一个口-面-指综合征1型家系的OFD1基因分析及产前诊断

Pathological variant of OFD1 gene identified in a pedigree affected with oral-facial-digital syndrome type 1

目的对1个口-面-指综合征1型(oral-facial-digital syndrome type 1,OFD1)家系进行致病基因分析,明确其致病变异,为家系的遗传咨询和产前诊断提供依据。方法应用全外显子测序技术对先证者进行基因变异筛查,发现OFD1基因可疑变异位点后,用Sanger测序技术对该家系成员和100名正常对照进行验证,确定该家系的致病位点。使用X染色体失活分析判断两条X染色体的活性比例,并对家系中孕20周胎儿抽取羊水标本进行产前诊断。结果先证者及家系中所有患者均携带OFD1基因c.1189_1192delAATC(p.Q398Lfs*2)杂合变异,而家系中正常成员和100名正常对照均未检测到此变异。孕妇及其妹妹存在X染色体非随机失活,家系中其余女性患者均为X染色体随机失活。产前诊断结果为胎儿携带OFD1基因c.1189_1192delAATC(p.Q398Lfs*2)杂合变异。结论OFD1基因c.1189_1192delAATC(p.Q398Lfs*2)杂合变异是该家系的致病原因,新变异的检出丰富了OFD1基因变异谱,但家系内表型差异性的原因仍需要更深入的研究证实。

Objective To detect pathological variant in a Chinese pedigree affected with oral-facial-digital syndrome type 1(OFD1).Methods Whole-exome sequencing was used to scan the whole exome of the proband.Potential variant of the OFD1 gene was also detected in all members of the pedigree and 100 healthy controls by Sanger sequencing.X chromosome inactivation analysis was performed.With the determination of the genotype,prenatal diagnosis was carried out by amniotic fluid sampling.Results A c.1189_1192delAATC(p.Q398Lfs*2)variant was identified in the OFD1 gene of the proband,other patients from this pedigree,as well as the fetus.The same variant was not found among healthy members from this pedigree and the 100 healthy controls.X chromosome inactivation analysis identifies the pregnant woman and her younger sister both had a non-random inactivation,other women patients had a random inactivation.Conclusion The c.1189_1192delAATC(p.Q398Lfs*2)variant of the OFD1 gene probably underlies the pathogenesis in this case.The new variant has enriched pathological spectrum of the OFD1 gene.The reason of intrafamilial clinical variability still need to be further confirmed.