A landmark study in China covering 42,703 families affected by rare diseases across 32 provincial regions of China has established a new diagnosis framework for rare diseases. It offers new hope to millions of patients struggling with delayed or incorrect diagnoses.
The study, led by Peking Union Medical College Hospital and with support from BGI Genomics, was published in Science Bulletin , on August 25th. The findings come from the UPWARDS Project, a nationwide public welfare initiative led by Peking Union Medical College Hospital (PUMCH) between August 2022 and July 2024.
The project tested and analyzed the genetic data of 94,749 individuals, resulting in 12,633 confirmed diagnoses. With an overall diagnostic rate of 29.58%, UPWARDS represents China's first and largest genome-based rare disease program.
Rare Diseases Burden in China
According to estimates based on Orphanet's database and China's 2017 population report, 48 to 82 million Chinese citizens may live with a rare condition.
Yet, diagnosis remains a major hurdle. A national survey in 2018 revealed that nearly 73% of patients had been misdiagnosed. The average time to receive a correct diagnosis was 4.3 years. Some patients visited up to 10 hospitals before receiving an accurate result.
"Diagnosis is the first step toward treatment," explained PUMCH's Rare Disease Center expert. "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. It aims to build a standardized framework for rare disease genome testing and clinical services across the country.
The established framework feature a 3-in-1 model, involving genetic testing as the starting point, follow with multidisciplinary consultation, bringing together experts from multiple medical fields, and lastly clinical education, training doctors to recognize rare disease patterns.
To ensure consistency, 444 hospitals submitted patient data through a centralized UPWARDS system, and all testing was carried out by accredited laboratories.
Advanced Sequencing and Classification
The project used two major technologies, Whole-exome sequencing (WES) for 77% of patients and Whole-genome sequencing (WGS) for 23% of patients. All genetic variations were interpreted using international guidelines from the American College of Medical Genetics and Genomics (ACMG).
To better organize cases, 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 (52%). Category E cases, with multiple unexplained conditions, still achieved a notable 26% diagnosis rate, showing the power of genome testing even in the most challenging cases.
Key Findings
Family testing helps to improve the diagnosis rate. 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. Certain conditions showed local concentration, 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 have raised 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 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. Our 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.
