A groundbreaking study in China has developed a new diagnostic framework for rare diseases, offering renewed hope to millions of patients who endure prolonged and often incorrect diagnoses. This extensive study encompassed 42,703 families across 32 provincial regions, marking a significant leap forward in the field of genomics.
Led by Peking Union Medical College Hospital (PUMCH) with support from BGI Genomics, the study was published in Science Bulletin on August 25th. The findings are part of the UPWARDS Project, a nationwide public welfare initiative conducted between August 2022 and July 2024. The project analyzed the genetic data of 94,749 individuals, resulting in 12,633 confirmed diagnoses, achieving an overall diagnostic rate of 29.58%. This initiative represents China’s first and largest genome-based rare disease program.
Rare Diseases Burden in China
According to estimates derived from Orphanet’s database and China’s 2017 population report, between 48 to 82 million Chinese citizens may be living with a rare condition. However, diagnosis remains a critical challenge. A national survey in 2018 revealed that nearly 73% of patients had been misdiagnosed, with an average wait of 4.3 years for a correct diagnosis. Some patients visited up to 10 hospitals before receiving an accurate result.
“Diagnosis is the first step toward treatment,” explained an expert from PUMCH’s Rare Disease Center. “But the complexity of symptoms and genetic factors makes these diseases particularly hard to identify.”
Building a Nationwide Diagnostic Network
The UPWARDS Project was launched with support from the National Health Commission and the Ministry of Finance. Its goal is to establish a standardized framework for rare disease genome testing and clinical services nationwide. The framework features a 3-in-1 model, starting with genetic testing, followed by multidisciplinary consultations involving experts from various medical fields, and concluding with clinical education to train doctors in recognizing rare disease patterns.
To ensure consistency, 444 hospitals submitted patient data through a centralized UPWARDS system, with all testing conducted by accredited laboratories.
Advanced Sequencing and Classification
The project employed two major technologies: Whole-exome sequencing (WES) for 77% of patients and Whole-genome sequencing (WGS) for 23%. All genetic variations were interpreted using international guidelines from the American College of Medical Genetics and Genomics (ACMG).
Researchers developed a five-level classification system (A–E) based on complexity. Category A cases, with clearer symptoms and fewer possible genes, achieved the highest diagnosis rate at 52%. Category E cases, involving multiple unexplained conditions, still achieved a notable 26% diagnosis rate, demonstrating the power of genome testing even in the most challenging cases.
Key Findings
- Family testing improves diagnosis rates. When genetic data from four or more family members were included, diagnosis rates rose to 39%, compared to 23% for single patients.
- Multi-system conditions are more detectable. Patients with disorders affecting multiple organs were diagnosed more often (34%) than those with a single-organ condition (28%).
- Regional differences emerged. Most patients came from eastern and central provinces, but participation from western and northeastern regions is steadily increasing.
- Genetic hotspots were identified in different provinces, such as the F8 gene (hemophilia A) in Guangxi and the DMD gene (Duchenne muscular dystrophy) in Qinghai.
“This achievement not only benefits Chinese patients but also provides valuable data for the global rare disease community,” noted the research team. “It brings us closer to the goal that every patient with a rare disease should one day have a diagnosis.”
Future of The Unsolved 70%
While nearly one-third of patients received a diagnosis, 70% remain undiagnosed. Researchers believe this gap stems from China’s unique genetic diversity, the limited use of WGS, and insufficient study of non-coding DNA regions. The UPWARDS team is now exploring next-generation approaches to improve the diagnosis rate.
The team is considering the future integration of multi-omics data, such as RNA sequencing, which could potentially raise diagnostic rates by up to 17%. Using AI-assisted analysis to interpret complex data could also help identify genetic mutations linked to conditions. More comprehensive patient and clinician engagement platforms and clinical handbooks will educate the broader public on rare conditions, potentially supporting the early recognition of these conditions.
The program has laid the foundation for a Rare Disease Center, combining patient databases with expert networks to accelerate precision medicine and new treatments. By analyzing the genetic data of more than 42,000 families, the UPWARDS Project has created the most comprehensive picture yet of rare disease distribution in China and is potentially empowering the fight against rare diseases globally.
About BGI Genomics
BGI Genomics, headquartered in Shenzhen, China, is the world’s leading integrated solutions provider of precision medicine. Their services cover more than 100 countries and regions, involving more than 2,300 medical institutions. In July 2017, as a subsidiary of BGI Group, BGI Genomics (300676.SZ) was officially listed on the Shenzhen Stock Exchange.
