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

Dau Ming Niu, Betau Hwang, Han Wei Hwang, Nana H. Wang, Jer Yuarn Wu, Pi Chang Lee, Jen Chung Chien, Ru Chi Shieh, Yuan Tsong Chen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)817-821
Number of pages5
JournalJournal of Medical Genetics
Volume43
Issue number10
DOIs
StatePublished - Oct 2006

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