WEE2基因纯合突变Lys195Asn导致受精失败和女性不孕的家系分析

Lys195Asn homozygous mutation of WEE2 gene causes fertilization failure and a pedigree analysis of female infertility

目的鉴定一个在辅助生殖治疗中表现出反复受精失败和不孕的患者的遗传致病基因。方法通过全外显子组测序技术对夫妻双方DNA进行检测,然后对可疑的致病突变进行Sanger测序验证,并通过生物信息学预测其有害性。另外,通过先证者家系分析对突变携带者的表型进行分析。结果夫妇双方中男性未检测到与表型有关的可疑致病突变,而女性患者WEE2基因检测出c.G585C(p.K195N)纯合错义突变,其哥哥同为突变纯合子,父母均为突变杂合子。该突变暂未收录在ExAC、gnmoAD和HGMD数据库中。结论全外显子测序适合于辅助生殖治疗中受精失败案例的遗传学病因的确诊。鉴定出的WEE2基因纯合突变导致受精失败和女性不孕的遗传方式符合常染色体隐性遗传。该家系中WEE2基因突变纯合子男性表型正常,为世界首次报道。

Objective To determine the disease⁃causing gene in a family with fertilization failure and female infertility during assisted reproductive technology(ART)treatment.Methods Whole⁃exome sequencing(WES)and Sanger sequencing were performed for the couple and family.The possible pathogenic variant was evaluated with in silico tools.Genotype and phenotypic relationship were further analyzed through pedigree analysis.Results No suspicious pathogenic mutations related to the phenotype were detected in the males of spouses,.In female patients,a homozygous missense mutation of c.G585C(p.K195N)was detected in the WEE2 gene.Both her brotherand her parents are heterozygous carriers.The mutation has not yet been included in the ExAC,gnmoAD and HGMD database.Conclusion The whole⁃exome sequencing can be used to discover the genetic etiology of fertilization failure and female infertility.The phenotype of fertilization failure caused by WEE2 mutation was shown to follow a Mendelian recessive inheritance pattern.To our knowledge,the male homozygous for the WEE2 gene mutation in this family has a normal phenotype,which is the first report in the world.