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. 2018 Sep 18;138(12):1195-1205.
doi: 10.1161/CIRCULATIONAHA.118.035070.

Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome

S Mohsen Hosseini  1 , Raymond Kim  1   2   3 , Sharmila Udupa  4 , Gregory Costain  2 , Rebekah Jobling  1   2 , Eriskay Liston  1   2 , Seema M Jamal  2 , Marta Szybowska  3 , Chantal F Morel  3 , Sarah Bowdin  1   2 , John Garcia  5 , Melanie Care  6 , Amy C Sturm  7 , Valeria Novelli  8 , Michael J Ackerman  9 , James S Ware  10 , Ray E Hershberger  11 , Arthur A M Wilde  12   13 , Michael H Gollob  4   6   14 ; National Institutes of Health Clinical Genome Resource Consortium
Affiliations

Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome

S Mohsen Hosseini et al. Circulation. .

Abstract

Background: Implicit in the genetic evaluation of patients with suspected genetic diseases is the assumption that the genes evaluated are causative for the disease based on robust scientific and statistical evidence. However, in the past 20 years, considerable variability has existed in the study design and quality of evidence supporting reported gene-disease associations, raising concerns of the validity of many published disease-causing genes. Brugada syndrome (BrS) is an arrhythmia syndrome with a risk of sudden death. More than 20 genes have been reported to cause BrS and are assessed routinely on genetic testing panels in the absence of a systematic, evidence-based evaluation of the evidence supporting the causality of these genes.

Methods: We evaluated the clinical validity of genes tested by diagnostic laboratories for BrS by assembling 3 gene curation teams. Using an evidence-based semiquantitative scoring system of genetic and experimental evidence for gene-disease associations, 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 that could modify the classifications based on their independent review and consensus.

Results: Of 21 genes curated for clinical validity, biocurators classified only 1 gene ( SCN5A) as definitive evidence, whereas all other genes were classified as limited evidence. After comprehensive review by the clinical domain Expert panel, all 20 genes classified as limited evidence were reclassified as disputed with regard to any assertions of disease causality for BrS.

Conclusions: Our results contest the clinical validity of all but 1 gene clinically tested and reported to be associated with BrS. These findings warrant a systematic, evidence-based evaluation for reported gene-disease associations before use in patient care.

Keywords: Brugada syndrome; genetics; sudden death.

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Figures

Figure 1.
Figure 1.
Genes included on clinical gene test panels for Brugada syndrome. Thirty multigene panels exclusively offered for Brugada syndrome were analyzed. The x axis shows the number of panels including each gene. Bars are color coded based on the labs offering the test. A list of labs is provided in the legend to the right of the graph. *The 2 Brugada syndrome panels testing for ANK3 and CACNA1D have marked them as “candidate genes with no evidence, but likely to be related to the phenotype.” formula imageLabPLUS offers a panel for BrS types 2, 5, 7, which does not include SCN5A, CACNA1C, and CACNB2.
Figure 2.
Figure 2.
Clinical validity classifications and matrix scores for Brugada syndrome gene associations. Of the 21 Brugada syndrome genes (y-axis) curated, only SCN5A reached definitive classification; all other genes were classified as limited. Each bar represents scores from a single curator group (G) (G1, G2, G3).
Figure 3.
Figure 3.
ClinVar variants for Brugada syndrome by gene and clinical interpretation. A, All variants submitted to ClinVar (http://clinvar.com/) by clinical labs for Brugada syndrome have been plotted (N=1223, excluding 182 variants that were literature only or research). Genes are listed along the y axis, whereas the x axis shows the count of variants for each gene. Bars are color coded based on the clinical classification of variants (see legend). B, The relative proportion of submitted variant interpretation classifications for SCN5A and Limited evidence genes.
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Comment in

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