Disruption of the ASTN2 / TRIM32 locus at chr9q33.1 in gender modulated risk for autism, ADHD and other neurodevelopmental phenotypes. K. Tammimies1, A. C. Lionel1,2, A. K. Vaags3, J. A. Rosenfeld4, J. W. Ahn5, A. Noor6, C. K. Runke7, V. Pillalamarri8, M. T. Carter6, C. Fagerberg9, B. R. Lowry10, M. J. Gazzellone1,2, R. K. C. Yuen1, S. Walker1, B. A. Fernandez11, D. Tolson12, D. S. Cobb12, P. A. Arnold13, P. Szatmari14, R. Schachar15, C. R. Marshall1,2, C. Brasch-Andersen9, M. Speevak16, M. Fichera17,18, C. M. Ogilvie5, D. J. Stavropoulos19, Y. Shen20, J. C. Hodge7, M. E. Talkowski8,20,21, S. W. Scherer1,2 1) The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; 2) Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, ON, Canada; 3) Department of Anatomic Pathology, Cancer Cytogenetics Laboratory & Alberta Childrens Hospital, Calgary, AB, Canada; 4) Signature Genomic Laboratories, Perkin Elmer, Spokane, WA, USA; 5) Cytogenetics Department, Guy's and St Thomas' NHS Foundation Trust, London, UK; 6) Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada; 7) Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA; 8) Program in Medical and Population Genetics, Broad Institute of Harvard and M.I.T., Cambridge, MA, USA; 9) Department of Clinical Genetics Odense University Hospital, Odense C, Denmark; 10) Departments of Medical Genetics and Pediatrics, Alberta Childrens Hospital, University of Calgary, Calgary, AB, Canada; 11) Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St. John's, NL, Canada; 12) Pediatric genetics Madigan Army Medical Center, Tacoma , WA, USA; 13) Department of Psychiatry and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; 14) Department of Psychiatry and Behavioural Neurosciences, Offord Centre for Child Studies, McMaster University, Hamilton, ON, Canada; 15) Department of Psychiatry and Neurosciences and Mental Health Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; 16) Genetics Department, Credit Valley Hospital, Mississauga, ON, Canada; 17) Laboratorio Genetica Medica, I.R.C.C.S. Associazione Oasi Maria Santissima, Troina, Italy; 18) Genetica Medica, UniversitÓ di Catania, Italy; 19) Department of Pediatric Laboratory Medicine, Cytogenetics Laboratory, Hospital for Sick Children, Toronto, ON, Canada; 20) Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA; 21) Departments of Genetics and Neurology, Harvard Medical School, Cambridge, MA, USA.
Genomic studies have begun to uncover the architecture of genetic risk for different neurodevelopment disorders (NDDs) including Autism Spectrum Disorder (ASD). The data have highlighted rare de novo and inherited copy number variants (CNVs) and single nucleotide variants impacting several genes encoding cell-adhesion and scaffolding proteins at the neuronal synapse. Recently, CNVs disrupting ASTN2 and/or TRIM32, a small gene intronic to ASTN2, have been detected by genome-wide studies in a few individuals with different NDDs. The vertebrate-specific astrotactins, ASTN2 together with its closely related paralog, ASTN1, have critical role in neuronal migration during brain development. The genetic findings together with a consistent functional role of the astrotactins necessitate the need to determine the prevalence of mutations in NDDs including ASD. Here, we present a screening of the ASTN2/TRIM32 locus at chr9q33.1 and the ASTN1 locus at chr1q25.2 for CNVs in clinical microarray data from 89,318 individuals, including 63,901 NDD subjects. We identified 45 deletions and 11 duplications affecting the ASTN2/TRIM32 locus. The strongest signal for significant enrichment was found for deletions at the 3 end that disrupted all isoforms of ASTN2 and/or included TRIM32 in the cases with NDDs (p-value = 0.006) compared to population-based controls containing 41,536 individuals. More strikingly a greater penetrance of the deletions was observed in males compared to females. The most common traits observed in 45 individuals with ASTN2 deletions included ASD, ADHD, anxiety, OCD and speech delay. Deletions affecting ASTN1 were rarer in occurrence than those at ASTN2 and were predominantly of de novo origin. In addition, we measured the expression of ASTN2 isoforms in human brain samples showing that the short isoforms transcribed from the significant 3 region were expressed. The spatiotemporal expression profiles of the astrotactins in human brain revealed dynamic expression pattern for ASTN2 in the cerebellar cortex and neocortex and a steady, high level of expression for ASTN1. Future studies are required to investigate the molecular basis of the findings presented here including the gender-biased penetrance and phenotypic heterogeneity of the ASTN2/TRIM32 deletions, the functional relevance of the ASTN2 shorter isoforms and the complex interplay of the astrotactins in brain development and psychopathology.
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