The penetrance of rare variants in cardiomyopathy-associated genes: a cross-sectional approach to estimate penetrance for secondary findings
Authors: McGurk Kathryn A. , Zhang Xiaolei , Theotokis Pantazis , Thomson Kate , Harper Andrew , Buchan Rachel J. , Mazaika Erica , Ormondroyd Elizabeth , Wright William T. , Macaya Daniela , Pua Chee Jian , Funke Birgit , MacArthur Daniel G. , Prasad Sanjay , Cook Stuart A. , Allouba Mona , Aguib Yasmine , Yacoub Magdi H. , O’Regan Declan P. , Barton Paul J. R. , Watkins Hugh , Bottolo Leonardo , Ware James S. 
Published: March 2023

Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of patients referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 cases, 1,340 variants) and dilated cardiomyopathy (DCM; 2,564 cases, 665 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220).

In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant CM. Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare, and for males compared to females for variants in HCM-associated genes.

We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (51% HCM and 17% DCM cases). 49 variants were observed at least ten times (14% of cases) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry, and simulate the impact of including future cohorts.

This dataset is the first to report penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some carriers of highly penetrant variants may benefit from SFs.

Graphical Abstract

A flowchart of the estimated penetrance for dominant cardiomyopathy by late adulthood for a variant of interest. The estimates of penetrance in this study are for carriers identified from unselected populations (e.g., consumer-initiated elective genomic testing or as secondary (2°) findings in clinical settings). If the variant is ultra-rare (i.e., identified once or less in population datasets), only estimates by variant subgroup in aggregate are available. If the variant is identified multiple times in both case and population datasets, variant-specific penetrance estimates may be available. If the variant is curated as a variant of uncertain significance (VUS), the penetrance estimate is low. If the variant is a likely pathogenic predicted loss of function (pLoF) variant and is identifiable multiple times in cases and population cohorts, penetrance estimates vary by gene (Figure 2). High aggregate penetrance represents an estimate of >25%; moderate aggregate penetrance represents 10%-25%, and low penetrance represents <10%. This flowchart was created with draw.io.