The genetic basis of Brugada syndrome: A mutation update

Abstract

Brugada syndrome (BrS) is a condition characterized by a distinct ST-segment elevation in the right precordial leads of the electrocardiogram and, clinically, by an increased risk of cardiac arrhythmia and sudden death. The condition predominantly exhibits an autosomal dominant pattern of inheritance with an average prevalence of 5:10,000 worldwide. Currently, more than 100 mutations in seven genes have been associated with BrS. Loss-of-function mutations in SCN5A, which encodes the a-subunit of the Na v 1.5 sodium ion channel conducting the depolarizing I Na current, causes 15-20% of BrS cases. A few mutations have been described in GPD1L, which encodes glycerol-3-phosphate dehydrogenase-1 like protein; CACNA1C, which encodes the a-subunit of the Ca v 1.2 ion channel conducting the depolarizing I L,Ca current; CACNB2, which encodes the stimulating b2-subunit of the Ca v 1.2 ion channel; SCN1B and SCN3B, which, in the heart, encodes b-subunits of the Na v 1.5 sodium ion channel, and KCNE3, which encodes the ancillary inhibitory b-subunit of several potassium channels including the Kv4.3 ion channel conducting the repolarizing potassium I to current. BrS exhibits variable expressivity, reduced penetrance, and ''mixed phenotypes,'' where families contain members with BrS as well as long QT syndrome, atrial fibrillation, short QT syndrome, conduction disease, or structural heart disease, have also been described.

Cardiac ion channels

“…Loss-of-function mutations in CACNA1C, as well as mutations in the genes encoding the associated subunits b2 and a2d, account for 12-13% of patients with Brugada syndrome, characterized by an elevated ST segment and increased risk for ventricular fibrillation and sudden cardiac death. 27 In mice, global and cardiac-specific deletion of Cav1.2 is lethal, whereas smooth muscle specific knockout lowered blood pressure and reduced myogenic tone and contractility in isolated small-diameter arteries. 28 A role for Cav1.3 in modulating heart rate has only recently been appreciated.…”

H558R polymorphism in SCN5A is associated with Keshan disease and QRS prolongation in Keshan disease patients

“…The ECG characteristics of loss-of-function mutation-related cardiac diseases, such as BrS1 and PFHB1, include right bundle branch block (RBBB), CRBBB, and ST-T changes, etc. (Brugada et al, 1992;Gussak et al, 1999;Akai et al, 2000;Kyndt et al, 2001;Olson et al, 2005;Hedley et al, 2009;Amin et al, 2010). Interestingly, they are in accordance with the ECG characteristics of KSD, such as bundle branch block, especially CRBBB, and ST elevation as BrS1.…”

Brugada Syndrome Patient Undertaken Brachial Plexus Block

“…Seven genotypes of BS have been characterized, including mutations in cardiac sodium (types 1, 2, 5, and 7), potassium (type 6), and calcium (types 3 and 4) channels [2].…”