Integration of 60,000 exomes and ACMG guidelines question the role of Catecholaminergic Polymorphic Ventricular Tachycardia‐associated variants

• Published in: Clinical genetics Vol. 91; no. 1; pp. 63 - 72
• Main Authors: Paludan‐Müller, C., Ahlberg, G., Ghouse, J., Herfelt, C., Svendsen, J.H., Haunsø, S., Kanters, J.K., Olesen, M.S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-01-2017
• Subjects: ACMG; Alleles; American Medical Association; Cardiac arrhythmia; Catecholaminergic Polymorphic Ventricular Tachycardia; CPVT; Databases, Genetic; Electrocardiography; ExAC; Exome - genetics; Gene Frequency; Genetic Predisposition to Disease - genetics; Genetics; Genetics, Medical; Genomics; Genotype; Guidelines as Topic; HGMD; Humans; Mutation; Polymorphism, Single Nucleotide; Tachycardia, Ventricular - genetics; United States; Genetics; ACMG; Catecholaminergic Polymorphic Ventricular Tachycardia; CPVT; ExAC; HGMD
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1111/cge.12847

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is a highly lethal cardiac arrhythmia disease occurring during exercise or psychological stress. CPVT has an estimated prevalence of 1:10,000 and has mainly been associated with variants in calcium‐regulating genes. Identification of potential false‐positive pathogenic variants was conducted by searching the Exome Aggregation Consortium (ExAC) database (n = 60,706) for variants reported to be associated with CPVT. The pathogenicity of the interrogated variants was assessed using guidelines from the American College of Medical Genetics and Genomics (ACMG) and in silico prediction tools. Of 246 variants 38 (15%) variants previously associated with CPVT were identified in the ExAC database. We predicted the CPVT prevalence to be 1:132. The ACMG standards classified 29% of ExAC variants as pathogenic or likely pathogenic. The in silico predictions showed a reduced probability of disease‐causing effect for the variants identified in the exome database (p < 0.001). We have observed a large overrepresentation of previously CPVT‐associated variants in a large exome database. Based on the frequency of CPVT in the general population, it is less likely that the previously proposed variants are associated with a highly penetrant monogenic form of the disease.