Rare and undiagnosed diseases: From disease-causing gene identification to mechanism elucidation

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.

Keywords

• Rare and undiagnosed diseases
• Next-generation sequencing
• GWAS
• WGS
• Multiomics
• iPSC