ENOrphanet Journal of Rare Diseases | Epidemiological Analysis of TRAPS and Assessment of BNDMR Data Reliability
Date: April 05, 2025
Classification: Frontiers
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This study systematically evaluated the data reliability of the French National Rare Disease Registry (BNDMR) for TRAPS patients, revealing that over one-third of 'confirmed' cases lack clear pathogenic variant support. It also highlighted the critical role of genetic testing in epidemiological studies of rare diseases.
Literature Overview
The article titled 'Prevalence estimation of a rare disease with the French National Rare Disease Registry: example of TNF receptor associated periodic syndrome (TRAPS)' published in Orphanet Journal of Rare Diseases reviews the application of the French National Rare Disease Registry (BNDMR) in TRAPS epidemiological studies. The study indicates that despite data being entered by expert physicians, the diagnostic accuracy of BNDMR still shows significant discrepancies, with only 69% of cases carrying clearly pathogenic variants and about 31% classified as variants of uncertain significance (VUS). The article further analyzes the association between different diagnostic statuses and variant pathogenicity and estimates the minimum prevalence of TRAPS in the French population.Background Knowledge
TRAPS (TNF Receptor-Associated Periodic Syndrome) is an autosomal dominant rare autoinflammatory disease caused by mutations in the TNFRSF1A gene. Clinical manifestations are nonspecific and include periodic fever, abdominal pain, chest pain, periorbital edema, myalgia, and rash. Confirming TRAPS relies on identifying pathogenic or likely pathogenic variants in the TNFRSF1A gene. Variants in TNFRSF1A are classified by the Infevers database and verified by the International Network for Systemic Autoinflammatory Diseases (INSAID). In 2019, Gattorno et al. proposed that TRAPS diagnosis should combine variant analysis with clinical criteria such as duration of attacks, myalgia, migratory rash, periorbital edema, and family history.
Although 80% of rare diseases have a genetic basis, most lack clear diagnostic criteria. The French National Rare Disease Registry (BNDMR), established in 2013, aims to systematically collect rare disease data to support national health policies and disease management. The registry requires physicians to update information at each patient visit and classifies diseases by ORPHA code. TRAPS is one of the earliest monogenic autoinflammatory diseases described, and its variant classification and diagnostic criteria have been continuously updated in recent years, leading to possible misclassification or diagnostic bias in historical data.
This study selected TRAPS as a model due to its clear pathogenic gene (TNFRSF1A) and the availability of authoritative variant databases, making it suitable for assessing BNDMR data quality. The study also notes that the registration of TRAPS cases in the database lags, and some cases lack genetic information, requiring manual follow-up, which increases research costs and potential bias.
Research Methods and Experiment
The research team extracted all TRAPS patient data registered in the BNDMR database as of January 2023 and obtained complete genetic information from respective centers between January and March 2023. Among 132 initially included patients, 101 were analyzed after excluding duplicates and those missing genetic data. All patients underwent Sanger sequencing or high-throughput sequencing to detect TNFRSF1A gene variants, which were then categorized according to the pathogenicity classification from the Infevers database. Researchers also analyzed the relationship between diagnostic status (confirmed, probable, under investigation) and variant type and assessed gender ratios to detect data bias.Key Findings and Insights
Implications and Future Directions
The study emphasizes the importance of integrating genetic information into epidemiological research and suggests that BNDMR should be automatically linked with national genomic sequencing platforms (e.g., Seqoia and Auragen) to enhance data quality. It also recommends implementing multi-disciplinary reviews or mandatory diagnostic criteria forms to improve data accuracy. Future studies could extend to other monogenic rare diseases to comprehensively evaluate BNDMR's reliability across different conditions.
Conclusion
This study analyzed genetic data of TRAPS patients in the French National Rare Disease Registry (BNDMR) and revealed significant issues in data reliability for epidemiological studies of rare diseases. Despite being managed by expert physicians, BNDMR shows discrepancies in TRAPS diagnosis, with only 69% of patients carrying confirmed pathogenic variants, and 31% having VUS or benign variants. Moreover, the 'confirmed' diagnostic label does not align with genetic evidence. The study also estimates the minimum prevalence of TRAPS in France as 1/1,156,711, which is significantly lower than the prevalence in German children, likely due to differences in study populations and diagnostic criteria. This work provides methodological insights for future epidemiological studies of rare diseases and underscores the necessity of integrating pathogenicity classifications and automatic update mechanisms into the BNDMR database. Additionally, it suggests that current data collection in BNDMR requires improvement, especially in standardizing diagnostic criteria and data backtracking. Future efforts could integrate more specialized databases (e.g., JIRcohort) to enhance data depth and accuracy.
