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Davogustto, Giovanni E; Glazer, Andrew; Shaffer, Christian M; Farber-Eger, Eric; Dikilitas, Ozan; Ning, Shang; Pacheco, Jennifer; Mosley, Jonathan; Van Driest, Sara; Wells, Quinn; Rinke, Lauren L; Kalash, Olivia; Wada, Yuko; Bland, Sarah; Yoneda, Zachary T; Kroncke, Brett; Iftikhar, Kullo; Jarvik, Gail P; Gordon, Adam; LARSON, eric B; Manolio, Teri A; Mirshahi, Tooraj; Luo, Jonathan; Schaid, Daniel; [...]

Abstract 14663: High Rate of Arrhythmia Diagnoses Following Return of Pathogenic/likely Pathogenic Variants in an Unselected Population

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  • Media type: E-Article
  • Title: Abstract 14663: High Rate of Arrhythmia Diagnoses Following Return of Pathogenic/likely Pathogenic Variants in an Unselected Population
  • Contributor: Davogustto, Giovanni E; Glazer, Andrew; Shaffer, Christian M; Farber-Eger, Eric; Dikilitas, Ozan; Ning, Shang; Pacheco, Jennifer; Mosley, Jonathan; Van Driest, Sara; Wells, Quinn; Rinke, Lauren L; Kalash, Olivia; Wada, Yuko; Bland, Sarah; Yoneda, Zachary T; Kroncke, Brett; Iftikhar, Kullo; Jarvik, Gail P; Gordon, Adam; LARSON, eric B; Manolio, Teri A; Mirshahi, Tooraj; Luo, Jonathan; Schaid, Daniel; [...]
  • Published: Ovid Technologies (Wolters Kluwer Health), 2020
  • Published in: Circulation, 142 (2020) Suppl_3
  • Language: English
  • DOI: 10.1161/circ.142.suppl_3.14663
  • ISSN: 0009-7322; 1524-4539
  • Keywords: Physiology (medical) ; Cardiology and Cardiovascular Medicine
  • Origination:
  • Footnote:
  • Description: 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.
  • Access State: Open Access