Abstract 13280: Genetic Variants Previously Associated with Brugada Syndrome in Newly Exome Data
Introduction: Today, hundreds of variants in 13 genes have been associated with Brugada Syndrome (BrS), which is considered a monogenic disorder with a prevalence between 1:2.000 and 1:100.000. Until recently, the knowledge of genetic variations in the general populations has been limited, but newly published data from the NHLI GO Exome Sequencing Project (ESP) has provided important insight into this. In ESP next-generation sequencing was performed in all protein-coding regions in persons from different population studies. Using ESP, we aimed to identify possible false positive variants previously associated with BrS.
Methods: We performed a search in ESP for variants previously associated with BrS. Functional data and familial co-segregation was recorded. In addition, the four most prevalent variants in ESP were genotyped using Taqman assays in a second Danish control population (n=534) with available ECGs. The ECGs were examined for BrS type 1 pattern by two physicians independently.
Results: In ESP we identified 31 out of 263 (11.8%) variants previously associated with BrS. All variants were missense and affected 180 alleles in 5245 individuals. If they all are heterozygote carriers with only one variant, it corresponds to a prevalence of 1:29 in the ESP population. Functional data and familial co-segregation were rarely present. Genotyping the four most common variants, CACNA2D1 S709N; CACNB2 S143F, T450I and SCN5A F2004L revealed a similar prevalence compared to ESP. The ECGs in these patients with a mean age of 63 years (range 56-66) showed no BrS type 1 pattern.
Conclusion: Some variants previously associated with BrS are most likely false-positive. If these variants were truly disease causing, this would correspond to a possible prevalence of BrS in 1:29 in the general population. We suggest that ESP data are used in research and in the everyday clinical practice to test the likelihood of pathogenicity of novel variants in patients suspected for BrS.
- © 2012 by American Heart Association, Inc.