Pulse Brain · Growing Health Evidence Index
Tier 4 — Narrative / commentaryPeer-reviewed

Guidance for estimating penetrance of monogenic disease-causing variants in population cohorts

Caroline F. Wright, Luke N Sharp, Leigh Jackson, Anna Murray, James S. Ware, Daniel G. MacArthur, Heidi L. Rehm, Kashyap Patel, Michael N. Weedon

Nature Genetics · 2024

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Summary

This 2024 Nature Genetics paper presents evidence-based guidance for estimating penetrance of disease-causing monogenic variants in large population cohorts. The authors, affiliated with major genomic research institutions, outline statistical and study design considerations necessary for robust penetrance calculation, which is essential for variant classification and clinical reporting. As suggested by the journal and authorship, the work aims to standardise penetrance assessment across genomic medicine practice.

Regional applicability

This methodological guidance applies internationally to genomic medicine practitioners and variant interpretation across healthcare systems, including the United Kingdom's NHS Genomic Medicine Service. The principles and statistical frameworks are not geography-dependent and are directly transferable to UK research infrastructure and clinical genetics services.

Key measures

Penetrance estimation methods; variant effect sizes; population cohort analyses for disease manifestation rates

Outcomes reported

The study provides guidance on estimating penetrance (proportion of individuals carrying a disease-causing variant who manifest the phenotype) for monogenic Mendelian disease variants using population-based genomic cohorts. This addresses methodological challenges in variant interpretation and clinical implementation.

Theme
Measurement & metrics
Subject
Measurement methods & nutrient profiling
Study type
Guideline
Study design
Guideline
Source type
Peer-reviewed study
Status
Published
Geography
International
System type
Human clinical
DOI
10.1038/s41588-024-01842-3
Catalogue ID
SNmp6e6wxx-xl9tw1

Topic tags

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