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Abstract：
Rare and undiagnosed diseases substantially decrease patient quality of life and have increasingly become a heavy burden on healthcare systems. Because of the challenges in disease-causing gene identification and mechanism elucidation, patients are often confronted with difficulty obtaining a precise diagnosis and treatment. Due to advances in sequencing and multiomics analysis approaches combined with patient-derived iPSC models and gene-editing platforms, substantial progress has been made in the diagnosis and treatment of rare and undiagnosed diseases. The aforementioned techniques also provide an operational basis for future precision medicine studies. In this review, we summarize recent progress in identifying disease-causing genes based on GWAS/WES/WGS-guided multiomics analysis approaches. In addition, we discuss recent advances in the elucidation of pathogenic mechanisms and treatment of diseases with state-of-the-art iPSC and organoid models, which are improved by cell maturation level and gene editing technology. The comprehensive strategies described above will generate a new paradigm of disease classification that will significantly promote the precision and efficiency of diagnosis and treatment for rare and undiagnosed diseases.
摘要：
罕见和未诊断的疾病大大降低了患者的生活质量，并日益成为医疗保健系统的沉重负担。由于在致病基因鉴定和机制阐明方面的挑战，患者通常面临难以获得精确的诊断和治疗。由于测序和多组学分析方法与患者来源的iPSC模型和基因编辑平台相结合的进步，在罕见和未诊断疾病的诊断和治疗方面取得了实质性进展。上述技术也为未来的精准医学研究提供了操作基础。在这次审查中,我们总结了基于GWAS/WES/WGS指导的多组学分析方法鉴定致病基因的最新进展.此外,我们用最先进的iPSC和类器官模型讨论疾病致病机制和治疗的最新进展，通过细胞成熟水平和基因编辑技术提高。上述综合策略将产生一种新的疾病分类范式，将显著提高罕见和未诊断疾病的诊断和治疗的精度和效率。
