The spectrum of FVIII gene variants detected by next generation sequencing in 236 Chinese non-inversion hemophilia A pedigrees

• Published in: Thrombosis research Vol. 202; pp. 8 - 13
• Main Authors: Chen, Juanjuan, Li, Qiang, Lin, Sheng, Li, Fenxia, Huang, Limin, Jin, Wangjie, Yang, Xu, Li, Yihong, Li, Kun, Xiong, Yufeng, Fan, Dongmei, Zheng, Lei, Luo, Dixian, Li, Liyan, Yang, Xuexi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.06.2021
• Subjects: Hemophilia A; Molecular diagnosis; Next generation sequencing; Novel variant; Variant spectrum; Novel variant; F8; Molecular diagnosis; Next generation sequencing; Hemophilia A; Variant spectrum
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/j.thromres.2021.02.027

The reported variants of hemophilia A are mainly from European subjects and American subjects of European descent, and limited data are available from more diverse ethnic backgrounds. This study was performed to identify the causative variants in a large HA cohort from Chinese population. A total of 236 HA pedigrees were included. Molecular analysis of F8 gene was performed using next-generation sequencing (NGS) and then validated by Sanger sequencing and multiplex ligation probe amplification (MLPA) results. Variants were classified as pathogenic, likely pathogenic, variant of unknown significance, likely benign, and benign according to the American College of Medical Genetics and Genomics guidelines. A total of 186 F8 variants were identified, with 139 (139/186, 74.73%) point mutations, 44 (44/186, 23.66%) small insertions/deletions (InDels), and 3 (3/186, 1.61%) large deletions, they included 80 pathogenic and 84 likely pathogenic variants. Of these variants, 119 had been reported previously, and 67 were novel. No potentially causative mutations were found in the targeted F8 region in seventeen HA pedigrees. The spectrum of F8 variants identified in this study provides additional information about HA and enriches our knowledge of the variant spectrum in a wider range of ethnic backgrounds. •Enriching the spectrum of F8 gene variants in more diverse ethnic backgrounds•NGS can be an alternative method of detecting non-inversion hemophilia risk variants.•67 novel variants in the F8 gene were identified.•There were more than one gene variants of F8 gene identified in six patients.•There were no candidate variants identified in 17 HA pedigrees.