Genetic counseling in sudden arrhythmia death syndrome : the science and the art

Abstract

Background: Sudden arrhythmia death syndrome (SADS) is a genotypically and phenotypically heterogeneous condition that might produce fatal ventricular arrhythmia in otherwise healthy individuals. Congenital long QT syndrome (LQTS) is the most common type of SADS with a frequency of 1 in 2500 individuals. Up to 13 genes have been shown to be associated with LQTS and genetic testing has a role in disease diagnosis, prognostication, treatment guidance, cascade testing, and reproductive counseling. Interdisciplinary care is the standard but such service is unavailable in Hong Kong. Objectives: In this study, we aim to evaluate the clinical characteristics of a local cohort of pediatric patients with LQTS, establish the practicability of a model on interdisciplinary delivery of care for SADS, and explore the process of genetic counseling in Chinese families with LQTS from the perspective of discourse analysis. Method: Pediatric patients with LQTS and their families were recruited from the Department of Paediatric Cardiology, Queen Mary Hospital between 1 January 2011 and 31 December 2012. With informed consent, patients underwent genetic testing for 6 LQTS genes (KCNQ1, KCNH2, SCN5A, KCNE1, KCNE2, KCNJ2). Clinical characteristics were documented and the process of pre-test and post-test counseling was videotaped and transcribed. Data was mapped and analyzed for discourse strategies in the focal themes of uncertainty management in risk communication. Results: 19 patients were identified, 9 were male, with the corrected QT interval (QTc) ranging from 460-619ms. Mode of presentation included syncope (n=9), ventricular tachycardia (n=2), convulsion (n=1) and as incidental finding (n=7). Pathogenic mutations were identified in 9 patients (LQT1=3, LQT2=4, LQT3=1, LQT5=1), likely pathogenic mutations in 2 (LQT2), unclassified variants in 2, and no mutation in 6. Patients with pathogenic and likely pathogenic mutations had significantly longer mean QTc than those without such mutations (p=0.046). Three mutations, all in the LQT2 genes, represented novel mutations. All 3 patients with mutations in the pore-looping forming domains of the KCNH2 (LQT2) channel had personal or family histories of malignant arrhythmia or sudden cardiac death compatible with previously reported genotype-phenotype correlation. Eight families involving 18 family members underwent cascade testing, and family mutations were identified in 10 individuals from 6 families. Autosomal dominant transmission was the likely mode of inheritance in these 6 families. Counseling sessions involved the joint input from clinical geneticist, genetic counsellor and pediatric cardiologist. Discourse analysis on 2 counseling sessions of a selected family with unclassified variants revealed increased uncertainty after genetic testing in the index patient and family members. Strategies used to mitigate uncertainty included abstraction, generalization and categorization. Conclusion: Genetic testing was crucial in the comprehensive assessment of patients with congenital LQTS, and we demonstrated a feasible model to delivery interdisciplinary care for patients with SADS in Hong Kong. The process of genetic counseling is highly complex and deserves further examination.