Topic: Advances and Innovations in Improving Rare Disease Diagnosis and Treatment

Rare diseases collectively affect millions worldwide, yet most patients endure a prolonged “diagnostic odyssey”—often lasting years—before receiving an accurate diagnosis. Rapid scientific and technological advances are now reshaping this landscape. With the evolution of molecular and cytogenomic testing modalities, significant progress has been made in shortening diagnostic timelines, discovering disease mechanisms, and expanding therapeutic options. Equally important, pre-analytical, analytical, and post-analytical innovations across medical genetics, translational bioscience, and clinical medicine are transforming how rare diseases are diagnosed, understood, and treated.

As a joint effort by ACGA and JTGG, this Special Topic highlights recent breakthroughs and cutting-edge developments that are redefining rare disease research and clinical practice. The collection will encompass the following key areas:

1. Genomic Technologies and OMIC Platforms

Modern high-resolution OMIC tools now play a central role in rare disease diagnosis. WGS/WES detects variants previously missed by traditional methods, while long-read, RNA, and epigenomic sequencing uncover complex structural, intronic, imprinting, and mosaic alterations not seen with short-read sequencing approaches. Rapid sequencing in critically ill newborns accelerates diagnosis and management. Genome-wide methylation profiling helps classify variants and differentiate disorders with overlapping features. Optical genome mapping further improves the detection of structural variants that karyotype, microarray, and sequencing may miss, strengthening diagnoses for cytogenetically complex rare diseases.

2. AI-Driven Interpretation and Decision Support

AI and machine learning greatly enhance variant interpretation and the recognition of phenotypic features. Tools that integrate multi-OMIC, population, and functional data streamline pathogenic variant identification. AI-based imaging and facial analysis detect subtle syndrome-specific patterns, while NLP of EHR data enables earlier identification of rare disease signals and automated prompts for genetic testing. These innovations shorten the diagnostic odyssey and improve clinical decision-making.

3. Targeted Drugs and Gene-Based Therapies

Therapies are advancing rapidly. Precision small-molecule drugs increasingly target disease mechanisms directly. Gene therapy, genome editing, and RNA-based treatments offer potential long-term or curative benefits for some monogenic conditions. Enzyme replacement, chaperone, and protein-replacement therapies continue to grow for metabolic and neuromuscular disorders. Improved humanized and engineered models now support more accurate preclinical testing, advancing individualized treatment options.