TY - JOUR
T1 - New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia
AU - Jabbari, Javad
AU - Jabbari, Reza
AU - Nielsen, Morten Wagner
AU - Holst, Anders G
AU - Nielsen, Jonas B
AU - Haunsø, Stig
AU - Tfelt-Hansen, Jacob
AU - Svendsen, Jesper H
AU - Olesen, Morten S
PY - 2013/10
Y1 - 2013/10
N2 - 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.
AB - 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.
U2 - 10.1161/CIRCGENETICS.113.000118
DO - 10.1161/CIRCGENETICS.113.000118
M3 - Journal article
C2 - 24025405
SN - 1942-3268
VL - 6
SP - 481
EP - 489
JO - Circulation. Cardiovascular Genetics (Online)
JF - Circulation. Cardiovascular Genetics (Online)
IS - 5
ER -
