Novel homozygous CASQ2-mutation in a family with catecholaminergic polymorphic ventricular tachycardia and sinus node dysfunction: Clinical and pharmacological stratification of a rare entity

Background

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life threatening heritable arrhythmic disease which is primarily caused by RYR2-gene mutations (type 1). Homozygous CASQ2-gene variants (type 2) are an additional rare genetic background. CPVT typically leads to bidirectional or polymorphic ventricular tachycardia (VT) in response to adrenergic stress, with approximately 30% of affected patients suffering cardiac arrest during their lifetime if left untreated. While medical stratification using betablockers and/or flecainide has gained improved evidence, existent data are mainly based on patients suffering from the more frequent form - CPVT type 1. Little is known about stratification and therapy effectiveness in patients with disease-causing variants in rare genes, especially homozygous CASQ2-variants. 

 

Clinical Report

A young female patient was admitted to an external clinic after survived sudden cardiac death primarily caused by asystole. During cardiopulmonary resuscitation using adrenaline the patient presented recurrent polymorphic ventricular arrhythmias requiring defibrillations. After stabilization a cardiac-CT ruled out coronary occlusion or anomalies and a cardiac-MRI revealed a slightly reduced systolic function, while overt structural anomalies or significant fibrosis were excluded. An implanted cardioverter-defibrillator was implanted to protect the patient from future arrhythmic events. She was referred to our ambulance for additional investigation of the arrhythmia background. The arrhythmogenic response to adrenaline suggested a stress-induced arrhythmic syndrome leading us to performing an exercise stress test (bicycle ergometry), which provoked non-sustained VT under low level physical stress (75 Watt). 

Next-generation sequencing using an established panel of arrhythmia genes unraveled a previously undescribed homozygous missense variant in the CASQ2-gene (p.Trp261Gly) with a rare allele frequency (<0.0005). A combined drug therapy of flecainide and propranolol reduced the arrhythmia burden during physical stress and assured patient well-being without stress-induced symptoms. Family screening identified another affected family member with a history of stress-induced dizziness and pre-syncope, homozygously carrying the variant. Clinical workup revealed a similar phenotype characterized by sinus bradycardia, lack of functional or structural cardiac abnormalities and stress-induced bidirectional and polymorphic non-sustained VT, provokable by stress-test (75-100 Watt). Due to sinus-bradycardia the patient tolerated only small propranolol dosages, but stepwise up-titration of flecainide resulted in lack of clinical symptoms and absence of VT under physical stress. Of note, tested unaffected family members showed the variant in a heterozygous form. 

 

Conclusion

We present a family with a combined clinical phenotype of sinus node dysfunction and CPVT caused by a novel homozygous CASQ2 missense variant. Affected patients were successfully treated with a regimen primarily based on flecainide using only small dosages of betablocker. This clinical report extends knowledge of CPVT therapy to a rare entity of homozygous CASQ2-mutation carriers. In addition, molecular analyses using patient-specific iPSC-CMs are in progress to evaluate the underlying arrhythmia mechanisms and provide the basis for individualized pharmacological testing to optimize drug treatment of our patients.