Caractérisation génétique et phénotypique des conductrices de l’hémophilie A : Synthèse de la littérature publiée depuis 2000

Abstract

Haemophilia A (HA) is an X-linked recessive hereditary bleeding disorder characterized by a deficiency in coagulation factor VIII, which can lead to severe haemorrhagic complications. Long considered asymptomatic, female carriers actually exhibit high biological and clinical variability, thus posing a major diagnostic and therapeutic challenge. The objective of this thesis was to perform a structured synthesis of the scientific literature regarding the genetic and phenotypic characterization of these carriers, in order to better understand the mechanisms involved in their clinical expression. To achieve this, an exhaustive search was conducted on the PubMed/PMC medical scientific databases for studies published between 2000 and 2026. Subsequently, a rigorous selection and a mathematical and biological standardization of the data were performed. From 379 initial articles selected in this review, we ultimately included 25 studies that met the inclusion criteria, encompassing a total of 440 carriers. The analysis of the results revealed a predominance of familial case series studies (48%). Regarding the genetic analysis, point mutations were the most frequent (52%) on the F8 gene; with missense variants representing the majority; followed by major rearrangements (30%) of which the inversion of intron 22 was predominant. Phenotypically, the mean factor VIII level ranged from 3.58% to 66% among the 336 carriers included in this specific section. This level was frequently associated with major haemorrhagic symptoms, such as menorrhagia. In this study, we demonstrated that X-chromosome inactivation was the primary mechanism responsible for the clinical severity observed in certain carriers. In conclusion, the results of this review provide concrete evidence for genetic counselling in families affected by haemophilia A. The diversity of the identified mutations underscores the necessity of an individualized diagnostic approach tailored to each family.