Impact of RNA testing on cardiac variant interpretation and patient management

The identification of the substrate of idiopathic ventricular fibrillation (VF) in the absence of structural heart disease or electrocardiographic changes remains a challenge for patient management and family counseling. The availability of expanded genetic testing panels and clinical exome screening has not led to a significant increase in the identification of genetic causes of these events, as shown by recent reports.1, 2 Indeed, the majority of studies detected only a small number of genetic variants1, 2 that could explain a sudden cardiac arrest event. Additionally, most variants still remain classified as “of unknown significance” and do not provide information useful for mechanistic understanding and cascade screening. Variants of unknown significance (VUS) of particular complex adjudication are those located at, and possibly altering, RNA splicing sites. RNA testing is thus critical in characterizing splicing alterations and could provide more precise insights compared to in silico prediction algorithms alone. We present here a case of idiopathic VF where RNA studies on the patient’s blood cells helped revise the adjudication of a VUS, providing valuable insights and implications for cascade screening.