P2A227: When Genetics Change Management: Identification of a Novel Mutation Causing Catecholaminergic Polymorphic Ventricular Tachycardia

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial syndrome that causes ventricular tachycardia, generally in the absence of structural heart disease. Defects in the cardiac ryanodine receptor (RyR2) are known to be associated with CPVT. RyR2 is primarily found in cardiac myocytes and assists with cardiac muscle contraction. Here, we present a case of CPVT caused by a novel mutation in RyR2 identified by Critical Whole Trio Exome Sequencing (Critical Trio WES) during the patient’s critical care admission.

Case Description: A previously healthy 16 year-old male presented in cardiac arrest after moderate exertional exercise. At the scene, bystander CPR was started, emergency medical services arrived, and the patient was found to be in ventricular fibrillation. In both pre- and in-hospital resuscitations, he received a total of five rounds of unsynchronized cardiac defibrillation and multiple resuscitation medications with return of spontaneous circulation (ROSC). During continued resuscitation in the ED, he again became pulseless, and rhythm was pulseless electrical activity. Time of death was called approximately 1.5 hours after the initial event with cardiac standstill was confirmed twice using bedside ultrasound. Approximately five minutes later, patient noted to have agonal breathing by parents. Carotid pulse was palpable, resuscitation resumed, and ROSC was achieved.

Echocardiogram demonstrated normal biventricular function and coronary anatomy. As his condition stabilized, he was started on nadolol and flecainide and underwent left cardiac sympathetic denervation with plans for implantable cardiac defibrillator placement.

Family history was notable for a brother who died at the age of ten years from Sudden Unexplained Death in Epilepsy as well as palpitations and syncope in his 45-year-old biological mother.

Critical Trio WES was positive for an autosomal dominant variant in RYR2. The variant was a c.6957_6959deletion (exon 46 of 105), resulting in a valine deletion at position 2321 located towards the N-terminal of the RyR2 protein. This variant was also identified in his biological mother and deceased brother.

Discussion: This patient was previously healthy and found to have a novel RyR2 mutation on Trio WES during ICU admission. Use of Trio WES has been shown to alter therapeutic interventions in up to 81% of patients that received testing and decrease time to diagnosis when used urgently in critical care settings. This case supports the use of Trio WES for patients with unclear etiologies of cardiac arrest during their ICU admission. For this patient, there was discussion about genetic testing through other means, including channelopathy panels, which would not have yielded the ultimate diagnosis given his novel mutation. These results ultimately led to significant alterations in his treatment plan.

Conclusion: Providers should consider Trio WES for critically ill patients to guide management, family counseling, and utilization of critical care resources.