1. Disruption of the ASTN2 / TRIM32 locus at 9q33.1 is a risk factor in males for Autism Spectrum Disorders, ADHD and other neurodevelopmental phenotypes
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Patricia I. Bader, Christina Chrysler, Pietro Cavalli, Mohammed Uddin, Carlo Poggiani, Noam Soreni, Andrew D. Paterson, Roberto Ciccone, Diana Postorivo, Sebastiano A. Musumeci, Lonnie Zwaigenbaum, Eli Hatchwell, Michael E. Talkowski, Sarah M. Nikkel, Paul D. Arnold, H. Melanie Bedford, Vincenzo Antona, Sylvia Lamoureux, Caroline Mackie Ogilvie, Timothy Wilks, John Wei, Eva M Tomiak, Ugo Cavallari, Marc Woodbury-Smith, Orsetta Zuffardi, Susan Walker, Bob Argiropoulos, Judy Chernos, Charu Deshpande, Jeffrey R. MacDonald, Bai-Lin Wu, Thomas Nalpathamkalam, Lone W. Laulund, Anna Maria Nardone, Gioacchino Scarano, Bridget A. Fernandez, Christian R. Marshall, John Trounce, Susan Leather, Peter Szatmari, Anath C. Lionel, Jennelle C. Hodge, Ann C White, Dimitri J. Stavropoulos, Matteo Della Monica, David S Cobb, Cassandra K. Runke, Zhuozhi Wang, Corrado Romano, Michael T. Geraghty, Leopoldo Zelante, Joo Wook Ahn, Matthew J. Gazzellone, Leonardo Zoccante, Marsha Speevak, Bhooma Thiruvahindrapuram, Russell Schachar, Jennifer L. Howe, Jill Clayton-Smith, Christina Fagerberg, R. Brian Lowry, Francesca Novara, Marco Fichera, Jill A. Rosenfeld, Charlotte Brasch-Andersen, Stephen W. Scherer, Giovanna Pellecchia, Divya Mandyam, Vamsee Pillalamarri, Yu An, Wendy Roberts, Abdul Noor, Daniel Tolson, Melissa T. Carter, Peggy S. Eis, Joyce So, Jennifer Crosbie, Massimo Carella, Ryan K. C. Yuen, Andrea K. Vaags, Mark J Sorensen, Daniele Merico, Kristiina Tammimies, and Yiping Shen
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Male ,Receptors, Cell Surface/genetics ,Autism ,Child Development Disorders, Pervasive/genetics ,Gene Expression ,Genome-wide association study ,Medical and Health Sciences ,Tripartite Motif Proteins ,Risk Factors ,Receptors ,2.1 Biological and endogenous factors ,Protein Isoforms ,Nerve Tissue Proteins/genetics ,Copy-number variation ,Aetiology ,Child ,Genetics (clinical) ,Sequence Deletion ,Pediatric ,Genetics & Heredity ,Genetics ,education.field_of_study ,Single Nucleotide ,Articles ,General Medicine ,Exons ,Biological Sciences ,Mental Health ,Phenotype ,Autism spectrum disorder ,Organ Specificity ,Cerebellar cortex ,Child, Preschool ,Cell Surface ,Speech delay ,Female ,medicine.symptom ,Transcription Initiation Site ,Attention Deficit Disorder with Hyperactivity/genetics ,Chromosomes, Human, Pair 9 ,Human ,Pair 9 ,Adult ,Pediatric Research Initiative ,Child Development Disorders ,Adolescent ,DNA Copy Number Variations ,Intellectual and Developmental Disabilities (IDD) ,Ubiquitin-Protein Ligases ,Population ,Transcription Factors/genetics ,Nerve Tissue Proteins ,Receptors, Cell Surface ,Biology ,Polymorphism, Single Nucleotide ,Chromosomes ,Young Adult ,Clinical Research ,Protein Isoforms/genetics ,Behavioral and Social Science ,medicine ,Attention deficit hyperactivity disorder ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,Preschool ,education ,Molecular Biology ,Genetic Association Studies ,Pervasive ,Glycoproteins ,Human Genome ,Neurosciences ,Infant, Newborn ,Glycoproteins/genetics ,Infant ,Newborn ,medicine.disease ,Brain Disorders ,Attention Deficit Disorder with Hyperactivity ,Child Development Disorders, Pervasive ,Case-Control Studies ,Transcription Factors - 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.
- Published
- 2014
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