Mendelian rare genetic diseases affect 5-10% of the population, and with over 5,300 genes responsible for ∼7,000 different diseases, they are challenging to diagnose. The use of whole genome sequencing (WGS) has bolstered the diagnosis rate significantly. Effective use of WGS relies upon 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 which 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 which 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.

中文翻译：

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GeneBreaker：变异模拟可改善孟德尔罕见遗传病的诊断

孟德尔罕见的遗传病影响着5-10％的人口，并且有5300多个基因与7,000种不同的疾病有关，因此难以诊断。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基因破坏的能力。该过程涉及基因组变异的调用和优先排序，并且受益于测序技术，变异调用方法的改进以及对具有潜在致病性的基因变异进行优先排序的能力的提高。随着分析流程的不断改进，对其有效性进行仔细测试至关重要。但是，现实生活中的案例通常会轶事出现，规范和限制了临床敏感和可识别数据用于测试管道改进的利用。我们确定了对基于基因的变体模拟框架的需求，该框架可以利用已知的病原体变体或通过创建新的破坏基因的变体来创建模拟罕见疾病。为满足这一需求，我们介绍了GeneBreaker，该工具可创建合成的罕见病病例，可用于对变种调用方法进行基准测试，测试变种优先级的功效，以及作为在扩展的基因组医学领域培训诊断从业人员的教育机制。GeneBreaker可从http://GeneBreaker.cmmt.ubc.ca免费获得。利用已知的病原体变体或通过创建新的破坏基因的变体。为了满足这一需求，我们介绍了GeneBreaker，该工具可创建合成的罕见病病例，可用于对变种调用方法进行基准测试，测试变种优先级的功效，以及作为在扩展的基因组医学领域培训诊断从业人员的教育机制。GeneBreaker可从http://GeneBreaker.cmmt.ubc.ca免费获得。利用已知的病原体变体或通过创建新的破坏基因的变体。为了满足这一需求，我们介绍了GeneBreaker，该工具可创建合成的罕见病病例，可用于对变种调用方法进行基准测试，测试变种优先级的功效，以及作为在扩展的基因组医学领域培训诊断从业人员的教育机制。GeneBreaker可从http://GeneBreaker.cmmt.ubc.ca免费获得。并作为一种教育机制，在不断扩大的基因组医学领域培训诊断从业人员。GeneBreaker可从http://GeneBreaker.cmmt.ubc.ca免费获得。并作为一种教育机制，在不断扩大的基因组医学领域培训诊断从业人员。GeneBreaker可从http://GeneBreaker.cmmt.ubc.ca免费获得。