title: New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia.
abstract: BACKGROUND
  Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal, rare hereditary disease with an estimated prevalence of 1:10 000. The genetic variants that cause CPVT are usually highly penetrant. To date, about 189 variants in 5 genes (RYR2, CASQ2, CALM1, TRND, and KCNJ2) have been associated with CPVT pathogenesis.
  
  
  RESULTS
  The Exome Sequencing Project database (ESP; n=6503) was systematically searched for previously published missense and nonsense CPVT-associated variants reported in several comprehensive reviews and in 2 databases: The Human Gene Mutation Database and The Inherited Arrhythmias Database. We used 4 different prediction tools to assess all missense variants previously associated with CPVT and compared the prediction of protein damage between CPVT-associated variants identified in the ESP and those variants not identified in the ESP. We identified 11% of the variants previously associated with CPVT in the ESP population. In the literature, 57% of these variants were reported as novel disease-causing variants absent in the healthy control subjects. These putative CPVT variants were identified in 41 out of 6131 subjects in the ESP population, corresponding to a prevalence of CPVT of up to 1:150. Using an agreement of ≥3, in silico prediction tools showed a significantly higher frequency of damaging variants among the CPVT-associated variants not identified in the ESP database (83%) compared with those variants identified in the ESP (50%; P=0.021).
  
  
  CONCLUSIONS
  We identified a substantial overrepresentation of CPVT-associated variants in a large exome database, suggesting that these variants are not necessarily the monogenic cause of CPVT.
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia.
authors.forename: Javad
authors.initials: J
authors.lastname: Jabbari
authors.forename: Reza
authors.initials: R
authors.lastname: Jabbari
authors.forename: Morten W
authors.initials: MW
authors.lastname: Nielsen
authors.forename: Anders G
authors.initials: AG
authors.lastname: Holst
authors.forename: Jonas B
authors.initials: JB
authors.lastname: Nielsen
authors.forename: Stig
authors.initials: S
authors.lastname: Haunsø
authors.forename: Jacob
authors.initials: J
authors.lastname: Tfelt-Hansen
authors.forename: Jesper H
authors.initials: JH
authors.lastname: Svendsen
authors.forename: Morten S
authors.initials: MS
authors.lastname: Olesen
mesh_terms: D002147:Calmodulin / Q000235:genetics; D002155:Calsequestrin / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D018389:Codon, Nonsense; D030541:Databases, Genetic; D059472:Exome / Q000235:genetics*; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics; D020125:Mutation, Missense; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D011237:Predictive Value of Tests; D015995:Prevalence; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: C443109:CASQ2 protein, human; D002147:Calmodulin; D002155:Calsequestrin; D002352:Carrier Proteins; D018389:Codon, Nonsense; C489457:KCNJ2 protein, human; D009124:Muscle Proteins; D024661:Potassium Channels, Inwardly Rectifying; D019837:Ryanodine Receptor Calcium Release Channel; C498269:TRDN protein, human
keywords: CPVT; catecholaminergic polymorphic ventricular tachycardia; exome sequencing database; genetic heart disease; genetic testing; human gene mutation database; variants