The burden of cardiac genetic disease in Newfoundland and Labrador: elucidating the pathogenicity and genotype-phenotype profile of a Ryanodine Receptor 2 variant- RYR2 p.Y4962N

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially fatal inherited arrhythmia commonly linked to genetic variants in the Ryanodine Receptor 2 (RYR2) gene. This thesis investigates a Newfoundland family with suspected CPVT brought to attention after the sudden passing of a young individual carrying the RYR2 p.Y4962N variant. This variant was initially classified as likely pathogenic but was later downgraded to a variant of unknown significance (VUS) following updates to American College of Medical Genetics (ACMG) guidelines. A total of 655 family members were ascertained in the extended family pedigree across seven generations, with 93 individuals identified as being at 50% a priori risk of inheriting the RYR2 p.Y4962N variant. RYR2 p.Y4962N was identified in 33 individuals, with 27 individuals testing negative for the variant. Genetic status was unknown for 33 individuals. Four cases of sudden unexplained death (SUD) were identified within the family. However, comprehensive evaluation of the extended pedigree revealed no clear CPVT phenotype. Clinical assessments, including ESTs, ECGs, echocardiograms, and Holter monitoring, showed either no or mild abnormalities across both variant-positive and variant-negative individuals for all cardiac tests. These findings highlight the challenges of variant interpretation and raise the possibility that RYR2 p.Y4962N may be a benign or modifier variant. Functional characterization and investigations into a possible recessive variant may elucidate the genotype-phenotype relationship.