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

Reappraisal of Reported Genes for Sudden Arrhythmic Death.

Author information

Ted Rogers Cardiac Genome Clinic (S.M.H., R.K., R.J., E.L., S.B.), The Hospital for Sick Children, Toronto, Ontario, Canada.
Division of Clinical and Metabolic Genetics (R.K., G.C., R.J., E.L., S.M.J., S.B.), The Hospital for Sick Children, Toronto, Ontario, Canada.
Fred A. Litwin Family Center in Genetic Medicine, University Health Network, Toronto, Ontario, Canada (R.K., M.S., C.F.M.).
Toronto General Hospital Research Institute, University of Toronto, Ontario, Canada (S.U., M.H.G.).
Invitae Corporation, San Francisco, CA (J.G.).
Peter Munk Cardiac Centre, Department of Medicine (M.C., M.H.G.), Toronto General Hospital, University of Toronto, Ontario, Canada.
Geisinger Health System Genomic Medicine Institute, Danville, PA (A.C.S.).
Centro Benito Stirpe per la Morte Improvvisa del Giovane Atleta, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of the Sacred Heart, Rome, Italy (V.N.).
Departments of Cardiovascular Diseases, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics, Divisions of Heart Rhythm Services and Pediatric Cardiology, Windland Smith Rice Sudden Death Genomics Laboratory, Rochester, MN (M.J.A.).
National Heart and Lung Institute, MRC London Institute of Medical Sciences, Imperial College London, Royal Brompton & Harefield Hospitals, United Kingdom (J.S.W.).
Department of Internal Medicine, Division of Human Genetics and Cardiovascular Division, Ohio State University, Columbus (R.E.H.).
AMC Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands (A.A.M.W.).
Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia (A.A.M.W.). Columbia University Irving Medical Centre, New York (A.A.M.W.).
Department of Physiology, Peter Munk Cardiovascular Molecular Medicine Laboratory (M.H.G.), Toronto General Hospital, University of Toronto, Ontario, Canada.



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.


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.


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.


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.


Brugada syndrome; genetics; sudden death

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