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Cited by 875Congenital heart defects researchGenomics and Rare DiseasesCongenital Heart Disease Studies

Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands

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Jin, Sheng Chih, Homsy, Jason, Zaidi, Samir, Lu, Qiongshi, Morton, Sarah, DePalma, Steven R, Zeng, Xue, Qi, Hongjian +37 more·2017·Nature Genetics
DOI 10.1038/ng.3970PMC PMC5675000
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Abstract

Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

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  • Rare de novo genetic variations are substantial factors in TOF.

    “Rare, de novo genetic variations have been found as substantial factors in TOF (Jin et al., 2017).”

    From Genetic insights into non-syndromic Tetralogy of Fallot (2022) · cites this paper as Jin et al., 2017

    The Results section on FLT4 and tetralogy of Fallot reports two de novo FLT4 loss-of-function mutations and says 9 of 10 probands with FLT4 loss-of-function mutations had TOF. But eight FLT4 mutations were inherited, and the paper does not establish that de novo variants are a substantial factor in TOF overall. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • 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 Jin et al., 2017

    The Discussion reports a genetic contribution from inherited and de novo variants in 10.1% of CHD cases. The Results section on FLT4 reports ultra-rare loss-of-function variants in 2.3% of probands with tetralogy of Fallot (TOF). These findings support a contribution from rare damaging variants, including in TOF, but not the broader assertion that ultra-rare non-synonymous variants play a major role particularly in TOF. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Rare genetic variants are significant risk factors for CHD and are likely to cause some cases of TOF.

    “However, rare genetic variants have been identified as significant risk factors for CHD, and are likely to cause some cases of TOF.”

    From Genetic insights into non-syndromic Tetralogy of Fallot (2022) · cites this paper as Jin et al., 2017

  • A nonsense variant c.367C > T (p.Arg213Ter) in ABI1 was identified in a patient with cardiovascular dysfunction and neurodevelopmental disorder.

    “A nonsense variant, c.367C > T, p.Arg213Ter, in ABI1 was identified in a patient with cardiovascular dysfunction and NDD135–137 (Table 2v).”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [136]

    The Results section on de novo mutations in autism-associated genes reports an overlap between congenital heart disease and neurodevelopmental disorders, but does not identify the patient or ABI1 variant in the claim. Searches for ABI1, c.367C>T, and p.Arg213Ter found no passage in our copy documenting that specific case; page numbers were not provided. (LLM, conf=0.72)

    Experimental — accuracy not yet measured

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Authors
Jin, S. C., Homsy, J., Zaidi, S., Lu, Q., Morton, S., DePalma, S. R., Zeng, X., Qi, H., Chang, W., Sierant, M. C., Hung, W.-C., Haider, S., Zhang, J., Knight, J., Bjornson, R. D., Castaldi, C., Tikhonoa, I. R., Bilguvar, K., Mane, S. M., Sanders, S. J., Mital, S., Russell, M. W., Gaynor, J. W., Deanfield, J., Giardini, A., Porter, G. A., Srivastava, D., Lo, C. W., Shen, Y., Watkins, W. S., Yandell, M., Yost, H. J., Tristani-Firouzi, M., Newburger, J. W., Roberts, A. E., Kim, R., Zhao, H., Kaltman, J. R., Goldmuntz, E., Chung, W. K., Seidman, J. G., Gelb, B. D., Seidman, C. E., Lifton, R. P., & Brueckner, M.
Affiliations
  • Yale University (US)
  • Brigham and Women's Hospital (US)
  • Boston Children's Hospital (US)
  • Harvard University (US)
  • Columbia University (US)
  • UCL School of Pharmacy (GB)
  • University of California, San Francisco (US)
  • University of Toronto (CA)
  • University of Michigan (US)
  • Children's Hospital of Philadelphia (US)
  • Great Ormond Street Hospital (GB)
  • Gladstone Institutes (US)
  • Columbia University Irving Medical Center (US)
  • University of Utah (US)
  • Children's Hospital Los Angeles (US)
  • National Institutes of Health (US)
  • University of Pennsylvania (US)
  • Icahn School of Medicine at Mount Sinai (US)
Corresponding author
  • Kim, Richard
  • Seidman, Jonathan G
  • Gelb, Bruce D
  • Seidman, Christine E
  • Brueckner, Martina
ORCID
Venue
Nature Genetics
Publisher
Springer Science and Business Media LLC
Published
2017-10-09
Volume
49
Issue
11
Pages
1593-1601
ISSN
  • 1061-4036 (ISSN-L)
  • 1546-1718
DOI
10.1038/ng.3970
PMC
PMC5675000
OpenAlex
W2763010484
Cited by
875
References
6
Citations by year
2026: 65 · 2025: 103 · 2024: 123 · 2023: 102 · 2022: 114 · 2021: 117 · 2020: 92 · 2019: 88 · 2018: 68 · 2017: 3
FWCI
28.05
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Genetics (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institutes of Health (5ul1tr001067-05, 1s10od018522-01, 1s10od018521-01, UL1TR000003, UL1TR001863)
  • National Heart, Lung, and Blood Institute (U01HL098153, UM1HL098162, U01HL098123, U01HL098162, UM1HL098147, R01HL132024, U01HL098188, UM1HL128711, U01HL098160, UM1HL098160, U01HL131003, U01HL098163, U01HL098180, U01HL098147, UM1HL098123)
  • National Human Genome Research Institute (U54HG006504)
  • National Institute of General Medical Sciences (R01GM104390, T32GM007205)
  • National Center for Advancing Translational Sciences (UL1-TR001067)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255, T32HD007149)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Epidemiology › Congenital Heart Disease Studies
Keywords
congenital heart disease, de novo mutations, genetic architecture, autism spectrum disorder, MYH6, Shone complex, VEGFR-3, tetralogy of Fallot, neurodevelopmental anomalies, parent-offspring trios, exome sequencing
MeSH terms
Adult, Autistic Disorder, Child, Female, Heart Defects, Congenital, Heterozygote, Homozygote, Humans, Male, Mutation, Pedigree, Risk, Gene Expression, Case-Control Studies, Myosin Heavy Chains, Genetic Predisposition to Disease, Cardiac Myosins, Vascular Endothelial Growth Factor Receptor-3, Genome-Wide Association Study, Growth Differentiation Factor 1, High-Throughput Nucleotide Sequencing, Exome

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