PB1211 - Genetic Diagnosis of Hemophilia A in Korean Patients

Background: Hemophilia A (HA) is an X-linked recessive coagulation disorder associated with mutations in the factor VIII (FVIII) gene. The analysis of FVIII gene mutations is crucial for confirming the diagnosis, understanding genotype-phenotype correlations, and providing genetic counseling and family studies.

Aims: This study analyzes the incidence of causative mutations in the FVIII gene in Korean HA patients and to correlate the type of mutation with the risk of inhibitor development.

Methods: The medical records of HA patients registered at multiple centers in Korea were retrospectively investigated. Molecular analysis of the FVIII gene was performed using a combination of molecular techniques, including long-distance polymerase chain reaction (PCR), direct sequencing, and multiplex ligation-dependent probe amplification (MLPA).

Results: A total of 425 Korean patients with HA were enrolled in this study. In severe HA, inversion of intron 22 was the most common (39%), followed by frameshift mutations (21.4%), and missense mutations (15.3%). In moderate and mild HA, missense mutations comprised the majority (82%). In 2.1% of the patients (19 patients), the FVIII gene mutation could not be identified. A total of 71 patients (17%) developed a FVIII inhibitor at least once. The range of peak titers was from 1.0 to 1228 BU/mL. The incidence of FVIII inhibitor was 20% in patients with inversion 22, 28% in those with frameshift mutations, and 8.5% of missense mutations. It was highest in patients with large deletions (7 out of 11 patients, 64%) and lowest in those with nonsense mutations (0 of 30 patients).

Conclusion(s): The molecular diagnostic strategy including multiplex PCR, sequencing, and dosage analyses successfully identified causative mutations in Korean patients with HA. A higher risk of inhibitor development was associated with large deletion mutations, while patients with missense and nonsense mutations demonstrated a lower risk of developing inhibitors.