Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Autism & Developmental Medicine Institute, Geisinger, Danville, Pennsylvania, USA.
Hum Mutat. 2022 Aug;43(8):1031-1040. doi: 10.1002/humu.24291. Epub 2021 Nov 15.
Understanding whether there is enough evidence to implicate a gene's role in a given disease, as well as the mechanisms by which variants in this gene might cause this disease, is essential to determine clinical relevance. The National Institutes of Health-funded Clinical Genome Resource (ClinGen) has developed evaluation frameworks to assess both the strength of evidence supporting a relationship between a gene and disease (gene-disease validity), and whether loss (haploinsufficiency) or gain (triplosensitivity) of individual genes or genomic regions is a mechanism for disease (dosage sensitivity). ClinGen actively applies these frameworks across multiple disease domains, and makes this information publicly available via its website (https://www.clinicalgenome.org/) for use in multiple applications, including clinical variant classification. Here, we describe how the results of these curation processes can be utilized to inform the appropriate application of pathogenicity criteria for both sequence and copy number variants, as well as to guide test development and inform genomic filtering pipelines.
了解基因在特定疾病中的作用是否有足够的证据，以及该基因变异如何导致这种疾病的机制，对于确定临床相关性至关重要。美国国立卫生研究院资助的临床基因组资源（ClinGen）已经开发了评估框架，以评估基因与疾病之间关系的证据强度（基因-疾病有效性），以及单个基因或基因组区域的缺失（单倍不足）或获得（三倍体敏感性）是否是疾病的机制（剂量敏感性）。ClinGen 在多个疾病领域积极应用这些框架，并通过其网站（https://www.clinicalgenome.org/）公开这些信息，用于多种应用，包括临床变异分类。在这里，我们描述了如何利用这些策展过程的结果来告知序列和拷贝数变异致病性标准的适当应用，以及指导测试开发和告知基因组筛选管道。
