Genetic Diagnosis of Hemophilia A in Korean Patients

초록

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 inhibit