Clinical assessment incorporating a personal genome
Open accessAbstract
Background The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.Methods We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks.Findings Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported.Interpretation Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.Funding National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.
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Risk for one disease is conditioned on another disease in the same person.
“(iii) conditioning of the risk for one disease on another disease in the same individual106,107.”
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- Authors
- Ashley, E. A., Butte, A. J., Wheeler, M. T., Chen, R., Klein, T. E., Dewey, F. E., Dudley, J. T., Ormond, K. E., Pavlovic, A., Morgan, A. A., Pushkarev, D., Neff, N. F., Hudgins, L., Gong, L., Hodges, L. M., Berlin, D. S., Thorn, C. F., Sangkuhl, K., Hebert, J. M., Woon, M., Sagreiya, H., Whaley, R., Knowles, J. W., Chou, M. F., Thakuria, J. V., Rosenbaum, A. M., Zaranek, A. W., Church, G. M., Greely, H. T., Quake, S. R., & Altman, R. B.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Stanford University (US)
- Corresponding author
- Ashley, Euan A
- ORCID
- Ashley, Euan A
- Butte, Atul J
- Wheeler, Matthew T
- Chen, Rong
- Klein, Teri E
- Dudley, Joel T
- Ormond, Kelly E
- Neff, Norma F
- Hudgins, Louanne
- Gong, Li
- Thorn, Caroline F
- Sangkuhl, Katrin
- Woon, Mark
- Sagreiya, Hersh
- Whaley, Ryan
- Knowles, Joshua W
- Zaranek, Alexander Wait
- Church, George M
- Greely, Henry T
- Quake, Stephen R
- Altman, Russ B
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2010-05
- Volume
- 375
- Issue
- 9725
- Pages
- 1525-1535
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC2937184
- OpenAlex
- W2103184242
- Cited by
- 674
- References
- 57
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 6 · 2022: 14 · 2021: 19 · 2020: 16 · 2019: 20 · 2018: 22 · 2017: 25 · 2016: 27 · 2015: 45 · 2014: 64 · 2013: 98 · 2012: 130
- FWCI
- 71.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- Funders
- David and Lucile Packard Foundation
- Howard Hughes Medical Institute
- National Institutes of Health (1dp2od006511-01)
- National Heart, Lung, and Blood Institute (K08HL083914, F32HL097462, T32HL094274)
- National Human Genome Research Institute (P50HG003389, HG003389)
- National Institute of General Medical Sciences (GM 61374, U01GM061374, R01GM079719, R24GM061374, GM079719)
- U.S. National Library of Medicine (LM009719, R01LM009719, LM007033, T15LM007033)
- 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
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- whole genome sequencing, coronary heart disease risk prediction, sudden cardiac death, TMEM43, DSP, MYBPC3, LPA, CYP2C19, clopidogrel resistance, pharmacogenomics, warfarin dosing, variants of uncertain significance, copy number variation, gene-environment interaction, genetic counseling, myocardial infarction, type 2 diabetes, cancer risk
- MeSH terms
- Cytochrome P450 Family 4, Myosin Binding Protein C, Adult, Aryl Hydrocarbon Hydroxylases, Carrier Proteins, Cytochrome P-450 Enzyme System, Environment, Family Health, Genetic Counseling, Genetic Testing, Humans, Mixed Function Oxygenases, Male, Membrane Proteins, Mutation, Osteoarthritis, Pedigree, Pharmacogenetics, Vascular Diseases, Genome, Human, Death, Sudden, Cardiac, Lipoprotein(a), Sequence Analysis, DNA, Risk Assessment, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Desmoplakins, Vitamin K Epoxide Reductases, Cytochrome P-450 CYP2C19
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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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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