The penetrance of rare variants in cardiomyopathy-associated genes: a cross-sectional approach to estimate penetrance for secondary findings

Abstract

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 AbstractA 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{degrees}) 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 View larger version (33K): org.highwire.dtl.DTLVardef@ddccedorg.highwire.dtl.DTLVardef@1b8e441org.highwire.dtl.DTLVardef@1919151org.highwire.dtl.DTLVardef@1db7e78_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 2C_FLOATNO The aggregate estimates of penetrance of "loss of function" variants are high for specific genes. The plot depicts estimated penetrance of HCM-associated (left) and DCM-associated (right) rare variants. pLoF and non-pLoF variant groups are plotted in green and blue, respectively. pLoF, predicted loss of function variants; *, TTNtv that are PSI>90%. Pathogenic TNNT2 inframe deletions caused an increased penetrance signal for inframe deletions for both HCM and DCM (see Figure S12). C_FIG