多次妊娠多囊肾胎儿患者的基因学病因研究和再生育指导

Genomic etiology study and infertile guidance in patients with pregnancy history of recurrent fetal polycystic kidney

目的从基因水平为2次及2次以上妊娠胎儿多囊肾病变(PKD)患者寻找病因,并进行再生育指导,帮助患者生育健康新生儿。方法选取2014年1月至2017年12月于解放军总医院第一医学中心妇产科就诊的具有2次或2次以上妊娠PKD胎儿病史的8例患者,取不同标本(脐带血或引产后胎儿组织、先证者静脉血和/或夫妻双方静脉血)应用基因捕获及二代测序技术进行突变基因检测,一代测序验证明确诊断后,由患者知情选择自然受孕或进行胚胎植入前遗传学诊断(PGD),并在孕期进行绒毛穿刺或羊水穿刺产前诊断,超声检查排除畸形至妊娠足月分娩。结果为6例患者找到了致病突变基因(2例PKHD1、1例PKD1、1例TMEM67、1例CC2D2A、1例NPHP3)并行家系验证;2例诊断明确后自然妊娠,孕期产前诊断无异常,足月分娩1例正常新生儿、1例无表型携带者新生儿;2例行PGD,其中1例成功分娩正常新生儿,1例待移植;2例暂无计划妊娠;1例拟自然妊娠;1例不打算继续妊娠。结论胎儿PKD可以由不同基因突变致病,对于多次妊娠胎儿PKD病史患者,部分通过二代测序技术能从基因水平上明确诊断,进一步行PGD和产前诊断可以避免遗传性胎儿PKD疾病的发生和传递。

Objective To identify the genetical etiology in women with mutiple pregnancy histories of fetal polycystic kidney disease( PKD) and help them to have healthy babies. Methods From January 2014 to December2017,8 patients with mutiple pregnancy histories of fetal PKD who visited the First Medical Center,Chinese PLA General Hospital were enrolled. Cord blood and fetal tissue after induced labor,venous blood of the proband and/or husband and wife were separated for gene mutation screening through targeted exon capture and next-generation sequencing. Having preimplantation genetic diagnosis( PGD) before pregnancy or natural pregnancy was informed by the patients. Prenatal diagnosis was performed by amniocentesis and chorionic villus sampling. Ultrasonic examination was used to screen deformities. All pregnant patients had full-term delivery. Results Pathologic mutations of PKD were identified in 6 patients and verified in the family,including 2 PKHD1 mutants,1 PKD1 mutant,1 TMEM67 mutant,1 CC2 D2 A mutant and 1 NPHP3 mutant. Two women conceived naturally with no abnormal signs in prenatal examination and delivered 1 healthy baby and 1 non-phenotypic carrier. Two women received PGD;1 of them had normal delivery with healthy baby and the other was prepared for embryo implantation.Two women had no immediate pregnancy plan. One woman was waiting for natural pregnancy. One woman abandoned pregnancy. Conclusions Fetal PKD is associated with various genes mutations. Patients with pregnancy history of recurrent fetal PKD can ask for genomic diagnosis through next-generation sequencing technology to identify the pathologic mutation. Further PGD and prenatal diagnosis can help avoid the inheritance of hereditary PKD.