TY - JOUR
T1 - Prevalence and Electronic Health Record-Based Phenotype of Loss-of-Function Genetic Variants in Arrhythmogenic Right Ventricular Cardiomyopathy-Associated Genes
AU - Carruth, Eric D.
AU - Young, Wilson
AU - Beer, Dominik
AU - James, Cynthia A.
AU - Calkins, Hugh
AU - Jing, Linyuan
AU - Raghunath, Sushravya
AU - Hartzel, Dustin N.
AU - Leader, Joseph B.
AU - Kirchner, H. Lester
AU - Smelser, Diane T.
AU - Carey, David J.
AU - Kelly, Melissa A.
AU - Sturm, Amy C.
AU - Alsaid, Amro
AU - Fornwalt, Brandon K.
AU - Haggerty, Christopher M.
N1 - Funding Information:
Dr Calkins is a consultant for Medtronic Inc and St Jude Medical/Abbott. Dr Calkins receives research support from Boston Scientific Corp, and Dr James receives salary support from this grant. Dr James has received a lecture fee from Abbott. Dr Fornwalt is a consultant for the Novartis Cardiovascular Data Science Advisory Board. The other authors report no conflicts.
Funding Information:
This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) under Award Number R01HL141901. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The work was also supported by the Regeneron Genetics Center and Geisinger.
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
KW - desmosomes
KW - echocardiography
KW - electronic health records
KW - genomics
KW - whole exome sequencing
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U2 - 10.1161/CIRCGEN.119.002579
DO - 10.1161/CIRCGEN.119.002579
M3 - Article
C2 - 31638835
AN - SCOPUS:85075812697
SN - 1942-325X
VL - 12
SP - 487
EP - 494
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
IS - 11
ER -