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C Identification of the major genetic contributors to tetralogy of fallot
  1. Donna J Page1,2,
  2. Matthieu J Miossec3,4,
  3. Simon G Williams1,
  4. Richard M Monaghan1,
  5. Elisavet Fotiou1,
  6. Heather J Cordell4,
  7. Louise Sutcliffe4,
  8. Ana Topf4,
  9. Mathieu Bourgey5,6,
  10. Guillaume Bourque5,
  11. Robert Eveleigh5,
  12. Sally L Dunwoodie7,8,
  13. David S Winlaw9,10,11,
  14. Shoumo Bhattacharya12,
  15. Jeroen Breckpot13,
  16. Koenraad Devriendt14,
  17. Marc Gewillig14,
  18. David Brook15,
  19. Kerry Setchfield15,
  20. Frances A Bu’Lock16,
  21. John O’Sullivan17,
  22. Graham Stuart18,
  23. Connie Bezzina19,
  24. Barbara JM Mulder19,
  25. Alex V Postma20,21,
  26. James R Bentham22,
  27. Martin Baron23,
  28. Sanjeev S Bhaskar24,
  29. Graeme C Black24,
  30. William G Newman24,
  31. Kathryn E Hentges25,
  32. Mark Lathrop5,
  33. Mauro Santibanez-Koref4,
  34. Bernard D Keavney1
  1. 1Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PT, UK
  2. 2School of Healthcare Science, Manchester Metropolitan University, Manchester, M1 5GD, UK
  3. 3Center for Bioinformatics and Integrative Biology, Faculty of Biological Sciences, Universidad Andrés Bello, Santiago, Chile
  4. 4Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle-upon-Tyne, NE1 3BZ, UK
  5. 5McGill Genome Center, Montréal, QC, Canada
  6. 6Canadian Centre for Computational Genomics, Montréal, QC, Canada
  7. 7Faculties of Medicine and Science, University of New South Wales, Sydney, NSW, Australia
  8. 8Chain Reaction Program in Congenital Heart Disease Research, Victor Chang Cardiac, Research Institute, Sydney, NSW, Australia
  9. 9School of Child and Adolescent Health, Sydney Medical School, University of Sydney, Australia
  10. 10Victor Chang Cardiac Research Institute, Australia
  11. 11Heart Centre for Children, The Children's Hospital at Westmead, Sydney, NSW, Australia
  12. 12RDM Cardiovascular Medicine, Wellcome Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN
  13. 13Center for Human Genetics, Catholic University Leuven, Leuven, Belgium
  14. 14Pediatric and Congenital Cardiology, UZ Leuven, Leuven, Belgium
  15. 15School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH
  16. 16Honorary Associate Professor in Congenital and Paediatric Cardiology, East Midlands, Congenital Heart Centre and University of Leicester, Glenfield Hospital, Leicester, LE3 9QP
  17. 17MD, FRCPI, Adult Congenital and Paediatric Cardiac Unit, Freeman Hospital, Newcastle upon Tyne
  18. 18University Hospitals Bristol NHS Foundation Trust, Bristol UK
  19. 19Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands
  20. 20Department of Medical Biology, Academic Medical Center, Amsterdam, the Netherlands
  21. 21Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands
  22. 22Department of Paediatric Cardiology, Yorkshire Heart Centre, Leeds, UK
  23. 23Division of Molecular & Cellular Function, School of Biological Sciences, Faculty of Biology Medicine, and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PL, UK
  24. 24Manchester Centre for Genomic Medicine, Saint Mary's Hospital, Oxford Rd, Manchester M13 9WL
  25. 25Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Oxford Road, Manchester, M13 9PT, UK


There is strong evidence from familial recurrence studies for a genetic predisposition to sporadic, non-syndromic Tetralogy of Fallot (TOF). TOF is the most common, cyanotic congenital heart disease (CHD) phenotype yet the cause for the majority of cases remains elusive. Rare genetic variants have been identified as important contributors to the risk of CHD, but relatively small numbers of TOF cases have been studied to date. 829 TOF patients underwent whole exome sequencing (WES), the largest cohort of non-syndromic TOF patients reported to date. The prevalence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database (gnomAD) and a scaled combined annotation-dependent depletion (CADD) score of ≥20. Clustering analysis of variants revealed that two 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 harbour unique, deleterious variants. 31 variants were observed in 37 probands (4.5%; 95% confidence interval [CI]: 3.2–6.1%) and included seven loss-of-function variants, 22 missense variants and two in-frame indels. Sanger sequencing of the unaffected parents of seven cases identified five de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y and p.N1875S) were subjected to functional evaluation and two showed a reduction in Jagged1-induced NOTCH signalling. FLT4 variants were found in 2.4% (95% CI:1.6–3.8%) of TOF patients, with 21 patients harbouring 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 biologically plausible candidate genes. In summary, the NOTCH1 locus is the most frequent site of genetic variants predisposing to non-syndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.

  • Congenital Heart Disease
  • Tetralogy of Fallot
  • Genetics

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