A common SCN5A polymorphism attenuates a severe cardiac phenotype caused by a nonsense SCN5A mutation in a Chinese family with an inherited cardiac conduction defect.

Journal Article (Journal Article)

The SCN5A mutations have been associated with a variety of arrhythmic disorders, including type 3 long QT syndrome (LQT3), Brugada syndrome and inherited cardiac conduction defects. The relationship between genotype and phenotype in SCN5A mutations is complex. Some SCN5A mutations may cause death or severe manifestations in some people and may not cause any symptoms or arrhythmias in others. The causes of these unpredictable clinical manifestations remain incompletely understood. The molecular basis of a four-generation family with cardiac conduction abnormalities was studied and whether variants in the SCN5A gene could account for the cardiac phenotypic variability observed in this family was determined. A novel mutation (W1421X) of SCN5A was identified in a four-generation family with cardiac conduction abnormalities and several cases of sudden death. Most family members who carry this W1421X mutation have developed major clinical manifestations or electrocardiographic abnormalities, both of which became more prominent as the patients grew older. However, the 73-year-old grandfather, who carried both the W1421X and R1193Q mutations, had thus far remained healthy and presented with only subtle electrocardiographic abnormalities, whereas most of his offspring, who carried a single mutation (W1421X), had died early or had major disease manifestations. This observation suggests that the R1193Q mutation has a complementary role in alleviating the deleterious effects conferred by W1421X in the function of the SCN5A gene. This report provides a good model to explain the mechanism of penetrance of genetic disorders.

Full Text

Duke Authors

Cited Authors

  • Niu, D-M; Hwang, B; Hwang, H-W; Wang, NH; Wu, J-Y; Lee, P-C; Chien, J-C; Shieh, R-C; Chen, Y-T

Published Date

  • October 2006

Published In

Volume / Issue

  • 43 / 10

Start / End Page

  • 817 - 821

PubMed ID

  • 16707561

Pubmed Central ID

  • PMC2563172

Electronic International Standard Serial Number (EISSN)

  • 1468-6244

Digital Object Identifier (DOI)

  • 10.1136/jmg.2006.042192


  • eng

Conference Location

  • England