Sullivan Jennifer A, Spillmann Rebecca C, Schoch Kelly, Walley Nicole, Alkelai Anna, Stong Nicholas, Shea Patrick R, Petrovski Slavè, Jobanputra Vaidehi, McConkie-Rosell Allyn, Shashi Vandana
Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, USA.
Institute for Genomic Medicine, Columbia University Medical Center, New York, New York, USA.
Clin Genet. 2024 Jan;105(1):62-71. doi: 10.1111/cge.14437. Epub 2023 Oct 18.
Genomic medicine has been transformed by next-generation sequencing (NGS), inclusive of exome sequencing (ES) and genome sequencing (GS). Currently, ES is offered widely in clinical settings, with a less prevalent alternative model consisting of hybrid programs that incorporate research ES along with clinical patient workflows. We were among the earliest to implement a hybrid ES clinic, have provided diagnoses to 45% of probands, and have identified several novel candidate genes. Our program is enabled by a cost-effective investment by the health system and is unique in encompassing all the processes that have been variably included in other hybrid/clinical programs. These include careful patient selection, utilization of a phenotype-agnostic bioinformatics pipeline followed by manual curation of variants and phenotype integration by clinicians, close collaborations between the clinicians and the bioinformatician, pursuit of interesting variants, communication of results to patients in categories that are predicated upon the certainty of a diagnosis, and tracking changes in results over time and the underlying mechanisms for such changes. Due to its effectiveness, scalability to GS and its resource efficiency, specific elements of our paradigm can be incorporated into existing clinical settings, or the entire hybrid model can be implemented within health systems that have genomic medicine programs, to provide NGS in a scientifically rigorous, yet pragmatic setting.
基因组医学已因下一代测序（NGS）而发生变革，下一代测序包括外显子组测序（ES）和基因组测序（GS）。目前，ES在临床环境中广泛应用，还有一种不太常见的替代模式，即由将研究性ES与临床患者工作流程相结合的混合项目组成。我们是最早实施混合ES诊所的机构之一，已为45%的先证者做出诊断，并鉴定出几个新的候选基因。我们的项目得益于卫生系统的成本效益投资，其独特之处在于涵盖了其他混合/临床项目中不同程度包含的所有流程。这些流程包括仔细的患者选择、使用不依赖表型的生物信息学流程，随后由临床医生手动筛选变异并整合表型、临床医生与生物信息学家之间的密切合作、追踪有趣的变异、根据诊断的确定性将结果分类告知患者，以及随时间跟踪结果变化及其潜在机制。由于其有效性、向GS的可扩展性及其资源效率，我们模式的特定要素可纳入现有临床环境，或者整个混合模式可在拥有基因组医学项目的卫生系统内实施，以便在科学严谨但务实的环境中提供NGS。
