Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect |
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| Institution: | 1. Division of Cardiology, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada;2. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK;3. Department of Pathology, King Abdulaziz Medical City, Riyadh, Saudi Arabia;4. Heart Center, Academic Medical Center, Amsterdam, The Netherlands;5. Division of Cardiology, Department of Medicine, London Health Sciences Centre, London, Ontario, Canada;6. Department of Paediatrics, London Health Sciences Centre, London, Ontario,Canada;7. Department of Pediatrics, Hamilton Health Sciences Centre, Hamilton, Ontario, Canada;8. Division of Cardiology, Department of Medicine, Hamilton Health Sciences, Centre, Hamilton, Ontario, Canada;9. Division of Cardiology, Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada;10. Department of Pediatrics, Kingston General Hospital, Kingston, Ontario, Canada;11. Centre for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium;12. Radcliffe Department of Medicine & Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK;13. Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA;14. Division of Genetics, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada |
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| Abstract: | PurposeThe genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of nonsyndromic individuals with AVSD.MethodsWhole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD.ResultsA significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls (odds ratio (OR): 1.52; 95% confidence interval (CI): 1.35–1.71; P = 4.8 × 10?11). The enrichment was specific to AVSD probands, compared with a cohort without AVSD with tetralogy of Fallot (OR: 2.25; 95% CI: 1.84–2.76; P = 2.2 × 10?16). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, and MDM4) were enriched for rare variants in AVSD compared with controls, including three syndrome-associated genes (NIPBL, CHD7, and CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands.ConclusionMutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD, even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort. |
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