Compound heterozygous CASQ2 mutations and long‐term course of catecholaminergic polymorphic ventricular tachycardia

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited cardiac disorder characterized by episodic ventricular tachycardia during adrenergic stimulation. It is associated with significant morbidity and mortality. Knowledge of the underlying genetic cause, pathogenesis, and the natural history of the disease remains incomplete. Approximately 50% of CPVT cases are caused by dominant mutations in the cardiac ryanodine receptor (RYR2) gene, <5% of cases are accounted for by recessive mutations in cardiac calsequestrin (CASQ2) or Triadin (TRDN). METHODS: We report a family with two CASQ2 gene mutations. A research‐based next‐generation sequencing (NGS) initiative was used in a patient with a severe CPVT phenotype and her clinically unaffected son. Reverse transcription polymerase chain reaction (RT‐PCR) from platelet RNA was used to assess the consequences of predicted splice variants. RESULTS: NGS revealed that the proband carried a novel c.199C>T (p.Gln67*) mutation and a previously reported splice site mutation c.532+1G>A in CASQ2. Her son is a heterozygous carrier of the c.199C>T (p.Gln67*) mutation alone and the proband was compound heterozygous at CASQ2. RNA analysis demonstrated that the splice site mutation results in the retention of intron 3 with no full‐length CASQ2 mRNA. CONCLUSION: This study describes a novel CPVT genotype and further characterizes the effect of a previously reported CASQ2 splice site mutation. The long‐term follow‐up of 23 years since first symptom provides additional insight into the natural history of CASQ2‐associated CPVT.