The pathogenesis of a female hemophilia A patient with heterozygous variant and literature review
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摘要: 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。Abstract: To explore the pathogenetic mechanism for a female patient affected with mild hemophilia A caused by heterozygous variants in FⅧ genes, it analyzed the clinical characteristics and molecular characteristics of the patients' families. Relevant literature was reviewed by searching the International FⅧ Variant 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 FⅧ gene 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.
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Key words:
- femininity /
- hemophilia A /
- FⅧ gene /
- large deletion /
- X chromosome inactivation
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