Abstract Number: PB1036
Meeting: ISTH 2020 Congress
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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