Guidelines for investigating causality of sequence variants in human disease
Open accessAbstract
Acceleration in discovery of rare genetic variants possibly linked with disease may mean an increased risk of false-positive reports of causality; this Perspective proposes guidelines to distinguish disease-causing sequence variants from the many potentially functional variants in a human genome, and to assess confidence in their pathogenicity, and highlights priority areas for development. The wide-scale availability of high-throughput DNA sequencing technologies means that data on genetic variation in human diseases are accumulating rapidly. In this Perspective, Daniel MacArthur and colleagues sound a note of caution, pointing out that up to a quarter of reported disease-linked mutations have been found to either be common polymorphisms or have lacked sufficient evidence for pathogenicity. The authors discuss the key challenges associated with assessing sequence variants in human disease and propose guidelines for the robust differentiation between disease-causing genetic variants and other variants present in the human genome. They highlight several areas where research and resource development are urgently needed if genomic research findings are to be successfully translated into the clinical diagnostic setting. The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.
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Establishing the causal role of individual variants within genes associated with rare disorders remains problematic, and many patients with suspected rare genetic diseases lack a definitive diagnosis.
“Although huge strides have been made in associating specific genes with particular disorders, establishing the causal role of individual variants within those genes remains problematic, and many patients with suspected rare genetic diseases are left without a definitive diagnosis28.”
From A brief history of human disease genetics (2020) · cites this paper as [28]
For monogenic diseases, whose causal alleles are typically rare, penetrant and coding, genetic approaches have generally been both necessary and sufficient to implicate a gene as causal.
“For monogenic diseases, for which the alleles responsible are typically rare, penetrant and coding, genetic approaches have generally been both necessary and sufficient to implicate a gene as causal28.”
From A brief history of human disease genetics (2020) · cites this paper as [28]
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- Authors
- MacArthur, D. G., Manolio, T. A., Dimmock, D. P., Rehm, H. L., Shendure, J., Abecasis, G. R., Adams, D. R., Altman, R. B., Antonarakis, S. E., Ashley, E. A., Barrett, J. C., Biesecker, L. G., Conrad, D. F., Cooper, G. M., Cox, N. J., Daly, M. J., Gerstein, M. B., Goldstein, D. B., Hirschhorn, J. N., Leal, S. M., Pennacchio, L. A., Stamatoyannopoulos, J. A., Sunyaev, S. R., Valle, D., Voight, B. F., Winckler, W., & Gunter, C.
- Affiliations
- Broad Institute (US)
- National Institutes of Health (US)
- Medical College of Wisconsin (US)
- Harvard University (US)
- University of Washington (US)
- University of Michigan (US)
- Stanford University (US)
- University of Geneva (CH)
- Stanford Medicine (US)
- Wellcome Sanger Institute (GB)
- Washington University in St. Louis (US)
- HudsonAlpha Institute for Biotechnology (US)
- University of Chicago (US)
- Yale University (US)
- Duke University (US)
- Baylor College of Medicine (US)
- Lawrence Berkeley National Laboratory (US)
- Brigham and Women's Hospital (US)
- Johns Hopkins University (US)
- University of Pennsylvania (US)
- Corresponding author
- MacArthur, D. G.
- Gunter, C.
- ORCID
- MacArthur, D. G.
- Manolio, T. A.
- Dimmock, D. P.
- Rehm, H. L.
- Shendure, J.
- Abecasis, G. R.
- Adams, D. R.
- Altman, R. B.
- Antonarakis, S. E.
- Ashley, E. A.
- Barrett, J. C.
- Biesecker, L. G.
- Cooper, G. M.
- Cox, N. J.
- Daly, M. J.
- Gerstein, M. B.
- Goldstein, D. B.
- Hirschhorn, J. N.
- Leal, S. M.
- Pennacchio, L. A.
- Stamatoyannopoulos, J. A.
- Sunyaev, S. R.
- Valle, D.
- Voight, B. F.
- Winckler, W.
- Gunter, C.
- Venue
- Nature
- Published
- 2014-04
- Volume
- 508
- Issue
- 7497
- Pages
- 469-476
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4180223
- OpenAlex
- W2169567789
- Cited by
- 1,224
- References
- 58
- Citations by year
- 2026: 34 · 2025: 35 · 2024: 43 · 2023: 62 · 2022: 64 · 2021: 103 · 2020: 70 · 2019: 101 · 2018: 153 · 2017: 160 · 2016: 172 · 2015: 155 · 2014: 68 · 2013: 1 · 2012: 1
- FWCI
- 111.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion, cc-by-nc-sa)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion, public-domain)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- National Heart, Lung, and Blood Institute (R01HL117626)
- National Institute of Mental Health (R01MH101810)
- National Human Genome Research Institute (U54HG006997, U01HG007301, R01HG007022)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020595)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- variant pathogenicity assessment, rare variants, clinical genetic diagnosis
- MeSH terms
- Disease, False Positive Reactions, Genes, Humans, Publishing, Research Design, Genetic Variation, Reproducibility of Results, Guidelines as Topic, Genetic Predisposition to Disease, Information Dissemination, Translational Research, Biomedical
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