona, Vincenzo4; Carella, Massimo4; Zelante, Leopoldo4; Cavalli, Pietro4; Poggiani, Carlo4; Cavallari, Ugo4; Argiropoulos, Bob4; Chernos, Judy4; Brasch-Andersen, Charlotte5; Speevak, Marsha4; Fichera, Marco4; Ogilvie, Caroline Mackie4; Shen, Yiping4; Hodge, Jennelle C4; Talkowski, Michael E4; Stavropoulos, Dimitri J4; Marshall, Christian R4; Scherer, Stephen W4
1 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU2 Paediatrics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU3 The Centre for Applied Genomics.4 unknown5 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU6 Paediatrics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
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.
Human Molecular Genetics, 2014, Vol 23, Issue 10, p. 2752-2768