Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome.
Reappraisal of Reported Genes for Sudden Arrhythmic Death: Evidence-Based Evaluation of Gene Validity for Brugada Syndrome.
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DOI：
10.1161/circulationaha.118.035070
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发表时间：
2018-09-18
期刊：
影响因子：
37.8
通讯作者：
National Institutes of Health Clinical Genome Resource Consortium
中科院分区：
文献类型：
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作者：
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;National Institutes of Health Clinical Genome Resource Consortium
补充数字内容可在文本中找到。对疑似遗传性疾病患者进行遗传评估的隐含假设是，根据强有力的科学和统计证据，评估的基因是疾病的病因。然而，在过去的20年中，研究设计和支持报告的基因-疾病关联的证据质量存在相当大的差异，引起了对许多已发表的致病基因有效性的担忧。Brugada综合征（BrS）是一种心律失常综合征，具有猝死的风险。据报道，有20多个基因导致了BrS，在缺乏系统的、基于证据的评估证据支持这些基因的因果关系的情况下，基因检测小组对这些基因进行了常规评估。我们通过组建3个基因治疗团队，评估了BrS诊断实验室检测的基因的临床有效性。使用基因-疾病关联的遗传和实验证据的基于证据的半定量评分系统，策展团队独立地将基因分类为显示BrS疾病因果关系的有限，中等，强或明确证据。策展人团队的分类由临床领域专家小组审查，该专家小组可以根据其独立审查和共识修改分类。在为临床有效性而策划的21个基因中，生物鉴定者仅将1个基因（SCN 5A）归类为确定性证据，而所有其他基因均归类为有限证据。经过临床领域专家小组的全面审查，所有20个被归类为有限证据的基因被重新归类为关于BrS疾病因果关系的任何断言有争议的基因。我们的研究结果的临床有效性，但1基因临床测试和报告与BrS。这些发现保证了在用于患者护理之前对报告的基因-疾病关联进行系统的循证评价。
Supplemental Digital Content is available in the text. 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.