Reappraisal of reported genes for sudden arrhythmic death: Evidence-based evaluation of gene validity for brugada syndrome

S. Mohsen Hosseini; Raymond Kim; Sharmila Udupa; Gregory Costain; Rebekah Jobling; Eriskay Liston; Seema M. Jamal; Marta Szybowska; Chantal F. Morel; Sarah Bowdin; John Garcia; Melanie Care; Amy C. Sturm; Valeria Novelli; Michael J. Ackerman; James S. Ware; Ray E. Hershberger; Arthur A.M. Wilde; Michael H. Gollob

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, Raymond Kim, Sharmila Udupa, Gregory Costain, Rebekah Jobling, Eriskay Liston, Seema M. Jamal, Marta Szybowska, Chantal F. Morel, Sarah Bowdin, John Garcia, Melanie Care, Amy C. Sturm, Valeria Novelli, Michael J. Ackerman, James S. Ware, Ray E. Hershberger, Arthur A.M. Wilde, Michael H. Gollob

Cardiovascular Medicine

Research output: Contribution to journal › Article › peer-review

112 Scopus citations

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 genedisease associations before use in patient care.

Original language	English (US)
Pages (from-to)	1195-1205
Number of pages	11
Journal	Circulation
Volume	138
Issue number	12
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.118.035070
State	Published - 2018

Keywords

Brugada syndrome
Genetics
Sudden death

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine
Physiology (medical)

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10.1161/CIRCULATIONAHA.118.035070

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Hosseini, S. M., Kim, R., Udupa, S., Costain, G., Jobling, R., Liston, E., Jamal, S. M., Szybowska, M., Morel, C. F., Bowdin, S., Garcia, J., Care, M., Sturm, A. C., Novelli, V., Ackerman, M. J., Ware, J. S., Hershberger, R. E., Wilde, A. A. M., & Gollob, M. H. (2018). Reappraisal of reported genes for sudden arrhythmic death: Evidence-based evaluation of gene validity for brugada syndrome. Circulation, 138(12), 1195-1205. https://doi.org/10.1161/CIRCULATIONAHA.118.035070

Hosseini, SM, Kim, R, Udupa, S, Costain, G, Jobling, R, Liston, E, Jamal, SM, Szybowska, M, Morel, CF, Bowdin, S, Garcia, J, Care, M, Sturm, AC, Novelli, V, Ackerman, MJ, Ware, JS, Hershberger, RE, Wilde, AAM & Gollob, MH 2018, 'Reappraisal of reported genes for sudden arrhythmic death: Evidence-based evaluation of gene validity for brugada syndrome', Circulation, vol. 138, no. 12, pp. 1195-1205. https://doi.org/10.1161/CIRCULATIONAHA.118.035070

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title = "Reappraisal of reported genes for sudden arrhythmic death: Evidence-based evaluation of gene validity for brugada syndrome",

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 genedisease associations before use in patient care.",

keywords = "Brugada syndrome, Genetics, Sudden death",

author = "Hosseini, {S. Mohsen} and Raymond Kim and Sharmila Udupa and Gregory Costain and Rebekah Jobling and Eriskay Liston and Jamal, {Seema M.} and Marta Szybowska and Morel, {Chantal F.} and Sarah Bowdin and John Garcia and Melanie Care and Sturm, {Amy C.} and Valeria Novelli and Ackerman, {Michael J.} and Ware, {James S.} and Hershberger, {Ray E.} and Wilde, {Arthur A.M.} and Gollob, {Michael H.}",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors.",

year = "2018",

doi = "10.1161/CIRCULATIONAHA.118.035070",

language = "English (US)",

volume = "138",

pages = "1195--1205",

journal = "Circulation",

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TY - JOUR

T1 - Reappraisal of reported genes for sudden arrhythmic death

T2 - Evidence-based evaluation of gene validity for brugada syndrome

AU - Hosseini, S. Mohsen

AU - Kim, Raymond

AU - Udupa, Sharmila

AU - Costain, Gregory

AU - Jobling, Rebekah

AU - Liston, Eriskay

AU - Jamal, Seema M.

AU - Szybowska, Marta

AU - Morel, Chantal F.

AU - Bowdin, Sarah

AU - Garcia, John

AU - Care, Melanie

AU - Sturm, Amy C.

AU - Novelli, Valeria

AU - Ackerman, Michael J.

AU - Ware, James S.

AU - Hershberger, Ray E.

AU - Wilde, Arthur A.M.

AU - Gollob, Michael H.

PY - 2018

Y1 - 2018

N2 - 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 genedisease associations before use in patient care.

AB - 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 genedisease associations before use in patient care.

KW - Brugada syndrome

KW - Genetics

KW - Sudden death

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Reappraisal of reported genes for sudden arrhythmic death: Evidence-based evaluation of gene validity for brugada syndrome

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