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Molecular Mechanisms Underlying Haemophilia A and B Expression in 7 Females

1Rui Jin Hospital, Department of Laboratory Medicine, Shanghai, China, 2Rui Jin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China, 3Rui Jin Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China

Abstract Number: PB1036

Meeting: ISTH 2020 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical

Background: Haemophilia A and B (HA and HB) are X-linked recessive bleeding disorders and female are usually benign carriers. Few cases of female haemophilia were reported so far.

Aims: To investigate the causes of hamophilia in 7 females.

Methods: Comprehensive analysis of F8, F9 and the minimal promoter of XIST genotypes was performed in 5 unrelated HA and 2 HB females and related family members, XCI patterns (XIPs) have been conducted with methylation-based PCR assay using the androgen receptor (AR). Karyotype and high-density single nucleotide polymorphisms (SNPs) genotyping array were also detected, linkage analysis was undertaken using microsatellite markers of X chromosome in the families with tendency of familial XCI skewing.

Results: 5 unique heterozygous F8 mutations of Arg336*, Trp2081Gly, c.5998+1G>C, Ex2_6del (de novo, paternal allele), Ex2_26dup (de novo, maternal allele) in 5 female HA and 2 F9 mutations of Gly409Glu and c.255+5G>A in 2 HB females. In the 7 females, no pathogenic variants were identified in the XIST promoter, and karyotype analysis revealed no obvious alternations. Macroarray showed an unreported large 431 kb duplication involving F8 Ex2_26dup in the HA female, and a 2904kb deletion at Xq28 in the HB female’s paternal allele, and the F9 c.255+5G>A mutation inherited from her mother. XIPs >80:20 were detected in all the 7 females. The extremely XIPs >95:5 were detected in 5 females of 3 generations in one HA family, and Linkage analysis revealed that inactivation X chromosome tracing to the same maternally allele.

Conclusions: The haemophilia expression in our cohort was caused by the X chromosome carrying the normal F8 or F9 being preferential inactivated, coordinated with the other X chromosome carrying the causative mutation. We postulate that the large deletion identified in the HB female resulted in extreme skewing of X-inactivation via a cell lethal mechanism.

To cite this abstract in AMA style:

Ding Q, Liu J, Dai J, Wu W, Wang X. Molecular Mechanisms Underlying Haemophilia A and B Expression in 7 Females [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/molecular-mechanisms-underlying-haemophilia-a-and-b-expression-in-7-females/. Accessed November 29, 2023.

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