Department of Medical Genetics, Center for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
Hum Mutat. 2021 Apr;42(4):346-358. doi: 10.1002/humu.24163. Epub 2021 Feb 10.
Mendelian rare genetic diseases affect 5%-10% of the population, and with over 5300 genes responsible for ∼7000 different diseases, they are challenging to diagnose. The use of whole-genome sequencing (WGS) has bolstered the diagnosis rate significantly. The effective use of WGS relies on the ability to identify the disrupted gene responsible for disease phenotypes. This process involves genomic variant calling and prioritization, and is the beneficiary of improvements to sequencing technology, variant calling approaches, and increased capacity to prioritize genomic variants with potential pathogenicity. As analysis pipelines continue to improve, careful testing of their efficacy is paramount. However, real-life cases typically emerge anecdotally, and utilization of clinically sensitive and identifiable data for testing pipeline improvements is regulated and limiting. We identified the need for a gene-based variant simulation framework that can create mock rare disease scenarios, utilizing known pathogenic variants or through the creation of novel gene-disrupting variants. To fill this need, we present GeneBreaker, a tool that creates synthetic rare disease cases with utility for benchmarking variant calling approaches, testing the efficacy of variant prioritization, and as an educational mechanism for training diagnostic practitioners in the expanding field of genomic medicine. GeneBreaker is freely available at http://GeneBreaker.cmmt.ubc.ca.
孟德尔式罕见遗传病影响了 5%-10%的人群，并且有超过 5300 个基因负责约 7000 种不同的疾病，因此诊断具有挑战性。全基因组测序 (WGS) 的使用大大提高了诊断率。WGS 的有效利用依赖于识别导致疾病表型的异常基因的能力。这一过程涉及基因组变异的调用和优先级排序，并且受益于测序技术、变异调用方法的改进，以及增加对具有潜在致病性的基因组变异进行优先级排序的能力。随着分析管道的不断改进，对其功效进行仔细测试至关重要。然而，实际案例通常是偶然出现的，并且利用临床敏感和可识别的数据来改进测试管道受到监管和限制。我们认识到需要一个基于基因的变异模拟框架，该框架可以创建模拟罕见疾病的情况，利用已知的致病性变异，或通过创建新的基因破坏性变异来实现。为了满足这一需求，我们提出了 GeneBreaker，这是一个工具，可以创建具有实用价值的合成罕见疾病病例，用于基准测试变异调用方法、测试变异优先级排序的效果，以及作为培训基因组医学领域诊断从业者的教育机制。GeneBreaker 可在 http://GeneBreaker.cmmt.ubc.ca 免费获得。
