Concomitant Brugada-like and short QT electrocardiogram linked to SCN5A mutation

Abstract

Mutations in the a-subunit of cardiac sodium channel gene SCN5A can lead to the overlapping phenotypes of both the Brugada and type 3 long QT syndromes. However, the combination of Brugada and a short QT phenotype resulting from mutation in SCN5A has not previously been described. A man with concomitant Brugada-like and short QT electrocardiogram (ECG) was identified and the SCN5A gene was sequenced. Whole-cell patch clamp analysis of human embryo kidney (HEK) 293 cells expressing a SCN5A channel with the patient's sequence was used to investigate the biophysical properties of the channel. The patient with the family history of sudden death showed Brugada-like and short QT interval ECG. Sequence anlaysis of the coding region of the SCN5A gene, identified a G to A heterozygous missense mutation at nucleotide site 2066 that resulted in a amino-acid substitution of arginine to histidine at amino-acid site 689 (R689H). Patch clamp analysis showed that the R689H failed to generate current when heterologously expressed in HEK293 cells, indicating it was a loss-of-function mutation. Our finding firstly showes that a heterozygous missense mutation R689H in SCN5A gene results in the loss of protein function and the coexistents of the Brugada-like and short QT interval ECG phenotypes.

Characterization of 2 Genetic Variants of Nav1.5‐Arginine 689 Found in Patients with Cardiac Arrhythmias

“…It is however obvious that these findings cannot explain the very severe phenotype observed in this family. In addition, these results are difficult to reconcile with the ones from a recent study where no functional expression of this p.R689H variant was observed. We can only speculate on the fact that experimental details such as the plasmids or cells used may be at the origin of this discrepancy.…”

“…When analyzed with the “sorting tolerant from intolerant” (SIFT) algorithm, p.R689H was classified as “damaging,” while the Polyphen software classified it as “benign”; p.R689C was classified as “damaging” by SFIT and “possibly damaging” using Polyphen . These 2 variants were already reported several times in the literature (summarized in Table ), either in patients with LQTS or BrS, or in individuals from control cohorts.…”

“…In this study, the p.R689H variant was found in 5 females from a single Russian family with a history of sudden cardiac death (SCD) and cardiac conduction defect (published in Russian language). Notably, this p.R689H variant has been recently studied, since it was found in one asymptomatic Chinese patient with both short QT interval and an ECG with a BrS pattern . When transfected in HEK293 cells, the p.R689H SCN5A variant did not generate any measurable current .…”

“…Notably, this p.R689H variant has been recently studied, since it was found in one asymptomatic Chinese patient with both short QT interval and an ECG with a BrS pattern . When transfected in HEK293 cells, the p.R689H SCN5A variant did not generate any measurable current . The variant p.R689C was previously reported in one patient with LQTS, but thus far, no functional analyses have been performed.…”

Cardiac Ion Channelopathies and the Sudden Infant Death Syndrome

“…Crotti et al [128] identified six patients (4.6%) with a mutation in one of the 12 other genes tested: two with a mutation in CACNB2b and one with a mutation in each of HCN4 , KCND3 , KCNJ8, and SCN1Bb . The low <2% yield of mutations involving the L-type calcium channel genes CACNA1C , CACNB2b, and CACNA2D1 is in contrast with previous findings of 8.5% for CACNA1C and CACNB2b only [131] and 12.3% for CACNA1C , CACNB2b, and CACNA2D1 all three [132] and may be related to the presence of a concomitant short QT interval [128], as in the study by Burashnikov et al [132] and also reported by Hong et al [133]. …”