The E1784K mutation in SCN5A is associated with mixed clinical phenotype of type 3 long QT syndrome

Abstract

Phenotypic overlap of type 3 long QT syndrome (LQT3) with Brugada syndrome (BrS) is observed in some carriers of mutations in the Na channel SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A. Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction. Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. These results suggest that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and BrS and further indicate that class IC drugs should be avoided in patients with Na channels displaying these behaviors.

Identification of Six Novel SCN5A Mutations in Japanese Patients With Brugada Syndrome

“…The genetic analysis identified an E1784K mutation in SCN5A ( Figure 1C, Table), the prevalent SCN5A mutation in both type 3 long QT syndrome (LQT3) and BrS. 12,17,18) Patient B29, a 25-year-old male patient, had an episode of syncope. A saddle-back ST elevation in the precordial lead was present in an ECG ( Figure 1D), but a drug provocation test was not performed.…”

“…The presence of SCN5A mutations is not related to the severity of the disease. 9,10,12) However, Meregalli, et al have recently reported that the type of SCN5A mutation in BrS1 in European countries may determine the clinical severity. 13) Because the clinical features of BrS vary among different ethnicities, 14,15) it is of great value to investigate the genotype-phenotype relationship of BrS in Asians in whom the ratio of BrS patients is relatively high compared to subjects from different ethnic backgrounds.…”

The genetic basis of Brugada syndrome: A mutation update

“…The following conditions, which can account for the ECG changes and syncope, should be excluded: atypical right bundle branch block; left ventricular hypertrophy; early repolarization; acute pericarditis; acute myocardial ischemia or infarction; pulmonary embolism; Printzmetal angina; dissecting aortic aneurysm; central or peripheral nervous system abnormalities; Duchenne muscular dystrophy; thiamine deficiency; hyperkalemia; hypercalcemia; arrhythmogenic right ventricular cardiomyopathy; pectus excavatum; hypothermia, or mechanical compression of the right outflow tract (RVOT) as seen with mediastinal tumors or hemopericardium. Adapted from the 2005 consensus paper [Antzelevitch et al, 2007], BrS with conduction disease (CCD) [Rossenbacker et al, 2004], BrS with LQTS, CCD, and dilated cardiomyopathy (DCM) and combinations thereof, have been described elsewhere [Makita et al, 2008;Olson et al, 2005].…”

“…In the clinical sudden infant and adult death syndromes (SIDS and SADS), mutations are also found in SCN5A Behr et al, 2008;Wang et al, 2007]. Mixed phenotypes, where SCN5A mutations are associated with a combination of hereditary arrhythmias and structural heart disease, have also been described [Makita et al, 2008;Olson et al, 2005;Rossenbacker et al, 2004].…”

The role of genetic testing in unexplained sudden death

“…85 Conversely, although gain-of-function SCN5A mutations are found in LQT3, an overlap in phenotype exists between BrS and LQTS, both having been described in large families. 67 In addition, there are large SCN5A positive families that have affected individuals who are noncarriers, suggesting a modifier role rather than direct causation in these pedigrees. 86 Many other genes have been associated with the syndrome (Table I).…”