1例女性杂合变异致轻型血友病A的发病机制分析并文献复习

The pathogenesis of a female hemophilia A patient with heterozygous variant and literature review

通过对血友病A(hemophilia A,HA)患者家系进行临床特征分析和分子学检测,探讨女性FⅧ基因杂合变异致轻型HA的发病机制,并通过检索国际FⅧ基因变异数据库进行相关文献复习。结果显示先证者FⅧ:C 0.3%,为重型HA患者,伴有抑制物产生,基因变异检测发现先证者存在大片段缺失变异(c.delexons14_22),此变异为已知的致病性变异,目前国内外报道了6例患者,均为重型HA,其中5例报道了抑制物产生,1例患者未对抑制物进行描述。先证者母亲为大片段缺失变异的杂合变异,FⅧ:C 13%,为轻型HA,未见抑制物形成;X染色体失活检测发现该母亲的正常X染色体比携带FⅧ基因变异的X染色体表达活性低。大片段缺失变异(c.delexons14_22)可引起重型HA,且与抑制物产生高度相关。女性杂合变异致轻型HA的机制可解释为X染色体表达存在非随机不平衡失活。

To explore the pathogenetic mechanism for a female patient affected with mild hemophilia A caused by heterozygous variants in FⅧgenes,it analyzed the clinical characteristics and molecular characteristics of the patients'families.Relevant literature was reviewed by searching the International FⅧVariant Database.The proband,a 22-year-old boy was diagnosed with severe HA at 1-year-old,Sanger sequencing failed to identify molecular defects,and MLPA revealed a large duplication(c.delexons14_22).This variant has been observed in 6 HA patients,5 of whom had severe phenotype and had a history of inhibitors.His mother was a carrier of large duplication(c.delexons14_22),with a lower concentration of FⅧ(FⅧ:C 13%).X chromosome inactivation test found that the normal X chromosome of the mother had lower expression activity than the X chromosome carrying the FⅧgene variant.Large duplications(c.delexons14_22)can cause severe HA and is highly correlated with inhibitor production.The mechanism of mild HA induced by heterozygous variant can be explained by the non-random imbalance inactivation of the X chromosome.