New Exome Data Question the Pathogenicity of Genetic Variants Previously Associated With Catecholaminergic Polymorphic Ventricular Tachycardia
| Autor: | Javad Jabbari, Olesen, Jens Nielsen, Jacob Tfelt-Hansen, Anders G. Holst, Morten Wagner Nielsen, Stig Haunsø, Jesper Hastrup Svendsen, Reza Jabbari |
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| Rok vydání: | 2013 |
| Předmět: |
Genotype
Population Mutation Missense Muscle Proteins Biology Gene mutation Catecholaminergic polymorphic ventricular tachycardia Calmodulin Gene Frequency Predictive Value of Tests Databases Genetic Prevalence Genetics medicine Calsequestrin Humans Missense mutation Exome Potassium Channels Inwardly Rectifying education Gene Genetics (clinical) Exome sequencing Genetic testing education.field_of_study medicine.diagnostic_test business.industry Genetic variants Genetic disorder Genetic Variation Cardiac arrhythmia Ryanodine Receptor Calcium Release Channel Pathogenicity medicine.disease Codon Nonsense Tachycardia Ventricular Carrier Proteins business Cardiology and Cardiovascular Medicine |
| Zdroj: | Circulation: Cardiovascular Genetics. 6:481-489 |
| ISSN: | 1942-3268 1942-325X |
| DOI: | 10.1161/circgenetics.113.000118 |
| Popis: | 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. Methods and 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. |
| Databáze: | OpenAIRE |
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