Genetics of inherited primary arrhythmia disorders

Abstract

A sudden unexplained death is felt to be due to a primary arrhythmic disorder when no structural heart disease is found on autopsy, and there is no preceding documentation of heart disease. In these cases, death is presumed to be secondary to a lethal and potentially heritable abnormality of cardiac ion channel function. These channelopathies include congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome. In certain cases, genetic testing may have an important role in supporting a diagnosis of a primary arrhythmia disorder, and can also provide prognostic information, but by far the greatest strength of genetic testing lies in the screening of family members, who may be at risk. The purpose of this review is to describe the basic genetic and molecular pathophysiology of the primary inherited arrhythmia disorders, and to outline a rational approach to genetic testing, management, and family screening.

Evaluation and Management of Athletes With Long QT Syndrome

“…It is important to note that LQTS penetrance is variable, meaning genetically positive patients may have a normal or borderline QTc. 20,26,33 These silent mutation carriers accounted for 36% of LQT1 patients, 19% of LQT2 patients, and 10% of LQT3 patients in 1 cohort. 21 Genetic counseling prior to and after genetic testing should be administered so that the patient and family understand the uncertainties of testing interpretation and implications of the results.…”

“…34 In contrast, ventricular repolarization occurs with the activation of the rapid and slow inward delayed rectifier potassium currents, I Kr and I Ks , respectively. 33,34 …”

“…2 A mutated KCNQ1 gene causing a reduction (loss of function) in the I Ks current results in LQT1 by delaying repolarization, thereby prolonging the action potential. 18,25,31,33 The KCNH2 gene on chromosome 7 (locus 7q35-q36) encodes the alpha subunits (hERG) of the voltage-gated potassium channel (Kv11.1) that mediates the rapidly activating component of the repolarizing delayed rectifier current, I Kr . 2 Similar to LQT1, a mutated KCNH2 gene causes a reduction (loss of function) in the I Kr current, resulting in LQT2 by delaying repolarization and prolonging the action potential.…”

“…2 In contrast to LQT1 and LQT2, a gain of function mutation in the SCN5A gene causing increased I Na current results in LQT3 by prolonging the plateau phase of the action potential. 18,25,33 Action potential prolongation and decreases in repolarizing currents cause cytosolic Ca 2+ overload, which facilitates early after-depolarizations and triggering of torsades de pointes (TdP). 18,31,33,34 …”

“…This review will focus on the 3 most prevalent variants of LQTS, namely the autosomal-dominant LQT1-3 syndromes, as they compose 75% to 80% of clinically definite LQTS. 2,33,37 LQT1, LQT2, and LQT3 compose approximately 30% to 35%, 25% to 40%, and 5% to 10% of disease caused by LQTS, respectively. 2 Schwartz et al 30 have estimated the prevalence of LQTS to be approximately 1:2500.…”