ArticleAmerican journal of human genetics2019
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting.
Article in American journal of human genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers, 3 of them syntheses that pooled it.
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Who cites it
131 citing papers in PubMed, 3 syntheses or guidelines pooled it, 228 citations in OpenAlex.
- Evaluating whole genome sequencing for rare diseases in newborn screening: evidence synthesis from a series of systematic reviews.Health technology assessment (Winchester, England) · 2025Pooled it
- Sharing behavior and health care utilization following direct-to-consumer genetic testing: a systematic review.Open research Europe · 2025Pooled it
- Pooled it
- Sequencing for a Lifetime: Professional Perspectives on the Value and Feasibility of Lifelong Genomic Medicine.medRxiv : the preprint server for health sciences · 2026Article
- Common and rare genetic variant associations with cognitive performance across development in British birth cohorts.Nature human behaviour · 2026Article
- Digenic and multigenic heterozygous FHL genotypes are common but clinically silent in the general population.Blood advances · 2026Article
- Uncovering apparent incomplete penetrance of TSC1/TSC2 variants: Insights from multiple population cohorts and implications for newborn screening.European journal of human genetics : EJHG · 2026Article
- From clinical genetics to genomic-based public health screening programmes: duty-based ethics as a guide for responsible implementation.European journal of human genetics : EJHG · 2026Article
- Benchmarking genetic birth prevalence estimates against newborn screening data.American journal of human genetics · 2026Article
- Genetic background shapes AI-predicted variant effects.bioRxiv : the preprint server for biology · 2026Article
- The functional landscape of coding variation in the familial hypercholesterolemia geneScience (New York, N.Y.) · 2026Article
- Understanding Psychotic Depression.Advances in experimental medicine and biology · 2026Review
- Residual allelic activity likely underlies the low rates of disease expression for predicted loss-of-function variants in population-scale biobanks.American journal of human genetics · 2025Article
- Functional Profiling ofCirculation. Genomic and precision medicine · 2025Article
- MTHFR variant links homocysteine metabolism and endothelial cell dysfunction by targeting mitophagy in human thoracic aortic dissection patient induced pluripotent stem cell (iPSC) models.Journal of advanced research · 2025Article
- A scalable approach for genomic-first rare disorder detection in a healthcare-based population.American journal of human genetics · 2025Article
- Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database.Nature communications · 2025Article
- Whole-genome sequencing reveals rare and structural variants contributing to psoriasis and identifies CERCAM as a risk gene.Cell genomics · 2025Article
- SPINK1-related chronic pancreatitis: A model that encapsulates the spectrum of variant effects, genetic complexity, and classificatory challenges.American journal of human genetics · 2025Article
- Machine learning-based penetrance of genetic variants.Science (New York, N.Y.) · 2025Article
71 more citing papers are in PubMed but not listed here.
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as "clinically relevant" variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.