doi: 10.1161/CIRCRESAHA.109.199752
© 2009 American Heart Association, Inc.
Editorials |
Genetic Modulation of Impaired Cardiac Conduction
Sodium Channel β4 Subunit Missing in Action
From the Division of Genetic Medicine, Departments of Medicine and Pharmacology, and the Institute for Integrative Genomics, Vanderbilt University School of Medicine, Nashville, Tenn.
Correspondence to Alfred L. George, Jr, MD, Division of Genetic Medicine, 529 Light Hall, Vanderbilt University School of Medicine, 2215 Garland Ave, Nashville, TN 37232-0275. E-mail al.george@vanderbilt.edu
See related article, pages 1283–1292
Key Words: sodium channel • SCN5A • arrhythmia • gene expression
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
Inherited disorders of heart rhythm and cardiac conduction have received tremendous attention during the past 15 years. The discovery of mutations in several genes, mostly encoding subunits of ion channels, has revealed the molecular basis for various familial arrhythmia susceptibility syndromes and enabled deployment of clinical genetic testing to identify at-risk persons. Proper risk stratification in these settings is crucial for selecting the most appropriate treatments for individual patients, but knowledge of the primary mutation does not always help predict risk of serious cardiac events.
With more widespread use of genetic testing in disorders such as the congenital long QT syndrome (LQTS) and Brugada syndrome (BrS) has come the recognition that not all mutation carriers are equally affected.1–4 When asymptomatic mutation carriers belong to a family that segregates a Mendelian phenotype (ie, caused by a single gene defect) such as LQTS, we say that the mutation exhibits "reduced" or "incomplete penetrance." Similarly, certain mutations may confer variable risk of disease expression or variation in the signs and symptoms evident in related individuals ("variable expressivity"). Both incomplete penetrance and variable expressivity are likely attributable to genetic, environmental, or developmental factors that condition the host or help trigger disease onset. Genetic factors distinct from the primary disease-causing mutation are referred to as "modifiers." Identification of genetic modifiers of Mendelian disorders may improve the precision of molecular diagnostics and provide additional clues about disease mechanism. However, the search for genetic modifiers can be quite challenging.
In this issue of Circulation Research, Remme