| Title: | Population-Based Penetrance of Deleterious Clinical Variants |
| Journal: | JAMA |
| Published: | 25 Jan 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35076666/ |
| DOI: | https://doi.org/10.1001/jama.2021.23686 |
| URL: | https://jamanetwork.com/journals/jama/articlepdf/2788347/jama_forrest_2022_oi_210144_1643049438.93955.pdf |
| Citations: | 45 (31 in last 2 years) as of 8 Aug 2024 |
Publication 12587
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
Abstract
Importance: Population-based assessment of disease risk associated with gene variants informs clinical decisions and risk stratification approaches.</p>
Objective: To evaluate the population-based disease risk of clinical variants in known disease predisposition genes.</p>
Design, Setting, and Participants: This cohort study included 72 434 individuals with 37 780 clinical variants who were enrolled in the BioMe Biobank from 2007 onwards with follow-up until December 2020 and the UK Biobank from 2006 to 2010 with follow-up until June 2020. Participants had linked exome and electronic health record data, were older than 20 years, and were of diverse ancestral backgrounds.</p>
Exposures: Variants previously reported as pathogenic or predicted to cause a loss of protein function by bioinformatic algorithms (pathogenic/loss-of-function variants).</p>
Main Outcomes and Measures: The primary outcome was the disease risk associated with clinical variants. The risk difference (RD) between the prevalence of disease in individuals with a variant allele (penetrance) vs in individuals with a normal allele was measured.</p>
Results: Among 72 434 study participants, 43 395 were from the UK Biobank (mean [SD] age, 57 [8.0] years; 24 065 [55%] women; 2948 [7%] non-European) and 29 039 were from the BioMe Biobank (mean [SD] age, 56 [16] years; 17 355 [60%] women; 19 663 [68%] non-European). Of 5360 pathogenic/loss-of-function variants, 4795 (89%) were associated with an RD less than or equal to 0.05. Mean penetrance was 6.9% (95% CI, 6.0%-7.8%) for pathogenic variants and 0.85% (95% CI, 0.76%-0.95%) for benign variants reported in ClinVar (difference, 6.0 [95% CI, 5.6-6.4] percentage points), with a median of 0% for both groups due to large numbers of nonpenetrant variants. Penetrance of pathogenic/loss-of-function variants for late-onset diseases was modified by age: mean penetrance was 10.3% (95% CI, 9.0%-11.6%) in individuals 70 years or older and 8.5% (95% CI, 7.9%-9.1%) in individuals 20 years or older (difference, 1.8 [95% CI, 0.40-3.3] percentage points). Penetrance of pathogenic/loss-of-function variants was heterogeneous even in known disease predisposition genes, including BRCA1 (mean [range], 38% [0%-100%]), BRCA2 (mean [range], 38% [0%-100%]), and PALB2 (mean [range], 26% [0%-100%]).</p>
Conclusions and Relevance: In 2 large biobank cohorts, the estimated penetrance of pathogenic/loss-of-function variants was variable but generally low. Further research of population-based penetrance is needed to refine variant interpretation and clinical evaluation of individuals with these variant alleles.</p>
12 Keywords
- Aged
- Biological Specimen Banks
- Cohort Studies
- Female
- Genetic Predisposition to Disease
- Genetic Variation
- Humans
- Loss of Function Mutation
- Male
- Mutation
- Penetrance
- United Kingdom
11 Authors
- Iain S. Forrest
- Kumardeep Chaudhary
- Ha My T. Vy
- Ben O. Petrazzini
- Shantanu Bafna
- Daniel M. Jordan
- Ghislain Rocheleau
- Ruth J. F. Loos
- Girish N. Nadkarni
- Judy H. Cho
- Ron Do
1 Application
| Application ID | Title |
|---|---|
| 16218 | Dissecting the genetic and phenotypic architecture of cardiovascular disease |
Enabling scientific discoveries that improve human health