Molecular genetics of Brugada syndrome

Abstract

Brugada syndrome (BrS) is a life-threatening cardiac rhythm disorder characterized by persistent STsegment elevation in leads V1-V3 and right bundle branch block on electrocardiograms (ECG), and by syncope and sudden death from ventricular tachycardia (VT) and ventricular fibrillation (VF). BrS is responsible for nearly 4% of sudden cardiac deaths and considered to be the most common cause of natural death in males younger than 50 years in some Asian countries. Since the first diseasecausing gene for BrS (the cardiac sodium channel gene SCN5A) was identified in 1998, extensive investigations on both clinical and basic aspects of BrS have occurred rapidly. SCN5A mutations remain the most common cause of BrS; nearly 300 SCN5A mutations have been identified and are responsible for 20%-30% of BrS cases. Commercial genetic testing is available for SCN5A. Recently, seven other disease-causing genes for BrS have been identified and include GPD1L (BrS2), CACNA1C (Cav1.2, BrS3), CACNB2 (Cavβ2, BrS4), SCN1B (Navβ1, BrS5), KCNE3 (MiRP2, BrS6), SCN3B (Navβ3, BrS7), and HCN4 (BrS8). This article will briefly review the progress made over the past decade in our understanding of the clinical, genetic and molecular aspects of BrS.

Inherited Interstitial Deletion of 3p22.3—p23 Involving GPD1L Gene

“…While GPD1L has been anecdotally showed to account for 11%-12% of Brugada syndrome, other studies showed no pathogenic GPD1L mutation, suggesting that GPD1L may not be a major cause of Brugada syndrome. 16,17 On the DECIPHER database (https://decipher.sanger.ac.uk/ search?q=GPD1L#consented-patients/ results), 8 other patients had deletions involving GPD1L. These were much larger deletions than in our cases.…”

Brugada syndrome in a family with a high mortality rate: a case report

“…Whereas the prevalence of GPD1L mutations is estimated to be 11% to 12%, SCN5A mutations are found in 18% to 30% of BrS patients, and these variations currently represent the most common BrS genotype [3]. To date, approximately 300 mutations in the SCN5A gene have been described in association with BrS.…”

“…In addition to SCN5A alterations, mutations in the glycerol-3-phosphate dehydrogenase 1-like ( GPD1L ) gene cause abnormal trafficking of the cardiac sodium channel to the cell surface and a reduction of approximately 50% of the inward sodium current. To date, mutations in the SCN5A and GPD1L genes are estimated to account for approximately 18% to 30% and 11% to 12% of BrS probands, respectively; the prevalence of variants in other disease-related genes (such as CACNA1C , CACNB2 , SCN1B , KCNE3 , SCN3B , and HCN4 ) is yet unknown [3]. …”

Brugada syndrome: a fatal disease with complex genetic etiologies – still a long way to go

“…Another study [ 36 ] showed that the GPD1-L mutation itself causes a loss function of enzymatic activity, and decreased GPD1-L activity would have then increased the substrate G3P, and fed the PKC-mediated phosphorylation of SCN5A at S1503 where such phosphorylation was known to decrease I Na . A study showed that GPD1-L gene accounted for 11%–12% BrS probands [ 37 ], but other studies showed no identification on any missense GPD1-L gene mutation, suggesting that GPD1-L may not be a major cause of BrS [ 38 , 39 ]. Further studies are needed to obtain the accurate prevalence of GPD1-L variants in BrS.…”