Frequency of genetic variants associated with arrhythmogenic right ventricular cardiomyopathy in the genome
Charlotte L Hall1, Henry Sutanto1, Chrysoula Dalageorgou1
1Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.
Insights
Analyzing population data improves arrhythmogenic right ventricular cardiomyopathy (ARVC) variant interpretation. Many variants previously deemed pathogenic may be common, suggesting reduced penetrance or polygenic causes for ARVC.
Area of Science:
- Genetics
- Cardiology
- Population Genomics
Background:
- Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic heart disorder causing arrhythmias and sudden cardiac death, particularly in young adults.
- Accurate diagnosis is vital for managing ARVC and preventing sudden cardiac death (SCD).
- Five genes (PKP2, DSP, DSG2, DSC2, JUP) harbor variants responsible for 40-50% of ARVC cases.
Purpose of the Study:
- To re-evaluate the classification of known ARVC variants using large-scale population data.
- To determine the frequency of ARVC-associated variants in diverse populations.
- To improve the interpretation of genetic variants in ARVC diagnosis.
Main Methods:
- Utilized the Genome Aggregation Database (gnomAD) comprising 138,632 individuals.
- Searched gnomAD for previously identified pathogenic and unknown ARVC variants in key genes.
- Applied minor allele frequency (MAF) thresholds (0.001 and 0.0001) to distinguish rare from common variants across ethnic groups.
Main Results:
- Found that 32% of pathogenic and 57% of unknown ARVC variants were present in gnomAD.
- Identified 11 pathogenic and 57 unknown variants as common (MAF ≥ 0.001) in at least one population, questioning their pathogenicity.
- Calculated an overall pathogenic ARVC variant frequency of 1 in 257, and 1 in 845 using a stringent cutoff, aligning closer to disease prevalence.
Conclusions:
- Analysis of large, cross-ethnic population sequencing data significantly enhances disease variant interpretation.
- A higher-than-expected frequency of ARVC variants suggests potential misclassification of some variants.
- Findings imply reduced penetrance or a polygenic etiology for a proportion of ARVC cases.
Abstract:
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare inherited heart-muscle disorder, which is the most common cause of life-threatening arrhythmias and sudden cardiac death (SCD) in young adults and athletes. Early and accurate diagnosis can be crucial in effective ARVC management and prevention of SCD.The genome Aggregation Database (gnomAD) population of 138,632 unrelated individuals was searched for previously identified ARVC variants, classified as pathogenic or unknown on the disease genetic variant database ( http://www.arvcdatabase.info/ ), in five most-commonly mutated genes: PKP2, DSP, DSG2, DSC2 and JUP, where variants account for 40-50% of all the ARVC cases. Minor allele frequency (MAF) of 0.001 was used to define variants as rare or common.The gnomAD data contained 117/364 (32%) of the previously reported pathogenic and 152/266 (57%) of the unknown ARVC variants. The cross-ethnic analysis of MAF revealed that 11 previously classified pathogenic and 57 unknown variants were common (MAF ≥ 0.001) in at least one ethnic gnomAD population and therefore unlikely to be ARVC causing.After applying our MAF analysis the overall frequency of pathogenic ARVC variants in gnomAD was one in 257 individuals, but a more stringent cut-off (MAF ≥ 0.0001) gave a frequency of one in 845, closer to the estimated phenotypic frequency of the disease.Our study demonstrates that the analysis of large cross-ethnic population sequencing data can significantly improve disease variant interpretation. Higher than expected frequency of ARVC variants suggests that a proportion of ARVC-causing variants may be inaccurately classified, implying reduced penetrance of some variants, and/or a polygenic aetiology of ARVC.
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