Identification of a novel exon3 deletion of RYR2 in a family with catecholaminergic polymorphic ventricular tachycardia

Background RYR2 , encoding cardiac ryanodine receptor, is the major responsible gene for catecholaminergic polymorphic ventricular tachycardia (CPVT). Meanwhile, KCNJ2 , encoding inward‐rectifier potassium channel (I K1 ), can be the responsible gene for atypical CPVT. We recently encountered a family with CPVT and sought to identify a responsible gene variant. Methods A targeted panel sequencing (TPS) was employed in the proband. Copy number variation (CNV) in RYR2 was identified by focusing on read numbers in the TPS and long‐range PCR. Cascade screening was conducted by a Sanger method and long‐range PCR. KCNJ2 wild‐type (WT) or an identified variant was expressed in COS‐1 cells, and whole‐cell currents (I K1 ) were recorded using patch‐clamp techniques. Results A 40‐year‐old female experienced cardiopulmonary arrest while cycling. Her ECG showed sinus bradycardia with prominent U‐waves (≥0.2 mV). She had left ventricular hypertrabeculation at apex. Exercise induced frequent polymorphic ventricular arrhythmias. Her sister died suddenly at age 35 while bouldering. Her father and paternal aunt, with prominent U‐waves, received permanent pacemaker due to sinus node dysfunction. The initial TPS and cascade screening identified a KCNJ2 E118D variant in all three symptomatic patients. However, after focusing on read numbers, we identified a novel exon3 deletion of RYR2 ( RYR2 ‐exon3 deletion) in all of them. Functional analysis revealed that KCNJ2 E118D generated I K1 indistinguishable from KCNJ2 WT, even in the presence of catecholaminergic stimulation. Conclusions Focusing on the read numbers in the TPS enabled us to identify a novel CNV, RYR2 ‐exon3 deletion, which was associated with phenotypic features of this family.