Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays. A. S. Bassett1,9, G. A. Costain1, A. Lionel2,3, D. Merico2, P. J. Forsythe4, K. Russell1, C. Lowther1, T. Yuen1, J. Husted5, D. J. Stavropoulos6,7, M. Speevak8, E. W. C. Chow1,9, C. R. Marshall2,3, S. W. Scherer2,3 1) Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario M5S 2S1, Canada; 2) The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada; 3) Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, Ontario M5G 1L7, Canada; 4) Horizon Health and Dalhousie University, Saint John, New Brunswick E2L 4L4, Canada; 5) Health Studies, University of Waterloo, Waterloo, Ontario N2L 3G1, Canada; 6) Cytogenetics Laboratory, Department of Pediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; 7) Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A1, Canada; 8) Department of Genetics, Credit Valley Hospital, Mississauga, Ontario L5M 2N1, Canada; 9) Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada.

   Individually rare, large copy number variants (CNVs) contribute to genetic vulnerability for schizophrenia. Unresolved questions remain, however, regarding the anticipated yield of clinical microarray testing in schizophrenia. Using high resolution genome-wide microarrays and rigorous methods, we investigated rare CNVs in a prospectively recruited community-based cohort of 459 unrelated adults with schizophrenia and estimated the minimum prevalence of clinically significant CNVs that would be detectable on a clinical microarray. Blinded review by two independent clinical cytogenetic laboratory directors of all large (500 kb) rare CNVs in cases and well-matched controls showed that those deemed clinically significant were highly enriched in schizophrenia (16.4-fold increase, p0.0001). In a single community catchment area, the prevalence of individuals with these CNVs was 8.1%. Rare 1.7 Mb CNVs at 2q13 were found to be significantly associated with schizophrenia for the first time, compared with the prevalence in 23,838 population-based controls (42.9-fold increase, p=0.0002). Additional novel findings that will facilitate the future clinical interpretation of smaller CNVs in schizophrenia include: (i) a greater proportion of individuals with two or more rare exonic CNVs 10 kb in size (1.5-fold increase, p=0.0134) in schizophrenia; (ii) the systematic discovery of new candidate genes for schizophrenia; and (iii) functional gene enrichment mapping highlighting a differential impact in schizophrenia of rare exonic deletions involving diverse functions, including neurodevelopmental and synaptic processes (4.7-fold increase, p=0.0060). These findings suggest consideration of a potential role for clinical microarray testing in schizophrenia, as is now the suggested standard of care for related developmental disorders like autism.

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