Chelsea Lowther1, Gregory Costain2, Dimitri J Stavropoulos3, Rebecca Melvin2, Candice K Silversides4, Danielle M Andrade5, Joyce So6, Hanna Faghfoury7, Anath C Lionel8, Christian R Marshall8, Stephen W Scherer9, Anne S Bassett10. 1. 1] Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada [2] Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. 2. Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 3. 1] Cytogenetics Laboratory, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada [2] Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada. 4. 1] Division of Cardiology, Department of Medicine, University Health Network, Toronto, Ontario, Canada [2] Division of Obstetric Medicine, Medical Disorders of Pregnancy Program, Mount Sinai Hospital, Toronto, Ontario, Canada. 5. 1] Division of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada [2] Krembil Neurosciences Centre, University of Toronto, Toronto, Ontario, Canada. 6. 1] Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Ontario, Canada [2] Department of Clinical Genetics, Lakeridge Health Oshawa, Oshawa, Ontario, Canada. 7. The Fred A. Litwin and Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, Ontario, Canada. 8. 1] The Centre for Applied Genomics and Program in Genomics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada [2] Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada. 9. 1] Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada [2] The Centre for Applied Genomics and Program in Genomics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada [3] Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada. 10. 1] Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada [2] Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada [3] Division of Cardiology, Department of Medicine, University Health Network, Toronto, Ontario, Canada [4] Department of Psychiatry, University of Toronto and University Health Network, Toronto, Ontario, Canada.
Abstract
PURPOSE: Recurrent 15q13.3 deletions are enriched in multiple neurodevelopmental conditions including intellectual disability, autism, epilepsy, and schizophrenia. However, the 15q13.3 microdeletion syndrome remains ill-defined. METHODS: We systematically compiled all cases of 15q13.3 deletion published before 2014. We also examined three locally available cohorts to identify new adults with 15q13.3 deletions. RESULTS: We identified a total of 246 cases (133 children, 113 adults) with deletions overlapping or within the 15q13.3 (breakpoint (BP)4-BP5) region, including seven novel adult cases from local cohorts. No BP4-BP5 deletions were identified in 23,838 adult controls. Where known, 15q13.3 deletions were typically inherited (85.4%) and disproportionately of maternal origin (P < 0.0001). Overall, 198 cases (121 children, 77 adults; 80.5%) had at least one neuropsychiatric diagnosis. Accounting for ascertainment, developmental disability/intellectual disability was present in 57.7%, epilepsy/seizures in 28.0%, speech problems in 15.9%, autism spectrum disorder in 10.9%, schizophrenia in 10.2%, mood disorder in 10.2%, and attention deficit hyperactivity disorder in 6.5%. By contrast, major congenital malformations, including congenital heart disease (2.4%), were uncommon. Placenta previa occurred in the pregnancies of four cases. CONCLUSION: The 15q13.3 microdeletion syndrome is predominantly characterized by neuropsychiatric expression. There are implications for pre- and postnatal detection, genetic counseling, and anticipatory care.
PURPOSE: Recurrent 15q13.3 deletions are enriched in multiple neurodevelopmental conditions including intellectual disability, autism, epilepsy, and schizophrenia. However, the 15q13.3 microdeletion syndrome remains ill-defined. METHODS: We systematically compiled all cases of 15q13.3 deletion published before 2014. We also examined three locally available cohorts to identify new adults with 15q13.3 deletions. RESULTS: We identified a total of 246 cases (133 children, 113 adults) with deletions overlapping or within the 15q13.3 (breakpoint (BP)4-BP5) region, including seven novel adult cases from local cohorts. No BP4-BP5 deletions were identified in 23,838 adult controls. Where known, 15q13.3 deletions were typically inherited (85.4%) and disproportionately of maternal origin (P < 0.0001). Overall, 198 cases (121 children, 77 adults; 80.5%) had at least one neuropsychiatric diagnosis. Accounting for ascertainment, developmental disability/intellectual disability was present in 57.7%, epilepsy/seizures in 28.0%, speech problems in 15.9%, autism spectrum disorder in 10.9%, schizophrenia in 10.2%, mood disorder in 10.2%, and attention deficit hyperactivity disorder in 6.5%. By contrast, major congenital malformations, including congenital heart disease (2.4%), were uncommon. Placenta previa occurred in the pregnancies of four cases. CONCLUSION: The 15q13.3 microdeletion syndrome is predominantly characterized by neuropsychiatric expression. There are implications for pre- and postnatal detection, genetic counseling, and anticipatory care.
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