Key result
ARVC loss-of-function variants show low clinical penetrance of ~6% in a general population.
Why the study?
Loss-of-function variants in ARVC-associated desmosome genes are recommended for clinical reporting as secondary findings, but their prevalence and phenotype in a general clinical population are not fully characterized.
Does the presence of an ARVC loss-of-function variant predict clinical disease or phenotypic abnormalities in a general clinical population?
Observational (n=61,019)
Does the presence of an ARVC loss-of-function variant predict clinical disease or phenotypic abnormalities in a general clinical population?
Absolute Event Rate: 0% vs 0%
The low estimated penetrance (6.0%) and lack of observable clinical phenotype among unselected carriers of ARVC loss-of-function variants challenge the predictive value of these secondary genomic findings.
Cautions against overinterpreting ARVC variants in unselected patients; challenges penetrance assumptions from prior enriched cohorts.
Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with variants in desmosome genes. Secondary findings of pathogenic/likely pathogenic variants, primarily loss-of-function (LOF) variants, are recommended for clinical reporting; however, their prevalence and associated phenotype in a general clinical population are not fully characterized. Methods: From whole-exome sequencing of 61 019 individuals in the DiscovEHR cohort, we screened for putative loss-of-function variants in PKP2 , DSC2 , DSG2 , and DSP . We evaluated measures from prior clinical ECG and echocardiograms, manually over-read to evaluate ARVC diagnostic criteria, and performed a PheWAS (phenome-wide association study). Finally, we estimated expected penetrance using Bayesian inference. Results: One hundred forty individuals (0.23%; 59±18 years old at last encounter; 33% male) had an ARVC variant (G + ). None had an existing diagnosis of ARVC in the electronic health record, nor significant differences in prior ECG or echocardiogram findings compared with matched controls without variants. Several G + individuals satisfied major repolarization (n=4) and ventricular function (n=5) criteria, but this prevalence matched controls. PheWAS showed no significant associations of other heart disease diagnoses. Combining our best genetic and disease prevalence estimates yields an estimated penetrance of 6.0%. Conclusions: The prevalence of ARVC loss-of-function variants is ≈1:435 in a general clinical population of predominantly European descent, but with limited electronic health record-based evidence of phenotypic association in our population, consistent with a low penetrance estimate. Prospective deep phenotyping and longitudinal follow-up of a large sequenced cohort is needed to determine the true clinical relevance of an incidentally identified ARVC loss-of-function variant.
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Carruth et al. (2019) conducted an observational in Arrhythmogenic right ventricular cardiomyopathy (ARVC) (n=61,019). Putative loss-of-function variants in ARVC-associated genes (PKP2, DSC2, DSG2, DSP) vs. Matched controls without ARVC-associated variants was evaluated on Existing diagnosis of ARVC in the electronic health record. In a general clinical population of 61,019 individuals, the prevalence of ARVC loss-of-function variants was 0.23% (n=140), with zero individuals having an existing ARVC diagnosis, resulting in a low estimated penetrance of 6.0%.
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