Familial cardiological and targeted genetic evaluation: low yield in sudden unexplained death and high yield in unexplained cardiac arrest syndromes

Abstract

Background: It has been reported that cardiological screening and genetic evaluation in relatives of families with sudden unexplained death syndrome and unexplained cardiac arrest (UCA) may uncover a heritable etiology in a significant proportion of families.

Objective: To evaluate the yield of a comprehensive evaluation protocol of a large unselected cohort of consecutive families with autopsy-negative sudden unexplained death syndrome (termed sudden arrhythmic death syndrome [SADS]) and UCA.

Methods: We studied (1) 109 consecutive families (411 relatives) referred with 1 or more sudden deaths in the family and (2) 52 consecutive probands with UCA (91 relatives) referred by cardiologists between January 2007 and December 2012. A comprehensive cardiological screening was performed followed by targeted genetic evaluation if a clinical phenotype was proven or suspected. Diagnosis was made by a multidisciplinary team using published clinical criteria.

Results: A diagnosis was made in 19 of 109 families with SADS (yield 18%), with the majority having long QT syndrome (LQTS). Diagnosis varied according to proband age, with LQTS most common in the very young (≤20 years) and Brugada syndrome in the older age probands (≥40 years) (P = .03). In contrast, a diagnosis was made in 32 of 52 families with UCA (yield 62%), the majority of which had LQTS and Brugada syndrome. No clinical or circumstantial factors increased the likelihood of diagnosis in families with either SADS or UCA.

Conclusions: In contrast to previously published series, a comprehensive strategy of cardiological evaluation and targeted genetic testing in more than 100 families with SADS was found to have a lower diagnostic yield (18%). Diagnostic yield in families with UCA was approximately 4 times higher (62%), which is consistent with the published literature.

Keywords: ARVC; BrS; Brugada syndrome; CPVT; Cardiological screening; ECG; ER; EST; Genetic testing; HCM; LQTS; Long QT syndrome; MRI; SADS; SQT; SUDS; Sudden arrhythmic death syndrome; Sudden unexplained death syndrome; UCA; Unexplained cardiac arrest; arrhythmogenic right ventricular cardiomyopathy; catecholaminergic polymorphic ventricular tachycardia; early repolarization; electrocardiography/electrocardiogram; exercise stress test; hypertrophic cardiomyopathy; long QT syndrome; magnetic resonance imaging; short QT syndrome; sudden arrhythmic death syndrome; sudden unexplained death syndrome; unexplained cardiac arrest.