Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Background
- Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in
SCN5A
(mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K-
SCN5A
is the most common
SCN5A
mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and
SCN5A
mutation type on BrS phenotype in BrS families with
SCN5A
mutations.
Methods
- Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring
SCN5A
mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms (SNP) previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132 and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 SNP risk alleles).
Results
- In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio (OR) of 4.15 for BrS phenotype (95%CI:1.45-11.85, p=0.0078). Amongst
SCN5A
-positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio (OR) of 2.35 (95%CI:0.89-6.22, p=0.0846). In
SCN5A
-negative relatives (n=54), BrS-GRS ≥4 alleles yielded and OR of 22.29 (95%CI:1.84-269.30, p=0.0146). Among E1784K-
SCN5A
positive family members (n=79), hosting ≥4 risk alleles gave an OR=5.12 (95%CI:1.93-13.62, p=0.0011).
Conclusions
- Common genetic variation is associated with variable expressivity of BrS phenotype in
SCN5A
families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals.
SCN5A
mutation genotype and a BrS-GRS associate with BrS phenotype but the strength of association varies according to presence of a
SCN5A
mutation and severity of loss of function.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.