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

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder which usually presents in the first or second decade of life with syncope, which is typically induced by emotional stress or exercise. We describe a large family with a history of three sudden unexpected deaths. Investigations in the sibling of a deceased individual affected by emotion-induced syncope revealed ventricular bigeminy. Molecular genetic testing was performed on one symptomatic individual and a missense mutation in RYR2 was identified consistent with a diagnosis of CPVT. Subsequent cascade testing of family members excluded 37 of 43 individuals from risk and facilitated preventative intervention. This case highlights the value of genotyping in sudden cardiac death by defining the precise diagnosis and through the identification and exclusion of at-risk individuals. <Learning objective: The diagnosis of CPVT should be considered in families with a history of sudden death in a previously asymptomatic young person. Cascade molecular genetic testing should be undertaken as, if a pathogenic mutation is found, this can distinguish it from other arrhythmogenic disorders and can identify at-risk individuals allowing treatment to be targeted at those in need, thus helping to reduce the mortality associated with the condition.>