Clinical Impact of Genetic Studies in Lethal Inherited Cardiac Arrhythmias

Abstract

Over the past decade, molecular genetic studies have established a link between a number of inherited cardiac arrhythmias, including congenital long QT syndrome (LQTS) and Brugada syndrome (BrS), and mutations in genes encoding for ion channels or other membrane components. Twelve forms of LQTS have been identified in 50-70% of clinically affected patients. Genotype -phenotype correlations have been rigorously investigated in LQT1, LQT2 and LQT3 syndromes, which constitute more than 90% of genotyped LQTS patients, enabling stratification of risk and effective treatment of genotyped patients. Genotype-specific triggers for both the cardiac events and the clinical course have been reported, and genotype-specific therapy has been already introduced. More recently, mutation site-specific differences in the clinical phenotype have been reported in LQT1 and LQT2 patients, indicating the possibility of mutation site-specific management or treatment. In contrast, only one-third of BrS patients can be genotyped, and data on genotype -phenotype relationships in clinical studies are limited. A Haplotype B consisting of 6 individual DNA polymorphisms within the proximal promoter region of the SCN5A gene was recently identified only in Asians (frequency 22%). Individuals with Haplotype B show significantly longer duration of both PQ and QRS than those without Haplotype B, indicating that Haplotype B likely contributes to the higher incidence of BrS in Asian populations. (Circ J 2008; 72: 1926 -1936

Update of Diagnosis and Management of Inherited Cardiac Arrhythmias

“…1 Among such inherited cardiac arrhythmias, congenital LQTS is a Rosetta stone for investigating the genotype-phenotype correlations, because multiple genes encoding the different ion channels or membrane adaptors have been identified by genetic screening in approximately 50-80% of subjects with clinically diagnosed congenital LQTS. 1 Mutations in the cardiac RyR2 gene or calsequestrin gene can be found in approximately 60% of typical CPVT patients with associated bidirectional and/or multifocal ventricular tachycardia (VT).…”

“…1 Among such inherited cardiac arrhythmias, congenital LQTS is a Rosetta stone for investigating the genotype-phenotype correlations, because multiple genes encoding the different ion channels or membrane adaptors have been identified by genetic screening in approximately 50-80% of subjects with clinically diagnosed congenital LQTS. 1 Mutations in the cardiac RyR2 gene or calsequestrin gene can be found in approximately 60% of typical CPVT patients with associated bidirectional and/or multifocal ventricular tachycardia (VT). 1 Therefore, genotype-phenotype correlations have been rigorously investigated, especially in patients with congenital LQTS, and genetic testing has now become the gold standard for the diagnosis or LQTS, which enables us to stratify the risk of cardiac events and to manage LQTS patients theoretically and appropriately.…”

“…1 Therefore, genotype-phenotype correlations have been rigorously investigated, especially in patients with congenital LQTS, and genetic testing has now become the gold standard for the diagnosis or LQTS, which enables us to stratify the risk of cardiac events and to manage LQTS patients theoretically and appropriately. 1 However, the responsible mutations have been identified in only a small number of patients with other inherited cardiac arrhythmias. 1 In BrS, the first mutation was identified in an α subunit of the sodium channel gene, SCN5A, in 1998, 2 but a world-wide cohort study has reported that mutations in the major player, SCN5A, can be identified in only 11-28% of clinically diagnosed BrS patients.…”

Prevalence of the Brugada-Type Electrocardiogram and Incidence of Brugada Syndrome in Patients With Sick Sinus Syndrome

“…[1][2][3][4][5][6] Clinical examples of such an "overlap syndrome" have been reported among LQT3, BS, and cardiac conduction defect or SSS. [1][2][3]6,7 Recent reports have indicated that the loss of function of single SCN5A mutations can be responsible for both BS and SSS. [9][10][11] A functional defect of the sodium current could account for BS and a conduction disturbance in sinoatrial region.…”

Abnormal Atrial Repolarization and Depolarization Contribute to the Inducibility of Atrial Fibrillation in Brugada Syndrome

“…1) Several studies have demonstrated that some patients with Brugada syndrome have mutations in the gene that encodes the α subunit of the sodium channel. 2,3) More recent studies have shown the association between the syndrome and mutations in genes that encode the α and β subunits of the calcium channel 4) and the gene that encodes glycerol-3-phosphate dehydrogenase 1-like enzyme.…”