Electronic Health Record Phenotype in Subjects with Genetic Variants Associated with Arrhythmogenic Right Ventricular Cardiomyopathy: A Study in 30,716 Subjects with Exome Sequencing: Genotype-Phenotype Association in Incidental ARVC Genetic Findings

Haggerty, Christopher M.James, Cynthia A.Calkins, HughTichnell, CrystalLeader, Joseph B.Hartzel, Dustin N.Nevius, Christopher D.Pendergrass, Sarah A.Person, Thomas N.Schwartz, MarciRitchie, Marylyn D.Carey, David J.Ledbetter, David H.Williams, Marc S.Dewey, Frederick E.Lopez, AlexanderPenn, JohnOverton, John D.Reid, Jeffrey G.Lebo, MatthewMason-Suares, HeatherAustin-Tse, ChristinaRehm, HeidiDelisle, Brian P.Makowski, Daniel J.Mehra, Vishal C.Murray, Michael F.Fornwalt, Brandon K.2017-12-062017Haggerty, C. M., C. A. James, H. Calkins, C. Tichnell, J. B. Leader, D. N. Hartzel, C. D. Nevius, et al. 2017. “Electronic Health Record Phenotype in Subjects with Genetic Variants Associated with Arrhythmogenic Right Ventricular Cardiomyopathy: A Study in 30,716 Subjects with Exome Sequencing: Genotype-Phenotype Association in Incidental ARVC Genetic Findings.” Genetics in medicine : official journal of the American College of Medical Genetics 19 (11): 1245-1252. doi:10.1038/gim.2017.40. http://dx.doi.org/10.1038/gim.2017.40.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34492968Purpose Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained. Methods: 30,716 individuals underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFβ3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes. Results: 18 subjects had pLOF variants; none had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram (ECG), one had a minor diagnostic criterion, 13 were normal. 184 subjects had VUSs; none had an ARVC diagnosis. In subjects with VUSs, there was no difference in the proportion with major (4%) or minor (13%) ECG diagnostic criteria compared to variant-negative controls. ICD-9 codes showed no difference in defibrillator utilization, electrophysiologic abnormalities or non-ischemic cardiomyopathies in patients with pLOF or VUSs compared to controls. Conclusion: pLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain.en-USarrhythmogenic right ventricular cardiomyopathyexome sequencinggenotype-phenotype associationelectronic health recordincidental findingsElectronic Health Record Phenotype in Subjects with Genetic Variants Associated with Arrhythmogenic Right Ventricular Cardiomyopathy: A Study in 30,716 Subjects with Exome Sequencing: Genotype-Phenotype Association in Incidental ARVC Genetic FindingsJournal Article2017-12-0610.1038/gim.2017.40