Whole exome sequencing reveals the major genetic contributors to nonsyndromic tetralogy of Fallot
Open accessAbstract
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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Ultra-rare non-synonymous variants play a major role in the genetic aetiology of CHD, particularly TOF.
“Previous research revealed that ultra-rare non-synonymous variants play a major role in the genetic aetiology of CHD, particularly TOF (Jin et al., 2017; Page et al., 2019); and (Reuter et al., 2019).”
From Genetic insights into non-syndromic Tetralogy of Fallot (2022) · cites this paper as Page et al., 2019
The TOF susceptibility variants section reports unique, deleterious variants in the top nine genes in over 16% of the nonsyndromic TOF cohort, supporting a substantial genetic contribution in TOF. The study does not establish that ultra-rare non-synonymous variants play a major role across CHD generally, and its reported variants include frameshift and splice variants as well as missense variants. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFLT4 and NOTCH1 are the most significant genes that caused non-syndromic TOF in a cohort of 829 TOF patients.
“Likewise, exome sequence analysis revealed that FLT4 and NOTCH1 genes were the most significant genes that caused non-syndromic TOF in a cohort of 829 TOF patients (Page et al., 2019).”
From Genetic insights into non-syndromic Tetralogy of Fallot (2022) · cites this paper as Page et al., 2019
The Methods and Exome-Wide Analysis sections report exome sequencing of 829 nonsyndromic TOF cases. The TOF susceptibility variants section identifies NOTCH1 and FLT4 as by far the most significant contributors, but describes their variants as likely contributors to TOF pathogenesis; saying the genes “caused” TOF is more definitive than the paper's finding. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFive new de novo NOTCH1 variants were found in the TOF cohort; three were missense and two were truncating.
“A recent study conducted by (Page et al., 2019) found five new de novo NOTCH1 variants in the TOF cohort; three of these were missense variations, whereas the remaining two were truncating variants (Table 1): p. G200V, p. R448X, p. C1549Y, p. W1638X and p. N1875S.”
From Genetic insights into non-syndromic Tetralogy of Fallot (2022) · cites this paper as Page et al., 2019
Variants in NOTCH1 and FLT4 are detected in about 7% of TOF cases.
“Variants in these genes are detected in about 7% of TOF cases (Page et al., 2019).”
From Genetic insights into non-syndromic Tetralogy of Fallot (2022) · cites this paper as Page et al., 2019
The NOTCH1 locus, followed by FLT4, is the most common site of genetic variants leading to non-syndromic TOF.
“A recent study of the largest group of non-syndromic TOF patients observed to date, using WES of 829 TOF patients, has found that the NOTCH1 locus, followed by FLT4, is the most common site of genetic variants leading to non-syndromic TOF.”
From Genetic insights into non-syndromic Tetralogy of Fallot (2022) · cites this paper as Page et al., 2019
Two NOTCH1 variants, p.C607Y and p.N1875S, recognised in TOF patients who underwent functional testing, affect canonical NOTCH1 signalling.
“As a result, two variants, the p. C607Y and p. N1875S, recognised in TOF patients who underwent functional testing, were found to affect canonical NOTCH1 signalling (Page et al., 2019).”
From Genetic insights into non-syndromic Tetralogy of Fallot (2022) · cites this paper as Page et al., 2019
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- Authors
- Page, D. J., Miossec, M. J., Williams, S. G., Monaghan, R. M., Fotiou, E., Cordell, H. J., Sutcliffe, L., Topf, A., Bourgey, M., Bourque, G., Eveleigh, R., Dunwoodie, S. L., Winlaw, D. S., Bhattacharya, S., Breckpot, J., Devriendt, K., Gewillig, M., Brook, J. D., Setchfield, K. J., Bu’Lock, F. A., O’Sullivan, J., Stuart, G., Bezzina, C. R., Mulder, B. J. M., Postma, A. V., Bentham, J. R., Baron, M., Bhaskar, S. S., Black, G. C., Newman, W. G., Hentges, K. E., Lathrop, G. M., Santibanez-Koref, M., & Keavney, B. D.
- Affiliations
- Manchester Metropolitan University (GB)
- Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom (M.J.M., H.J.C., L.S., A.T., M.S.-K.)
- Congenital and Paediatric Cardiology, East Midlands Congenital Heart Centre and University of Leicester, Glenfield Hospital (F.A.B.)
- Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester (M.B.)
- McGill Genome Center, Montréal, QC, Canada (M.B., G.B., R.E., G.M.L.)
- Corresponding author
- Page, Donna J.
- Miossec, Matthieu J.
- ORCID
- Page, Donna J.
- Miossec, Matthieu J.
- Williams, Simon G.
- Monaghan, Richard M.
- Fotiou, Elisavet
- Cordell, Heather J.
- Bourgey, Mathieu
- Bourque, Guillaume
- Eveleigh, Robert
- Dunwoodie, Sally L.
- Winlaw, David S.
- Bhattacharya, Shoumo
- Breckpot, Jeroen
- Devriendt, Koenraad
- Gewillig, Marc
- Brook, J. David
- Setchfield, Kerry J.
- O’Sullivan, John
- Stuart, Graham
- Bezzina, Connie R.
- Mulder, Barbara J.M.
- Postma, Alex V.
- Bentham, James R.
- Bhaskar, Sanjeev S.
- Black, Graeme C.
- Newman, William G.
- Hentges, Kathryn E.
- Keavney, Bernard D.
- Venue
- Circulation Research
- Published
- 2019-02-15
- Volume
- 124
- Issue
- 4
- Pages
- 553-563
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC6377791
- OpenAlex
- W2903172740
- Cited by
- 189
- References
- 79
- Citations by year
- 2026: 12 · 2025: 31 · 2024: 34 · 2023: 23 · 2022: 28 · 2021: 28 · 2020: 20 · 2019: 13
- FWCI
- 7.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion, other-oa)
- e-space (Manchester Metropolitan University) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lirias (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion, other-oa)
- Repositorio Institucional Académico , Sistema de Bibliotecas Universidad Andrés Bello (UNAB) (Universidad Andrés Bello (UNAB)) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Victor Chang Cardiac Research Institute
- McGill University
- Manchester Metropolitan University
- University Hospitals Bristol NHS Foundation Trust
- British Heart Foundation (FS/11/63/28944, RG/15/12/31616, RG/13/10/30376, CH/09/003/26631, CH/13/2/30154, RG/10/17/28553, FS/14/51/30879)
- University of Leicester
- University of Oxford
- University of Manchester
- Newcastle University
- University of New South Wales
- Universidad Andrés Bello
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council (BB/M020797/1, BB/P000215/1)
- Sydney Medical School
- Universitaire Ziekenhuizen Leuven, KU Leuven
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Epidemiology › Congenital Heart Disease Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Notch1, VEGFR-3, de novo mutations, loss-of-function mutations, Notch signaling, Jagged1, Milroy disease, Tbx1, RyR1, Dlx6, PCM1, genetic susceptibility
- MeSH terms
- Loss of Function Mutation, Autoantigens, Calcium-Binding Proteins, Humans, Nuclear Proteins, Tetralogy of Fallot, Transcription Factors, Trans-Activators, Homeodomain Proteins, Cell Cycle Proteins, Mutation, Missense, Vascular Endothelial Growth Factor Receptor-3, Receptor, Notch1, Exome, Mutation Rate
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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