Yield of Molecular and Clinical Testing for Arrhythmia Syndromes: Report of a 15 Years' Experience
Background—Sudden cardiac death (SCD) is often caused by inherited arrhythmia syndromes, particularly if occurring at young age. In 1996, we started a cardiogenetics clinic aimed at diagnosing such syndromes, and providing timely (often presymptomatic) treatment to families in which such syndromes and/or SCD exist. We studied the yield of DNA testing for these syndromes using a candidate gene approach over our 15 years' experience.
Methods and Results—We analyzed the yield of DNA testing. In sub-analyses, we studied differences in the yield of DNA testing over time, between probands with 'isolated' or 'familial' cases, and between probands with or without clear disease-specific clinical characteristics. In sudden unexplained death cases (SUD, antemortem or postmortem analysis of the deceased not performed or providing no diagnosis), we analyzed the yield of cardiologic investigations. Among 7021 individuals who were counseled, 6944 from 2298 different families (41±19 years, 49% male) were analyzed. In 702 families (31%), a possible disease-causing mutation was detected. Most mutations were found in families with Long QT syndrome (47%) or hypertrophic cardiomyopathy (46%). Cascade-screening revealed 1539 mutation-positive subjects. The mutation detection rate decreased over time, partially because probands with a less severe phenotype were studied, and was significantly higher in familial than isolated cases. We counseled 372 families after SUD. In 29% (n=108) of them, an inherited arrhythmia syndrome was diagnosed.
Conclusions—The proportion of disease-causing mutations found decreased over time, partially because probands with a less severe phenotype were studied. Systematic screening of families identified many (often presymptomatic) mutation-positive subjects.
- Cardiogenetics, genetic counseling, predictive genetic testing
- sudden cardiac death
- genetic testing
- Received November 22, 2012.
- Revision received July 31, 2013.
- Accepted August 5, 2013.