TY - JOUR

T1 - Integration of 60,000 exomes and ACMG guidelines question the role of Catecholaminergic Polymorphic Ventricular Tachycardia-associated variants

AU - Paludan-Müller, Christian

AU - Ahlberg, Gustav

AU - Ghouse, Jonas

AU - Herfelt, Cecilie

AU - Svendsen, Jesper H

AU - Haunsø, Stig

AU - Kanters, Jørgen Kim

AU - Olesen, Morten S

N1 - This article is protected by copyright. All rights reserved.

PY - 2017/1

Y1 - 2017/1

N2 - 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.

AB - 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.

U2 - 10.1111/cge.12847

DO - 10.1111/cge.12847

M3 - Journal article

C2 - 27538377

VL - 91

SP - 63

EP - 72

JO - Clinical Genetics

JF - Clinical Genetics

SN - 0009-9163

IS - 1

ER -