Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA; Brotman-Baty Institute for Precision Medicine, Seattle, WA.
Center for Genetic Medicine Research, Children's National Research Institute, Washington, DC.
Genet Med. 2024 Oct;26(10):101199. doi: 10.1016/j.gim.2024.101199. Epub 2024 Jun 26.
Since the first novel gene discovery for a Mendelian condition was made via exome sequencing, the rapid increase in the number of genes known to underlie Mendelian conditions coupled with the adoption of exome (and more recently, genome) sequencing by diagnostic testing labs has changed the landscape of genomic testing for rare diseases. Specifically, many individuals suspected to have a Mendelian condition are now routinely offered clinical ES. This commonly results in a precise genetic diagnosis but frequently overlooks the identification of novel candidate genes. Such candidates are also less likely to be identified in the absence of large-scale gene discovery research programs. Accordingly, clinical laboratories have both the opportunity, and some might argue a responsibility, to contribute to novel gene discovery, which should, in turn, increase the diagnostic yield for many conditions. However, clinical diagnostic laboratories must necessarily balance priorities for throughput, turnaround time, cost efficiency, clinician preferences, and regulatory constraints and often do not have the infrastructure or resources to effectively participate in either clinical translational or basic genome science research efforts. For these and other reasons, many laboratories have historically refrained from broadly sharing potentially pathogenic variants in novel genes via networks such as Matchmaker Exchange, much less reporting such results to ordering providers. Efforts to report such results are further complicated by a lack of guidelines for clinical reporting and interpretation of variants in novel candidate genes. Nevertheless, there are myriad benefits for many stakeholders, including patients/families, clinicians, and researchers, if clinical laboratories systematically and routinely identify, share, and report novel candidate genes. To facilitate this change in practice, we developed criteria for triaging, sharing, and reporting novel candidate genes that are most likely to be promptly validated as underlying a Mendelian condition and translated to use in clinical settings.
自首次通过外显子组测序发现孟德尔疾病的新基因以来，已知导致孟德尔疾病的基因数量迅速增加，加上诊断检测实验室采用外显子组（最近更采用基因组）测序，这改变了罕见病基因组检测的格局。具体而言，许多疑似患有孟德尔疾病的个体现在通常接受临床外显子组测序。这通常会导致精确的基因诊断，但经常忽略新候选基因的鉴定。在没有大规模基因发现研究计划的情况下，此类候选基因也不太可能被识别。因此，临床实验室既有机会，也有人认为有责任为新基因发现做出贡献，这反过来又应该增加许多疾病的诊断产量。然而，临床诊断实验室必须在吞吐量、周转时间、成本效益、临床医生偏好和监管限制等方面平衡优先级，并且通常没有基础设施或资源来有效地参与临床转化或基础基因组科学研究工作。出于这些和其他原因，许多实验室历史上一直避免通过 Matchmaker Exchange 等网络广泛共享新基因中的潜在致病性变异，更不用说向订购者报告此类结果了。由于缺乏针对新候选基因中变异的临床报告和解释的指南，报告此类结果的工作变得更加复杂。然而，如果临床实验室系统地和常规地识别、共享和报告新的候选基因，对于许多利益相关者（包括患者/家庭、临床医生和研究人员）都有无数好处。为了促进这一实践的改变，我们制定了筛选、共享和报告最有可能迅速被证实为导致孟德尔疾病的新候选基因的标准，并将其转化为临床应用。
