1例胎儿羊水过少的基因诊断及植入前诊断 [中文引用][英文引用]

目的 通过高通量测序的方法，检测超声发现的1例孕25+周双肾回声增强、羊水过少的胎儿遗传学致病因素。并对该家系进行下一胎的遗传风险评估及再生育指导。方法 采用父母胎儿核心家系医学外显子测序技术分析可能的致病突变，并针对发现的突变位点进行植入前诊断。结果 发现异常胎儿ACE基因复合杂合变异c.1028G>A（p.W343*）和c.2948T>C（p.L983P），分别来自父亲和母亲。c.1028G>A位点变异可导致肽链合成提前终止，生成比野生蛋白少963个氨基酸的截断蛋白，且在相关病例中报道过。c.2948T>C位点变异为错义突变，生物信息学预测提示为有害突变，为本研究发现的新突变。植入前诊断结果提示第三次妊娠胎儿未携带父母双方的变异位点，且超声提示未见肾脏和羊水量的异常。结论 通过核心家系的高通量测序，本研究发现了ACE基因1个已报道突变，1个没有临床病例报道过的单碱基变异，结合ACE基因已知的功能学研究和该家系临床表现、遗传规律及后续的植入前诊断结果，提示这2个变异位点很可能是该家系的致病原因。

Objective To detect the fetal genetic factors of double kidney echo enhancement and oligohydramnios by high throughput sequencing. Genetic risk assessment and reproduction guidance for the next child were carried out in the family. Method We performed exome sequencing of the proband-parent trio for molecular genetic analyses to find pathogenic mutation, and the preimplantation diagnosis was carried out for the mutation sites found. Results We identified the compound heterozygous variations of abnormal fetal in ACE gene, c.1028G>A(p.W343*) and c.2948T>C(p.L983P), which were derived from father and mother respectively. The reported variant c.1028G>A was nonsense mutation resulted in the premature termination of peptide chain synthesis and the production of a truncated protein with 963 amino acids less than the wild type. The missense variant c.2948T>C was the novel mutation, the bioinformatics prediction indicated that it was deleterious. The prenetal diagnosis indicated that the PDG embryo did not carry the mutation sites of both parents, and the second trimester ultrasound showed no abnormalities in the fetal kidney and amniotic fluid. Conclusions Through high-throughput sequencing of nuclear families, two point mutations without clinical case reported in the ACE gene were found in this study. Combined with known functional studies of ACE gene and clinical manifestations, genetic rules and PGD results of the family, it is suggested that these two mutations may be the causal factor in this family.