Mutation analysis of a cohort of US patients with hemophilia B

Hemophilia B (HB) is a disorder resulting from genetic mutations in the Factor 9 gene (F9). Genotyping of HB patients is important for genetic counseling and patient management. Here we report a study of mutations identified in a large sample of HB patients in the US. Patients were enrolled through an inhibitor surveillance study at 17 hemophilia treatment centers. A total of 87 unique mutations were identified from 225 of the 226 patients, including deletions, insertions, and point mutations. Point mutations were distributed throughout the F9 gene and were found in 86% of the patients. Of these mutations, 24 were recurrent in the population, and 3 of them (c.316G>A, c.1025C>T, and c.1328T>A) accounted for 84 patients (37.1%). Haplotype analysis revealed that the high recurrence arose from a founder effect. The severity of HB was found to correlate with the type of mutation. Inhibitors developed only in severe cases with large deletions and nonsense mutations. None of the mild or moderate patients developed inhibitors. Our results provide a resource describing F9 mutations in US HB patients and confirm previous findings that patients bearing large deletions and nonsense mutations are at high risk of developing inhibitors.