VPS33B与GP1BA基因双重杂合变异致血浆VWF水平严重降低:1例报告及文献复习

Rare VPS33B gene mutation combined with GP1BA mutation causes severe decrease in plasma VWF levels:a case report and literature review

一例28岁女性,孕期常规体检发现凝血因子Ⅷ活性(FⅧ∶C)<1%、血管性血友病因子抗原(VWF∶Ag)<1%。二代测序未发现其VWF基因外显子区域存在致病变异。由于该患者临床表现与Ⅲ型血管性血友病(VWD)临床特征不符,因此采用三代测序技术对该患者及其家系成员进行全基因组测序,发现该患者父系家族中有多位成员中携带VPS33B基因杂合变异c.869G>C,携带该变异的家系成员均有不同程度的VWF水平降低(39%~56%)。同时,先证者还检出GP1BA基因杂合变异c.1474dupA,ACMG及Clinvar数据库判断该变异与"血小板型假性VWD"相关。VPS33B基因杂合变异导致的VWF水平降低家系为国际首次报道,VPS33B基因与GP1BA基因双重杂合变异引起血浆VWF水平严重降低病例之前也未见报道。

A 28-year-old woman was found to have coagulation factorⅧactivity(FⅧ∶C)<1%and von Willebrand factor antigen(VWF∶Ag)<1%during routine prenatal examinations.No pathogenic variation was found in the exon region of the VWF gene using next-generation sequencing.The clinical presentation of this patient does not match the clinical characteristics of typeⅢhemophilia[von Willebrand disease(VWD)];therefore,third-generation sequencing technology was used to perform whole-genome sequencing on the patient and her family members.Multiple members of the patient’s paternal family carried a heterozygous variant of VPS33B,c.869G>C.The family members carrying this variant all had varying degrees of reduced VWF levels(39%-56%).Moreover,the proband was detected with the heterozygous variant c.1474dupA in GP1BA.The ACMG and Clinvar databases determined that this variation was associated with platelet-type pseudo VWD.The decrease in VWF levels caused by heterozygous variations in VPS33B in families is the first international report,and no previous studies have reported cases of severe decrease in plasma VWF levels caused by double heterozygous variations in VPS33B and GP1BA.