Yield of Molecular and Clinical Testing for Arrhythmia Syndromes: Report of 15 Years’ Experience

• Published in: Circulation (New York, N.Y.) N.Y.), 2013-10, Vol.128 (14), p.1513-1521
• Main Authors: Hofman, Nynke, Tan, Hanno L., Alders, Mariëlle, Kolder, Iris, de Haij, Simone, Mannens, Marcel M.A.M., Lombardi, Maria Paola, dit Deprez, Ronald H. Lekanne, van Langen, Irene, Wilde, Arthur A.M.
• Format: Article
• Language: English
• Subjects: Adult; Arrhythmias, Cardiac - diagnosis; Arrhythmias, Cardiac - genetics; Biological and medical sciences; Blood and lymphatic vessels; Brugada Syndrome - genetics; Cardiac dysrhythmias; Cardiology. Vascular system; Cardiomyopathy, Hypertrophic - genetics; Death, Sudden, Cardiac - etiology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; DNA - genetics; DNA Mutational Analysis; Family Health; Female; Forecasting; General aspects. Genetic counseling; Genetic Association Studies; Genetic Counseling; Genetic Testing; Heart; Humans; Long QT Syndrome - genetics; Male; Medical genetics; Medical sciences; Middle Aged; Myocarditis. Cardiomyopathies; Phenotype; Polymorphism, Single-Stranded Conformational; Retrospective Studies; Sequence Analysis, DNA; Syndrome; Young Adult
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.112.000091

BACKGROUND—Sudden cardiac death is often caused by inherited arrhythmia syndromes, particularly if it occurs at a 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 or sudden cardiac death existed. We studied the yield of DNA testing for these syndromes using a candidate-gene approach over our 15 years of experience. METHODS AND RESULTS—We analyzed the yield of DNA testing. In subanalyses, 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 cases of sudden unexplained death (antemortem or postmortem analysis of the deceased not performed or providing no diagnosis), we analyzed the yield of cardiological investigations. Among 7021 individuals who were counseled, 6944 from 2298 different families (aged 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, in part because probands with a less severe phenotype were studied, and was significantly higher in familial than in isolated cases. We counseled 372 families after sudden unexplained death; in 29% of them (n=108), an inherited arrhythmia syndrome was diagnosed. CONCLUSIONS—The proportion of disease-causing mutations found decreased over time, in part because probands with a less severe phenotype were studied. Systematic screening of families identified many (often presymptomatic) mutation-positive subjects.