目的 探讨1例具有不良孕产史的女性的遗传学病因。 方法 以1例曾有1次胎停和2次横膈疝伴心脏复杂畸形胎儿引产史的女性作为研究对象，采集其第2次引产儿的组织，提取基因组DNA进行全外显子组测序，对候选变异进行Sanger测序家系验证。 结果 测序发现胎儿的KDM6A基因存在c.1228_1229del(p.Gln410GlufsTer2)半合子移码终止变异，既往未见报道。根据美国医学遗传学与基因组学学会相关指南判断为可能致病(PVS1＋PM2_Supporting)。该变异可导致歌舞伎综合征2型。孕妇及其母亲均携带相同的变异。孕妇身材矮小、眉毛外1/3稀疏，智力正常，存在女性生殖器官先天性发育异常(阴道不完全纵膈、双宫颈、双子宫和单侧卵巢缺失)，其外祖母表型大部分相似。对胎儿的产前影像学表型进行描述，对孕妇持续随访，探讨其在社区随访实践中的疾病管理策略。 结论 KDM6A基因的c.1228_1229del(p.Gln410GlufsTer2)变异可能是导致胎儿膈疝伴心脏结构畸形的遗传学病因。歌舞伎综合征2型胎儿的超声表型以及携带者双子宫畸形既往报道很少。本研究丰富了上述表型谱，为临床诊断和遗传咨询提供了依据。 Objective To explore the genetic basis for a pregnant woman with a history of adverse pregnancy outcomes. Methods A woman with an adverse history of pregnancies including one fetal demise and two induced abortions due to fetal diaphragmatic hernia and complex cardiac anomalies was selected as the study subject. Muscle tissue from the induced abortus was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing of the couple and other family members. Results Genetic sequencing revealed that the fetus has harbored a frameshift variant of the KDM6A gene (NM_001291415.2), namely c. 1228_1229del (p.Gln410GlufsTer2), which was inherited from the woman and her mother. The variant was unreported previously, and the woman was found to have short stature, sparse eyebrows in the outer third, peculiar facial features, but normal intelligence in addition with female congenital genital malformation, like incomplete vaginal septum, double cervix, double uterus, and unilateral ovary absence. mostly similar phenotypes observed in her mother. Conclusion The hemizygous c. 1228_1229del variant of the KDM6A gene probably underlay the abnormalities in the fetus. All findings have enabled genetic counseling for this family featuring X-linked inheritance, and the woman had given birth to a healthy girl with appropriate prevention and intervention.
Clinical characteristics and genetic counseling for a three-generation Chinese pedigree with recurrent fetal Kabuki syndrome due to variant ofKDM6A gene
Objective To explore the genetic basis for a pregnant woman with a history of adverse pregnancy outcomes. Methods A woman with an adverse history of pregnancies including one fetal demise and two induced abortions due to fetal diaphragmatic hernia and complex cardiac anomalies was selected as the study subject. Muscle tissue from the induced abortus was subjected to whole exome sequencing, and candidate variant was verified by Sanger sequencing of the couple and other family members. Results Genetic sequencing revealed that the fetus has harbored a frameshift variant of the KDM6A gene (NM_001291415.2), namely c. 1228_1229del (p.Gln410GlufsTer2), which was inherited from the woman and her mother. The variant was unreported previously, and the woman was found to have short stature, sparse eyebrows in the outer third, peculiar facial features, but normal intelligence in addition with female congenital genital malformation, like incomplete vaginal septum, double cervix, double uterus, and unilateral ovary absence. mostly similar phenotypes observed in her mother. Conclusion The hemizygous c. 1228_1229del variant of the KDM6A gene probably underlay the abnormalities in the fetus. All findings have enabled genetic counseling for this family featuring X-linked inheritance, and the woman had given birth to a healthy girl with appropriate prevention and intervention.
万方数据
