利用高通量测序的方法实现对母源印记基因的产前诊断

Using high-throughput sequencing to achieve prenatal diagnosis of a maternally imprinted gene

目的 对1例超声提示多发异常产前胎儿进行表型分析及基因检测,明确其遗传学病因。方法 对胎儿及父母行捕获高通量测序,筛选出潜在致病变异位点并行Sanger验证及生物信息学分析。结果 先证者IGF2基因3号外显子存在一个杂合错义突变c.224G>A(p.Cys75Tyr),遗传自无表型的父亲。该变异为尚未报道的新变异。单体型分析结果证实变异所在染色单体遗传自不携带该突变的祖母,多种在线软件预测结果均提示为“有害变异”,蛋白预测模型显示变异可能影响蛋白正常结构,按照ACMG指南判读为可能致病变异(PM1+PM2_Supporting+PM6+PP3)。结论IGF2基因c.224G>A(p.Cys75Tyr)变异可能为该家系胎儿的致病原因,该病例为我国首例开展银罗素综合征的产前诊断报道,新变异的检出拓展了IGF2基因的变异谱,为该疾病的遗传咨询和产前诊断提供理论依据。

Objective To analyze the clinical and genetic features of a prenatal fetus with Silver-Russell syndrome(SRS).Methods Genetic variant was detected by whole exome sequencing(WES),and the variant was verified by Sanger sequencing technology and bioinformatic analysis.Results WES revealed that the fetus carried a heterozygous missense c.224G>A in IGF2,which was inherited from the father without phenotype.Haplotype-association analysis confirmed that the variant chromatid was from the grandmother who did not carry the mutation.Bioinformatic analysis predicted that the variant was harmful and may alter the structure of the IGF2 protein.According to ACMG guidelines,the variant was classified as likely pathogenic.Conclusion The variant of IGF2 c.224G>A(p.Cys75Tyr) may be the reason for Silver-Russell syndrome in the fetus,and this case was the first report of SRS prenatal diagnosis in China.The detection of the new mutation expanded the variation spectrum of IGF2 and provided the theoretical basis for genetic counseling and prenatal diagnosis of Silver-Russell syndrome.