Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA, USA.
The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Genet Med. 2019 Oct;21(10):2239-2247. doi: 10.1038/s41436-019-0487-0. Epub 2019 Mar 21.
Proper interpretation of genomic variants is critical to successful medical decision making based on genetic testing results. A fundamental prerequisite to accurate variant interpretation is the clear understanding of the clinical validity of gene-disease relationships. The Clinical Genome Resource (ClinGen) has developed a semiquantitative framework to assign clinical validity to gene-disease relationships.
The ClinGen Hearing Loss Gene Curation Expert Panel (HL GCEP) uses this framework to perform evidence-based curations of genes present on testing panels from 17 clinical laboratories in the Genetic Testing Registry. The HL GCEP curated and reviewed 142 genes and 164 gene-disease pairs, including 105 nonsyndromic and 59 syndromic forms of hearing loss.
The final outcome included 82 Definitive (50%), 12 Strong (7%), 25 Moderate (15%), 32 Limited (20%), 10 Disputed (6%), and 3 Refuted (2%) classifications. The summary of each curation is date stamped with the HL GCEP approval, is live, and will be kept up-to-date on the ClinGen website ( https://search.clinicalgenome.org/kb/gene-validity ).
This gene curation approach serves to optimize the clinical sensitivity of genetic testing while reducing the rate of uncertain or ambiguous test results caused by the interrogation of genes with insufficient evidence of a disease link.
正确解读基因组变异对于基于基因检测结果的医疗决策至关重要。准确进行变异解读的一个基本前提是明确理解基因与疾病关系的临床有效性。临床基因组资源（ClinGen）已经开发了一个半定量框架，用于为基因-疾病关系分配临床有效性。
ClinGen 听力损失基因注释专家小组（HL GCEP）使用该框架，对来自遗传测试登记处的 17 个临床实验室的测试面板上的基因进行基于证据的注释。HL GCEP 对 142 个基因和 164 个基因-疾病对进行了注释和审查，包括 105 种非综合征性和 59 种综合征性听力损失。
最终的结果包括 82 个明确的（50%）、12 个有力的（7%）、25 个中等的（15%）、32 个有限的（20%）、10 个有争议的（6%）和 3 个反驳的（2%）分类。每次注释的摘要都带有 HL GCEP 批准的日期戳，是实时的，并将在 ClinGen 网站（https://search.clinicalgenome.org/kb/gene-validity）上保持最新。
这种基因注释方法有助于优化遗传测试的临床灵敏度，同时减少由于对疾病关联证据不足的基因进行询问而导致不确定或模棱两可的测试结果的发生率。
