| Title: | Guidance for estimating penetrance of monogenic disease-causing variants in population cohorts |
| Journal: | Nature Genetics |
| Published: | 29 Jul 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39075210/ |
| DOI: | https://doi.org/10.1038/s41588-024-01842-3 |
Publication 12761
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Abstract
Penetrance is the probability that an individual with a pathogenic genetic variant develops a specific disease. Knowing the penetrance of variants for monogenic disorders is important for counseling of individuals. Until recently, estimates of penetrance have largely relied on affected individuals and their at-risk family members being clinically referred for genetic testing, a 'phenotype-first' approach. This approach substantially overestimates the penetrance of variants because of ascertainment bias. The recent availability of whole-genome sequencing data in individuals from very-large-scale population-based cohorts now allows 'genotype-first' estimates of penetrance for many conditions. Although this type of population-based study can underestimate penetrance owing to recruitment biases, it provides more accurate estimates of penetrance for secondary or incidental findings. Here, we provide guidance for the conduct of penetrance studies to ensure that robust genotypes and phenotypes are used to accurately estimate penetrance of variants and groups of similarly annotated variants from population-based studies.</p>
9 Authors
- Caroline F. Wright
- Luke N. Sharp
- Leigh Jackson
- Anna Murray
- James S. Ware
- Daniel G. MacArthur
- Heidi L. Rehm
- Kashyap A. Patel
- Michael N. Weedon
Enabling scientific discoveries that improve human health