Sensitivity, advantages, limitations, and clinical utility of targeted next-generation sequencing panels for the diagnosis of selected lysosomal storage disorders

Abstract Lysosomal storage disorders (LSDs) constitute a heterogeneous group of approximately 50 genetic disorders. LSDs diagnosis is challenging due to variability in phenotype penetrance, similar clinical manifestations, and a high allelic heterogeneity. A powerful tool for the diagnosis of the disease could reduce the “diagnostic odyssey” for affected families, leading to an appropriate genetic counseling and a better outcome for current therapies, since enzyme replacement therapies have been approved in Brazil for Gaucher, Fabry, and Pompe diseases, and are under development for Niemann-Pick Type B. However, application of next-generation sequencing (NGS) technology in the clinical diagnostic setting requires a previous validation phase. Here, we assessed the application of this technology as a fast, accurate, and cost-effective method to determine genetic diagnosis in selected LSDs. We have designed two panels for testing simultaneously 11 genes known to harbor casual mutations of LSDs. A cohort of 58 patients was used to validate those two panels, and the clinical utility of these gene panels was tested in four novel cases. We report the assessment of a NGS approach as a new tool in the diagnosis of LSDs in our service.

摘要 溶酶体贮积症（Lysosomal storage disorders, LSDs）是一类涵盖约50种遗传疾病的异质性疾病谱系。此类疾病的诊断难度较高，原因在于其表型外显率存在差异、临床表现相似且等位基因异质性较强。一款高效的诊断工具可帮助患病家庭减少"诊断求索历程"，助力开展规范化遗传咨询并优化现有治疗的预后效果——目前巴西已批准酶替代疗法用于戈谢病（Gaucher disease）、法布雷病（Fabry disease）及庞贝病（Pompe disease）的治疗，尼曼-皮克B型病（Niemann-Pick Type B）的酶替代疗法仍处于研发阶段。然而，将下一代测序（next-generation sequencing, NGS）技术应用于临床诊断场景前，需预先完成验证环节。本研究评估了该技术作为快速、准确且具备成本效益的手段，在选定的溶酶体贮积症患者中实施基因诊断的应用价值。我们设计了两款基因检测panel，可同时筛查11个已知携带溶酶体贮积症致病突变的基因。本研究纳入58例患者组成的队列对这两款基因检测panel进行验证，并在4例新发病例中验证了该基因panel的临床实用性。本研究报告了下一代测序技术作为本中心溶酶体贮积症诊断新工具的评估结果。