Institute for Public Health Genetics, University of Washington, Seattle, WA 98195, United States.
Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, United States.
J Appl Lab Med. 2024 Jan 3;9(1):138-150. doi: 10.1093/jalm/jfad107.
Obtaining a precise molecular diagnosis through clinical genetic testing provides information about disease prognosis or progression, allows accurate counseling about recurrence risk, and empowers individuals to benefit from precision therapies or take part in N-of-1 trials. Unfortunately, more than half of individuals with a suspected Mendelian condition remain undiagnosed after a comprehensive clinical evaluation, and the results of any individual clinical genetic test ordered during a typical evaluation may take weeks or months to return. Furthermore, commonly used technologies, such as short-read sequencing, are limited in the types of disease-causing variation they can identify. New technologies, such as long-read sequencing (LRS), are poised to solve these problems.
Recent technical advances have improved accuracy, increased throughput, and decreased the costs of commercially available LRS technologies. This has resolved many historical concerns about the use of LRS in the clinical environment and opened the door to widespread clinical adoption of LRS. Here, we review LRS technology, how it has been used in the research setting to clarify complex variants or identify disease-causing variation missed by prior clinical testing, and how it may be used clinically in the near future.
LRS is unique in that, as a single data source, it has the potential to replace nearly every other clinical genetic test offered today. When analyzed in a stepwise fashion, LRS will simplify laboratory processes, reduce barriers to comprehensive genetic testing, increase the rate of genetic diagnoses, and shorten the amount of time required to make a molecular diagnosis.
通过临床基因检测获得准确的分子诊断，可以提供有关疾病预后或进展的信息，准确地告知复发风险，并使个体能够受益于精准治疗或参与个体临床试验。不幸的是，在进行全面的临床评估后，仍有超过一半的疑似孟德尔疾病患者未被诊断，并且在典型评估中订购的任何个体临床基因检测的结果可能需要数周或数月才能返回。此外，常用的技术（如短读测序）在可识别的致病变异类型方面存在局限性。新技术，如长读测序（LRS），有望解决这些问题。
最近的技术进步提高了准确性、增加了通量并降低了商业可用 LRS 技术的成本。这解决了许多关于在临床环境中使用 LRS 的历史问题，并为广泛采用 LRS 开辟了道路。在这里，我们回顾了 LRS 技术，它如何在研究环境中用于阐明复杂的变异或识别先前临床检测遗漏的致病变异，以及它如何在不久的将来在临床上使用。
LRS 的独特之处在于，作为单一数据源，它有可能取代当今提供的几乎所有其他临床基因检测。通过逐步分析，LRS 将简化实验室流程，减少全面基因检测的障碍，提高基因诊断率，并缩短获得分子诊断所需的时间。
