Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants

Abstract

Background: 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.

Methods: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative.

Results: Among 18 665 individuals included in the study, 1463 (7.8%) 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 cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes.

Conclusions: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.

Keywords: arrhythmias, cardiac; cardiomyopathies; death, sudden, cardiac; genetic testing; genetics; penetrance.

Figure 1.. Study population selection criteria.

A, Flowchart demonstrates the sequential inclusion/exclusion criteria for the study population. B, Venn diagram showing the number of participants within the whole UK Biobank population with whole exome sequencing (WES), 12-lead ECG, and cardiac magnetic resonance (CMR) imaging.

Figure 2.. Clinical and subclinical penetrance of putative pathogenic variants DCM-associated genes in middle and older aged adults.

For each DCM-associated gene, the height of the bar indicates the percentage of pathogenic/likely pathogenic variant carriers, by missense pLOF FAF filtering strategy, with the specified phenotypes. Total number of participants with a pathogenic/likely pathogenic variant for each DCM-associated gene is indicated below the bar. The phenotype prevalence in those without a pathogenic or likely pathogenic mutation is shown on the far right (labelled “G–“ ). The phenotype prevalence in those with more than 1 putative pathogenic variant is shown in the second from right column. Genes are categorized according to the strength of evidence determined by the ClinGen DCM gene curation expert panel and ordered alphabetically within each category.

Figure 3.

Central illustration of the study, demonstrating the methodology used for phenotype ascertainment, classification and clinical/subclinical phenotype in participants with putative pathogenic variants in DCM genes according to the three variant filtering strategies applied.