(2017) Haggerty, Christopher M.; James, Cynthia A.; Calkins, Hugh; Tichnell, Crystal; Leader, Joseph B.; Hartzel, Dustin N.; Nevius, Christopher D.; Pendergrass, Sarah A.; Person, Thomas N.; Schwartz, Marci; Ritchie, Marylyn D.; Carey, David J.; Ledbetter, David H.; Williams, Marc S.; Dewey, Frederick E.; Lopez, Alexander; Penn, John; Overton, John D.; Reid, Jeffrey G.; Lebo, Matthew; Mason-Suares, Heather; Austin-Tse, Christina; Rehm, Heidi; Delisle, Brian P.; Makowski, Daniel J.; Mehra, Vishal C.; Murray, Michael F.; Fornwalt, Brandon K.
Purpose 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.
