Gene Validity for Brugada Syndrome

Study Questions:

What is the clinical validity of genes tested by diagnostic laboratories for Brugada syndrome (BrS)?


The investigators used an evidence-based semi-quantitative scoring system of genetic and experimental evidence for gene-disease associations, and curation teams independently classified genes as demonstrating Limited, Moderate, Strong, or Definitive evidence for disease causation in BrS. The classification of curator teams was reviewed by a Clinical Domain Expert Panel who could modify the classifications based on their independent review and consensus. Experimental evidence scores were based on the interpretation and phenotypic relevance of in vitro assays assessing functional alterations of the disease-implicated gene variants, and model organism or rescue studies, as proposed by MacArthur et al.


Of 21 genes curated for clinical validity, biocurators classified only one gene (SCN5A) as Definitive evidence, while all other genes were classified as Limited evidence. Following comprehensive review by the Clinical Domain Expert Panel, all 20 genes classified as Limited evidence were re-classified as Disputed in regards to any assertions of disease causality for BrS.


The authors concluded that their results contest the clinical validity of all but one gene clinically tested and reported to be associated with BrS.


This study challenges the inclusion of 20 genes, out of 21, currently offered for clinical genetic testing for BrS. All three curator teams and the Clinical Domain Expert Panel agreed that only SCN5A has sufficient evidence for causality in BrS to warrant inclusion on clinical genetic testing panels, and that current evidence does not support causality or clinical testing of the 20 additional curated genes. Based on these data, routine genetic evaluation of genes other than SCN5A is not warranted in the clinical care of BrS patients at this time. Furthermore, genetic testing of genes without sufficient evidence supporting causality for BrS may lead to incorrect interpretation of rare variants in these genes and inappropriate/unindicated diagnostic conclusions or interventions for patients and family members.

Keywords: Arrhythmias, Cardiac, Brugada Syndrome, Consensus, Death, Sudden, Death, Sudden, Cardiac, Genetic Testing, Phenotype, Primary Prevention

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