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

Abstract

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. Thirty-eight out of 246 variants (15%) 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.

We identified a total of 246 CPVT-associated variants, of which 33 variants (15%) were identified in a large exome database (ExAC) (Figure 1). We analyzed the pathogenicity of the variants with the use of four in Silico prediction tools (Figure 2). All prediction tools, except Grantham Scare, significantly predicted variants found in ExAC to be less likely pathogenic . The same overall results were observed for the agreement of damage predicting scores. The variants identified in ExAC were considered less likely pathogenic.

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