title: Factor VIII mutation spectrum in haemophilia A patients in the population of Henan, China.
abstract: : Defects in the coagulation factor VIII gene cause haemophilia A, which is the most common X-linked recessive bleeding disorder. In total, 45 affected families were investigated to elucidate the factor VIII gene mutation spectrum. The families were subjected to clinical, biochemical, and molecular analyses. Inverse-shifting PCR was first applied to severe haemophilia A patients to identify inversions in introns 22 and 1. Then, next-generation sequencing was performed to detect mutations in inversion-negative patients with severe haemophilia A and moderate-mild haemophilia A patients. Finally, multiplex ligation-dependent probe amplification was utilized to identify rare cases with large fragment duplications or deletions in the factor VIII gene. In total, 41 mutations were identified, 19 of which (c.24C>A, c.49T>C, c.170_171delTT, c.533T>C, c.1126delG, c.1495delA, c.1660A>C, c.1736A>G, c.2711-2712insAATCT, c.3077C>G, c.3846delA, c.4238C>G, c.4349delG, c.4828G>C, c.5821A>C, c.6190C>T, c.6656T>C, c.6902T>G, and c.1904-2A>T) were novel and 80% (44/55) of the pathogenic mutations fell into the categories of missense (43.6%), nonsense (16.36%), frameshift (14.55%), and splice (5.45%) mutations. Additionally, 10 (18.18%) patients displayed inversions in intron 22 or 1 and one case (1.82%) exhibited a 3059-bp large fragment deletion in factor VIII. This study aimed to provide insight contributing to the genetic diagnosis of haemophilia A and to fill gaps in the factor VIII mutation spectrum in northern China.
authors.affiliation: Genetic and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China *Xiaofan Zhu and Nan Bai contributed equally to the writing of this article.
authors.forename: Nan
authors.initials: N
authors.lastname: Bai
authors.forename: Xiaofan
authors.initials: X
authors.lastname: Zhu
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Zhao
authors.forename: Ying
authors.initials: Y
authors.lastname: Bai
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wu
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Duo
authors.initials: D
authors.lastname: Chen
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Kong
mesh_terms: D044466:Asian People / Q000235:genetics; D002681:China; D005169:Factor VIII / Q000235:genetics* / Q000378:metabolism; D006467:Hemophilia A / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation
chemical_list: D005169:Factor VIII