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Recently, our group has reported a 13-bp deletion in a poly(T)-track in the F8 intron 13 as the causative variant in approximately 6% of all cases of mild haemophilia A (HA) in France. The systematic screening of mild HA patients for this deletion identified individuals carrying deletions from 9 to 14-bp in the same region. To demonstrate that these highly prevalent deletions could result from a recurrent molecular mechanism and to determine the clinical significance of deletions other than 13-bp in size. Haplotype analysis using five polymorphic markers was performed in 71 unrelated French mild hemophilia A patients. Minigene analysis was performed to study the splicing impact of deletions from 1 to 14-bp. A peculiar haplotype (H1) was identified in 22.5% of patients carrying the 13-bp deletion. Haplotypes differing from H1 only for the two most distal markers were found in more than the half of patients. These results confirmed the founder effect origin for the 13-bp deletion. However, the 9 patients carrying other sizes of deletion had a different haplotype suggesting that these deletions arose independently. Supporting the recurrent mechanism hypothesis, similar deletions were also found in 3/19 genetically unresolved mild Canadian patients. In vitro splicing analysis confirmed that deletions larger than 9-bp had a deleterious impact on splicing of F8 transcript. We demonstrated that the poly(T)-track in F8 intron 13 is a deletion hotspot. We recommend that deletions in this region should be specifically investigated in all genetically unresolved mild HA patients. © 2020 International Society on Thrombosis and Haemostasis.

Citation

Yohann Jourdy, Mathilde Frétigny, Fanny Lassalle, David Lillicrap, Claude Négrier, Christine Vinciguerra. The highly prevalent deletions in F8 intron 13 found in French mild hemophilia A patients result from both founder effect and recurrent de novo events. Journal of thrombosis and haemostasis : JTH. 2020 May;18(5):1087-1093

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PMID: 32073743

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