Donna J Page1, Matthieu J Miossec2,3, Simon G Williams1, Richard M Monaghan1, Elisavet Fotiou1, Heather J Cordell2, Louise Sutcliffe, Ana Topf2, Mathieu Bourgey4,5, Guillaume Bourque5, Robert Eveleigh5, Sally L Dunwoodie6,7,8, David S Winlaw9,10,11, Shoumo Bhattacharya11,12, Jeroen Breckpot12,13, Koenraad Devriendt12, Marc Gewillig13, J David Brook14, Kerry J Setchfield14, Frances A Bu'Lock15, John O'Sullivan16, Graham Stuart17, Connie R Bezzina18, Barbara J M Mulder19, Alex V Postma20, James R Bentham21, Martin Baron22, Sanjeev S Bhaskar23, Graeme C Black23, William G Newman24, Kathryn E Hentges, G Mark Lathrop5, Mauro Santibanez-Koref2, Bernard D Keavney1. 1. From the Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, United Kingdom (D.J.P., S.G.W., R.M.M., E.F., B.D.K.). 2. Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (M.J.M., H.J.C., L.S., A.T., M.S.-K.). 3. Center for Bioinformatics and Integrative Biology, Faculty of Biological Sciences, Universidad Andrés Bello, Santiago, Chile (M.J.M.). 4. Canadian Centre for Computational Genomics, Montréal, QC, Canada (M.B.). 5. McGill Genome Center, Montréal, QC, Canada (M.B., G.B., R.E., G.M.L.). 6. Chain Reaction Program in Congenital Heart Disease Research, Victor Chang Cardiac Research Institute, Sydney, NSW, Australia (S.L.D.). 7. Faculties of Medicine and Science, University of New South Wales, Sydney (S.L.D.). 8. Heart Centre for Children, The Children's Hospital at Westmead, Sydney, NSW (S.L.D.). 9. School of Child and Adolescent Health, Sydney Medical School, University of Sydney (D.S.W.). 10. Victor Chang Cardiac Research Institute, NSW, Australia (D.S.W.). 11. RDM Cardiovascular Medicine, Wellcome Centre for Human Genetics, University of Oxford (D.S.W., S.B.). 12. Center for Human Genetics, Catholic University Leuven, Belgium (S.B., J.B., K.D.). 13. Pediatric and Congenital Cardiology, UZ Leuven (J.B., M.G.). 14. School of Life Sciences, University of Nottingham, Queen's Medical Centre (J.D.B., K.J.S.). 15. Congenital and Paediatric Cardiology, East Midlands Congenital Heart Centre and University of Leicester, Glenfield Hospital (F.A.B.). 16. Adult Congenital and Paediatric Cardiac Unit, Freeman Hospital, Newcastle upon Tyne (J.O.). 17. University Hospitals Bristol NHS Foundation Trust, Bristol (G.S.). 18. Heart Center, Department of Clinical and Experimental Cardiology (C.R.B.), Academic Medical Center, Amsterdam, the Netherlands. 19. Department of Medical Biology (B.J.M.M.), Academic Medical Center, Amsterdam, the Netherlands. 20. Department of Clinical Genetics (A.V.P.), Academic Medical Center, Amsterdam, the Netherlands. 21. Department of Paediatric Cardiology, Yorkshire Heart Centre, Leeds (J.R.B.). 22. Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester (M.B.). 23. Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Oxford, Manchester (S.S.B., G.C.B.). 24. Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Oxford (W.G.N.); and Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK.
Abstract
RATIONALE: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date. OBJECTIVE: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date. METHODS AND RESULTS: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10-8) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%-6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%-3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1. CONCLUSIONS: The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.
RATIONALE: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date. OBJECTIVE: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date. METHODS AND RESULTS: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10-8) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%-6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%-3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1. CONCLUSIONS: The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.
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