Chong Jessica X, Berger Seth I, Baxter Samantha, Smith Erica, Xiao Changrui, Calame Daniel G, Hawley Megan H, Rivera-Munoz E Andres, DiTroia Stephanie, Bamshad Michael J, Rehm Heidi L
Department of Pediatrics, Division of Genetic Medicine, University of Washington, 1959 NE Pacific Street, Box 357371, Seattle, WA, 98195, USA.
Brotman-Baty Institute for Precision Medicine, 1959 NE Pacific Street, Box 357657, Seattle, WA, 98195, USA.
bioRxiv. 2024 Jun 21:2024.02.05.579012. doi: 10.1101/2024.02.05.579012.
Since the first novel gene discovery for a Mendelian condition was made via exome sequencing (ES), 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 disease. 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 like 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, 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.
自从通过外显子组测序（ES）首次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，同时诊断检测实验室采用外显子组（以及最近的基因组）测序，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经常接受临床外显子组测序。这通常会得出精确的基因诊断，但常常忽略了新候选基因的识别。在没有大规模基因发现研究项目的情况下，这些候选基因也不太可能被识别出来。因此，临床实验室既有机会，也有人可能认为有责任为新基因发现做出贡献，这反过来应该会提高许多疾病的诊断率。然而，临床诊断实验室必须在通量、周转时间、成本效益、临床医生偏好和监管限制等优先事项之间取得平衡，而且往往没有基础设施或资源来有效参与临床转化或基础基因组科学研究工作。由于这些以及其他原因，许多实验室历来都避免通过Matchmaker Exchange等网络广泛共享新基因中潜在的致病变异，更不用说将此类结果报告给下单的医疗机构了。由于缺乏新候选基因变异的临床报告和解释指南，报告此类结果的工作更加复杂。尽管如此，如果临床实验室系统地、常规地识别、共享和报告新候选基因，对许多利益相关者，包括患者/家庭、临床医生、研究人员来说都有无数好处。为了促进这种实践中的改变，我们制定了分类、共享和报告新候选基因的标准，这些基因最有可能迅速被确认为孟德尔疾病的病因并转化为临床应用。
