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Mutation spectrum and inhibitor risk in 100 K orean patients with severe haemophilia A
Author(s) -
Kim H.J.,
Chung H.S.,
Kim S. K.,
Yoo K.Y.,
Jung S.Y.,
Park I.A.,
Lee K.O.,
Kim S.H.,
Kim H.J.
Publication year - 2012
Publication title -
haemophilia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.213
H-Index - 92
eISSN - 1365-2516
pISSN - 1351-8216
DOI - 10.1111/j.1365-2516.2012.02895.x
Subject(s) - multiplex ligation dependent probe amplification , haemophilia a , point mutation , medicine , genotype , mutation , polymerase chain reaction , genetics , haemophilia , gene mutation , multiplex , microbiology and biotechnology , gene , gastroenterology , biology , pediatrics , exon
Summary Haemophilia A ( HA ) is an X‐linked recessive bleeding disorder caused by defects in the F8 gene encoding the coagulation factor VIII. Mutation analysis in HA is important to confirm the diagnosis, genotype‐phenotype correlations and for genetic counselling and family study. The aim of this study was to detect causative mutations of F8 in severe HA patients in Korea and to correlate the mutation type with the risk of inhibitor development. A total of 100 unrelated Korean patients with severe HA were enrolled for this study. The Nijeman modification of the Bethesda assay was used to determine the presence of inhibitor. Molecular analysis of F8 was performed using a combination of molecular techniques, including long‐distance polymerase chain reaction, direct sequencing and multiplex ligation‐dependent probe amplification ( MLPA ). We identified causative mutations in 98% of severe HA patients (98/100). Inv22 and Inv1 mutations were detected in 30 patients and one patient, respectively. A total of 59 unique mutations were identified in 69 non‐inversion patients, including 24 novel mutations. The overall prevalence of inhibitor was 26%. Inhibitor risk was highest in patients with large deletion mutations identified using MLPA (100%). Among those with point mutations, the prevalence of inhibitor was highest when the mutation occurred in the A 3 and C 2 domains (60% and 50%, respectively). The molecular diagnostic strategy involving multiplex PCR , sequencing and dosage analyses identified causative mutations in most cases of severe HA . The high inhibitor risk was associated with large deletion mutations and point mutations in A 3 and C 2 domains.