Introduction: Sudden arrhythmic death syndrome (SADS) arises through disorders of ion channel function or structural heart disease. It accounts for over 400 deaths in the UK per annum. To date there has been no comprehensive analysis of the diagnostic yield and efficacy of a family screening approach in SADS index cases where the post mortem heart is structurally normal after expert pathological review.
Methods: 118 SADS families where the SADS victim died between 1 and 35 years of age were evaluated in a systematic family screening programme between 2003–2006. All SADS index cases had a structurally normal heart after expert review of all available tissue. All studied relatives underwent resting, signal averaged ECG, 24h Holter, exercise ECG with V0
2
max, transthoracic echocardiography and an ajmaline challenge test after initial clinical screening. Systematic mutation analysis was performed on the known long QT (LQT)genes including SCN5A & ryanodine receptor/ARVC genes when clinically suspected.
Results: The most common modes of death were rest in 28%, sleep in 25% and exercise in 18%. Clinical screening identified an inherited electrical cause of SADS in 41 of the 118 families (35%)-20 Brugada, 18 LQT Syndrome, 3 Catecholiminergic Polymorphic Ventricular Tachycardia (CPVT). Structural heart disease was identified in 5 ARVC & 2 DCM families. 26 ICDs have been implanted in affected family members-4 LQTS, 7 Brugada, 2 CPVT, 2 ARVC, 2 DCM and 9 on clinical grounds without a definitive diagnosis. The ECG (37%) and ajmaline challenge test (49%) had the highest diagnostic yield in families with a positive diagnosis. To date, genetic testing has increased the diagnostic yield by 5% (6/118 families-2 KCNQ1, 1 HERG, 2 SCN5A, 1 ARVC ), confirming a clinical diagnosis in 6.6%–3 KCNQ1, 3 SCN5A, 1 HERG, 1 KCNH2.
Conclusions: Systematic clinical screening in relatives of SADS victims has a diagnostic yield of 35% increasing to 40% with genetic testing. Electrical causes of SADS predominate in these families. These findings demonstrate that a systematic clinical screening programme in SADS families is both achievable and effective. The full impact of gene testing (including RyR mutations) upon diagnostic yield is awaited.
Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing
