The investigation of sudden arrhythmic death syndrome (SADS)—the current approach to family screening and the future role of genomics and stem cell technology

Abstract

SADS is defined as sudden death under the age of 40 years old in the absence of structural heart disease. Family screening studies are able to identify a cause in up to 50% of cases-most commonly long QT syndrome (LQTS), Brugada and early repolarization syndrome, and catecholaminergic polymorphic ventricular tachycardia (CPVT) using standard clinical screening investigations including pharmacological challenge testing. These diagnoses may be supported by genetic testing which can aid cascade screening and may help guide management. In the current era it is possible to undertake molecular autopsy provided suitable samples of DNA can be obtained from the proband. With the evolution of rapid sequencing techniques it is possible to sequence the whole exome for candidate genes. This major advance offers the opportunity to identify novel causes of lethal arrhythmia but also poses the challenge of managing the volume of data generated and evaluating variants of unknown significance (VUS). The emergence of induced pluripotent stem cell technology could enable evaluation of the electrophysiological relevance of specific ion channel mutations in the proband or their relatives and will potentially enable screening of idiopathic ventricular fibrillation survivors combining genetic and electrophysiological studies in derived myocytes. This also could facilitate the assessment of personalized preventative pharmacological therapies. This review will evaluate the current screening strategies in SADS families, the role of molecular autopsy and genetic testing and the potential applications of molecular and cellular diagnostic strategies on the horizon.

Effective cascade screening through identification of a mutation in RYR2 in a large family with a history of sudden death

“…CPVT usually presents in the first or second decade of life. The molecular basis of CPVT is due to mutations in RYR2 in 50-60% of affected individuals [1]. The phenotype is variable [7] and penetrance among RYR2 mutation carriers is incomplete, estimated to be 78% [4].…”

“…It is a genetically heterogeneous condition which is usually inherited in an autosomal dominant pattern. Mutations in RYR2 are identified in 50-60% of cases [1]. A rare recessive form of CPVT is due to mutations in calsequestrin 2 (CASQ2).…”

Utility of Exome Sequencing in A Familial Trio as A Diagnostic Tool in Cardiomyopathies

“…It is due to the lack of current data [27]. A genetic cause can be identified only in 35-45% of HCM patients and this increased to 60-65%, when family history is positive for HCM.…”

Exploring the Discussion of Risk of Sudden Cardiac Death

“…An individual's death is attributed to sudden arrhythmic death syndrome (SADS) in cases of SCD where a structural heart defect is not present [17]. Numerous studies have investigated the incidence of SADS; the estimated prevalence of SADS ranges from 0.16 to 0.24 per 100,000 people per year in the general population to 0.76 per 100,000 people per year in individuals aged 14-35 [10,17].…”