Abstract
Mutations in the α-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 analysis 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 shows 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.