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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.
- Source :
-
Journal of medical genetics [J Med Genet] 2006 Oct; Vol. 43 (10), pp. 817-21. Date of Electronic Publication: 2006 May 17. - Publication Year :
- 2006
-
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.
- Subjects :
- Adolescent
Adult
Aged
Asian People genetics
Cardiovascular Abnormalities genetics
Child, Preschool
DNA Mutational Analysis
Death, Sudden, Cardiac etiology
Electrocardiography
Humans
Infant
Middle Aged
NAV1.5 Voltage-Gated Sodium Channel
Pedigree
Phenotype
Codon, Nonsense physiology
Heart Conduction System abnormalities
Heart Diseases genetics
Muscle Proteins genetics
Polymorphism, Genetic
Sodium Channels genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1468-6244
- Volume :
- 43
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of medical genetics
- Publication Type :
- Academic Journal
- Accession number :
- 16707561
- Full Text :
- https://doi.org/10.1136/jmg.2006.042192