What is the role of genetic testing in the diagnosis of bleeding disorder of unknown cause (BDUC)?¶
Answer: Genetic testing complements the diagnosis but is unlikely to influence or change management for the majority of patients. The most important aspect of diagnosing a patient with a bleeding disorder is the clinical phenotype, period.
In true BDUC — where first-line hemostatic testing is normal — the diagnostic yield of genetic testing is very low: 3.2% in the largest panel study (below).
Genetic testing could be helpful in the following circumstances:
- Refining the classification and resolving overlapping phenotypes, such as type 2N von Willebrand disease or mild hemophilia — although these disorders will generally have abnormal first-line testing.
- Inherited platelet function disorders: this group of disorders is the most diagnostically challenging to confirm, given the heterogeneity in the available tests and the limited specificity of platelet function testing.
- Syndromes associated with other disorders that require specific monitoring, such as MYH9-related disorders or RUNX1 variants.
- A family history.
The evidence:
- Yield depends on phenotype. In 2396 index patients sequenced on a targeted panel, a molecular diagnosis was made in 49.2% across thrombotic, coagulation, platelet count, and platelet function disorders, but in only 3.2% of patients with unexplained bleeding and normal hemostasis tests (Downes et al., Blood 2019).
- In defined factor deficiencies the yield is high. A 22-gene panel in 515 patients with inherited coagulation factor deficiencies found a disease-causing variant in 69% of those with complete phenotypic data (Borràs et al., Haemophilia 2025).
- The GT4BD RCT will answer the question of when to introduce whole genome sequencing in the diagnostic pathway: newly referred patients with a suspected inherited bleeding disorder are randomized to early genome sequencing vs the standard pathway, with diagnostic yield as the primary outcome.
Related: 0021 — Diagnosing BDUC gives the ISTH minimum laboratory work-up that must be normal before the BDUC label applies.