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      Recent advances in genetic testing and counseling for inherited arrhythmias

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          Abstract

          Inherited arrhythmias, such as cardiomyopathies and cardiac ion channelopathies, along with coronary heart disease (CHD) are three most common disorders that predispose adults to sudden cardiac death. In the last three decades, causal genes in inherited arrhythmias have been successfully identified. At the same time, it has become evident that the genetic architectures are more complex than previously known. Recent advancements in DNA sequencing technology (next generation sequencing) have enabled us to study such complex genetic traits.

          This article discusses indications for genetic testing of patients with inherited arrhythmias. Further, it describes the benefits and challenges that we face in the era of next generation sequencing. Finally, it briefly discusses genetic counseling, in which a multidisciplinary approach is required due to the increased complexity of the genetic information related to inherited arrhythmias.

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          Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias.

          Peter J. Schwartz, Silvia G Priori, Carla Spazzolini … (2001)
          The congenital long-QT syndrome (LQTS) is caused by mutations on several genes, all of which encode cardiac ion channels. The progressive understanding of the electrophysiological consequences of these mutations opens unforeseen possibilities for genotype-phenotype correlation studies. Preliminary observations suggested that the conditions ("triggers") associated with cardiac events may in large part be gene specific. We identified 670 LQTS patients of known genotype (LQT1, n=371; LQT2, n=234; LQT3, n=65) who had symptoms (syncope, cardiac arrest, sudden death) and examined whether 3 specific triggers (exercise, emotion, and sleep/rest without arousal) differed according to genotype. LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. These percentages were almost reversed among LQT2 and LQT3 patients, who were less likely to have events during exercise (13%) and more likely to have events during rest/sleep (29% and 39%). Lethal and nonlethal events followed the same pattern. Corrected QT interval did not differ among LQT1, LQT2, and LQT3 patients (498, 497, and 506 ms, respectively). The percent of patients who were free of recurrence with ss-blocker therapy was higher and the death rate was lower among LQT1 patients (81% and 4%, respectively) than among LQT2 (59% and 4%, respectively) and LQT3 (50% and 17%, respectively) patients. Life-threatening arrhythmias in LQTS patients tend to occur under specific circumstances in a gene-specific manner. These data allow new insights into the mechanisms that relate the electrophysiological consequences of mutations on specific genes to clinical manifestations and offer the possibility of complementing traditional therapy with gene-specific approaches.
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            Long-term prognosis of patients diagnosed with Brugada syndrome: Results from the FINGER Brugada Syndrome Registry.

            C Wolpert, M Haïssaguerre, Elisabeth A. Wilde … (2010)
            Brugada syndrome is characterized by ST-segment elevation in the right precordial leads and an increased risk of sudden cardiac death (SCD). Fundamental questions remain on the best strategy for assessing the real disease-associated arrhythmic risk, especially in asymptomatic patients. The aim of the present study was to evaluate the prognosis and risk factors of SCD in Brugada syndrome patients in the FINGER (France, Italy, Netherlands, Germany) Brugada syndrome registry. Patients were recruited in 11 tertiary centers in 4 European countries. Inclusion criteria consisted of a type 1 ECG present either at baseline or after drug challenge, after exclusion of diseases that mimic Brugada syndrome. The registry included 1029 consecutive individuals (745 men; 72%) with a median age of 45 (35 to 55) years. Diagnosis was based on (1) aborted SCD (6%); (2) syncope, otherwise unexplained (30%); and (3) asymptomatic patients (64%). During a median follow-up of 31.9 (14 to 54.4) months, 51 cardiac events (5%) occurred (44 patients experienced appropriate implantable cardioverter-defibrillator shocks, and 7 died suddenly). The cardiac event rate per year was 7.7% in patients with aborted SCD, 1.9% in patients with syncope, and 0.5% in asymptomatic patients. Symptoms and spontaneous type 1 ECG were predictors of arrhythmic events, whereas gender, familial history of SCD, inducibility of ventricular tachyarrhythmias during electrophysiological study, and the presence of an SCN5A mutation were not predictive of arrhythmic events. In the largest series of Brugada syndrome patients thus far, event rates in asymptomatic patients were low. Inducibility of ventricular tachyarrhythmia and family history of SCD were not predictors of cardiac events.
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              Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome.

              Nikki Plaster, Rabi Tawil, Martin Tristani-Firouzi … (2001)
              Andersen's syndrome is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. We have mapped an Andersen's locus to chromosome 17q23 near the inward rectifying potassium channel gene KCNJ2. A missense mutation in KCNJ2 (encoding D71V) was identified in the linked family. Eight additional mutations were identified in unrelated patients. Expression of two of these mutations in Xenopus oocytes revealed loss of function and a dominant negative effect in Kir2.1 current as assayed by voltage-clamp. We conclude that mutations in Kir2.1 cause Andersen's syndrome. These findings suggest that Kir2.1 plays an important role in developmental signaling in addition to its previously recognized function in controlling cell excitability in skeletal muscle and heart.
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                Author and article information

                Contributors
                Yuka Mizusawa
                Journal
                Journal ID (nlm-ta): J Arrhythm
                Journal ID (iso-abbrev): J Arrhythm
                Title: Journal of Arrhythmia
                Publisher: Elsevier
                ISSN (Print): 1880-4276
                ISSN (Electronic): 1883-2148
                Publication date PMC-release: 05 February 2016
                Publication date (Print): October 2016
                Publication date (Electronic): 05 February 2016
                Volume: 32
                Issue: 5
                Pages: 389-397
                Affiliations
                [0005]Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Room K2-115, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands
                Author notes
                [* ]Tel.: +31 20 56 64682. Y.Mizusawa@ 123456amc.uva.nl
                Article
                Publisher ID: S1880-4276(16)00011-9
                DOI: 10.1016/j.joa.2015.12.009
                PMC ID: 5063262
                SO-VID: 5a117ea9-e108-4f9c-83cf-0f78c92213bb
                Copyright © © 2016 The Author
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 9 September 2015
                Date revision received : 1 December 2015
                Date accepted : 17 December 2015
                Categories
                Subject: Review

                Keywords: arvd/c, arrhythmogenic right ventricular dysplasia/cardiomyopathy,brs, brugada syndrome,chd, coronary heart disease,cpvt, catecholaminergic polymorphic ventricular tachycardia,dcm, dilated cardiomyopathy,gwas, genome wide association study,hcm, hypertrophic cardiomyopathy,hf, heart failure,icd, implantable cardioverter defibrillator,ngs, next generation sequencing,lqts, long qt syndrome,scd, sudden cardiac death,va, ventricular arrhythmia,vf, ventricular fibrillation,wes, whole exome sequencing,inherited arrhythmias,genetic testing,cardiac ion channelopathies,cardiomyopathies,genetic counseling
                Data availability:
                Keywords: arvd/c, arrhythmogenic right ventricular dysplasia/cardiomyopathy, brs, brugada syndrome, chd, coronary heart disease, cpvt, catecholaminergic polymorphic ventricular tachycardia, dcm, dilated cardiomyopathy, gwas, genome wide association study, hcm, hypertrophic cardiomyopathy, hf, heart failure, icd, implantable cardioverter defibrillator, ngs, next generation sequencing, lqts, long qt syndrome, scd, sudden cardiac death, va, ventricular arrhythmia, vf, ventricular fibrillation, wes, whole exome sequencing, inherited arrhythmias, genetic testing, cardiac ion channelopathies, cardiomyopathies, genetic counseling

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