The Frequency, Penetrance and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants
There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general, adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional and arrhythmic disease features. UK Biobank participants who had undergone whole exome sequencing (WES), ECG and cardiovascular magnetic resonance (CMR) imaging were selected for study. Three different variant calling strategies (one primary and two secondary) were used to identify subjects with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded to either 1) DCM (clinical or CMR diagnosis); 2) early DCM features, including arrhythmia and/or conduction disease, isolated ventricular dilation, and hypokinetic non-dilated cardiomyopathy; or 3) phenotype-negative. Among 18,665 individuals included in the study, 1,463 (7.8%) subjects possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and CMR analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in 15.9% of individuals with putative pathogenic variants. Arrhythmias and/or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic non-dilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all three variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes, as compared to those with variants in moderate/limited evidence genes. In the UK Biobank, approximately 1/6 of adults with putative pathogenic variants in DCM genes exhibited a subclinical phenotype based on ECG and/or CMR, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation/dysfunction. Among individuals with putative pathogenic DCM gene variants, subclinical DCM and early DCM features, detected by ECG and/or CMR, were nearly four times more common than clinically manifest DCM or early features (23.7% vs. 6.1%). Over 90% of subjects with a putative pathogenic variant in DCM-associated genes did not have a prior history of DCM. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes (13.9% for clinical and subclinical), as compared to those with variants in moderate/limited evidence genes, but there was no significant difference in combined clinical/subclinical phenotype by cluster. The overall clinical/subclinical penetrance of DCM-associated single putative pathogenic variants was highly variable between genes, ranging from 0 to 66.7%. Arrhythmias and cardiac conduction disease are the most common early manifestation of putative pathogenic variants implicated in DCM, mostly occurring prior to the development of structural/functional abnormalities. A genotype-first screening approach for DCM using a large genetic panel is currently not suitable in the general population due to incomplete understanding of DCM genetic architecture and reduced penetrance of DCM-associated putative pathogenic variants. Cardiomyopathy; Genetics; Sudden Cardiac Death
