Abstract 3399: Primary Inherited Electrical Heart Disease: Yield of Molecular Genetic Testing in Familial and Isolated Cases: A Ten Year Experience in the Netherlands
Introduction The congenital long QT syndrome (LQTS), Brugada syndrome (BS) and cat-echolaminergic polymorphic ventricular tachycardia (CPVT) are primary inherited cardiac arrhythmia syndromes which may cause syncope and sudden cardiac death in young individuals.
Purpose To study the yield of molecular genetic testing in familial and isolated index-cases.
Methods and Results In 1996–2005, we counseled 219 probands with a clinical diagnosis of LQTS, BS or CPVT in our outpatient Cardiogenetic Clinic. We studied how often a mutation was detected in these patients, and compared (Chi-square or Fisher’s Exact Test) the proportions of molecular diagnoses between isolated cases and familial cases (>1 clinically affected individual or a family history of unexplained sudden death at age ≤40 years). Among probands, a molecular diagnosis was reached in 51% (n=111): LQTS 61% (78/128), BS 36% (25/70), CPVT 38% 8/21). In all diseases, the yield of molecular genetic testing in probands was significantly higher in familial cases than in isolated cases, as follows. LQTS: 90% (61/68) vs.28% (17/60, p<0,001); BS: 50% (17/34) vs. 22% (8/36, p=0,015); CPVT: 75% (6/8) vs. 15% (2/13, p=0,018). Subsequently, cascade screening was performed in 946 relatives of all 111 probands with a disease causing mutation. The disease causing mutation was identified in 395 relatives: i.e. on average 3.7/family.
Conclusions Genetic testing in suspected primary inherited electrical heart disease in probands revealed a molecular substrate in 51% (LQTS 61%, BS 36%, and CPVT 38%). In all three diseases, mutation detection was significantly higher in familial cases than in isolated cases. Cascade screening in primary electrical heart disease resulted in identification of on average 3.7 mutation carriers per family, allowing for timely treatment.