Citations 1
Abstract 14663: High Rate of Arrhythmia Diagnoses Following Return of Pathogenic/likely Pathogenic Variants in an Unselected Population
Davogustto, Giovanni , Shaffer, Christian M., Ning, Shang, Pacheco, Jennifer , Rinke, Lauren Lee, Kalash, Olivia R., Yoneda, Zachary T. , Kroncke, Brett M. , Iftikhar, Kullo, Larson, Eric B. , Manolio, Teri A. , Schaid, Daniel J. , Namjou, Bahram , George, Albert R., Leppig, Kathleen A. , Sleiman, Patrick, Sohn, Sunghwan , Wei, Wei‐Qi, Shoemaker, M. Benjamin , Roden, Dan M. , Glazer, Andrew M. , Farber‐Eger, Eric , Dikilitas, Ozan , Ning, Shang, Mosley, Jonathan D , Driest, Sara L. Van , Wells, Quinn S. , Wada, Yuko , Bland, Harris T. , Jarvik, Gail P. , Gordon, Adam, Mirshahi, Tooraj , Luo, Jonathan Z. , Alsaied, Tarek , Singh, Rajbir , Singhal, Ashutosh , Ralston, James D. , McNally, Elizabeth M. , George, Albert, Chung, Wendy K. , Carrell, David , Håkonarson, Håkon , Glessner, Joseph , Denny, Joshua C. , Roden, Dan M.
Circulation | May 10, 2021 | Volume: 142 | Issue: Suppl_3 | Pages: No page available
10.1161/circ.142.suppl_3.14663
Background: Return of incidental genetic findings is recommended for pathogenic/likely pathogenic (P/LP) variants in Mendelian arrhythmia genes. The extent to which these variants are associated with arrhythmia phenotypes in unselected populations is unknown. Objective: Assess the impact of return of results (RoR) of P/LP variants in 4 arrhythmia genes in research participants not selected for cardiovascular disease. Methods: The cohort included 24,410 participants from the Electronic Medical Records and Genomics Network. Rare variants (minor allele frequency <1%) in KCNE1 , KCNH2 , KCNQ1 , and SCN5A were identified and classified according to ACMG guidelines. Arrhythmia phenotypes extracted from electronic health records (EHRs) included atrial fibrillation/flutter (AF/AFL), conduction system disease, long QT syndrome (LQTS), ventricular tachycardia/fibrillation (VT/VF), and premature ventricular contractions (PVCs). P/LP carriers’ phenotypes were compared to non-carriers using logistic regression adjusted for demographic covariates and site. Participants with P/LP variants were informed of their results and the impact of this RoR was assessed after 1 year of follow-up clinical care. Results: The participants included 53.7% females and 72.5% white individuals, with a median age of 57 years. 71 participants had a heterozygous P/LP variant in one of the 4 genes. LQTS diagnoses were associated with P/LP carrier status for all 4 genes ( KCNE1 OR 22.8, p=1.0e-4; KCNH2 OR 35.1, p=1.8e-7; KCNQ1 OR 27.3, p=3.6e-18; SCN5A OR 5.6, p=0.02). Carriers of SCN5A P/LP variants were also more likely to have PVCs (OR 4.3, p=0.003). Sensitivity analyses showed the associations predated the RoR. EHRs included a diagnosis of LQTS or Brugada Syndrome in 11/71 (16%) pre-RoR, and 16 more were diagnosed after RoR (27/71, 38%). A total of 47/71 (66%) participants had a documented arrhythmia phenotype 1 year after RoR, although 20 of these participants were not diagnosed with an inherited arrhythmia syndrome. Conclusion: Inherited arrhythmia diagnoses could be established in nearly half of participants with P/LP variants. These data indicate that return of incidental P/LP variants in these genes may facilitate the early diagnosis of arrhythmias.