三次多囊肾胎儿孕育史孕妇的家系基因突变分析

Genetic mutation analysis of a family with a history of three fetuses with polycystic kidney disease

背景 常染色体显性多囊肾病是终末期肾病最常见的单基因病因,有助于早期明确患者及家系成员的遗传学病因,并对患者及家系成员的生育指导提供帮助。目的 对2021年4月在解放军总医院第一医学中心产科门诊就诊的1例有3次多囊肾孕育史孕妇及家系成员进行分子遗传学检测,为再次妊娠提供遗传咨询。方法 采用高通量测序对孕妇既往引产胎儿进行基因检测,收集其他家系成员的外周血提取DNA,采用长链PCR结合巢式PCR对家系成员进行验证,确定孕妇及其大女儿、父亲、丈夫的基因型后再取孕妇羊水行产前诊断。结果 高通量测序结果提示孕妇既往引产胎儿存在PKD1基因c.7214G>A(p.Trp2405Ter)杂合无义突变和c.9884A>G(p.Asn3295Ser)杂合错义突变;家系验证检出孕妇携带c.7214G>A(p.Trp2405Ter)无义突变,孕妇丈夫携带c.9884A>G(p.Asn3295Ser)错义突变,孕妇父亲携带c.7214G>A(p.Trp2405Ter)无义突变,孕妇大女儿和既往引产胎儿基因检测结果一致。产前诊断检测到羊水标本PKD1基因存在c.7214G>A(p.Trp2405Ter)杂合无义突变和c.9884A>G(p.Asn3295Ser)杂合错义突变。结论 本研究推测c.7214G>A(p.Trp2405Ter)杂合无义突变为家系致病性变异位点,建议孕妇在孕期详细行胎儿肾超声检查以降低生育风险。

Background Autosomal dominant polycystic kidney disease(ADPKD)is the most common monogenic cause of end stage renal disease(ESKD).Early genetic diagnosis of patients is helpful to analyze the genetic etiology of patients and family members,and provide fertility guidance to patients and family members.Objective To provide genetic counseling to guide further pregnancy by performing molecular genetic detection on a pregnant woman with three fetuses history of polycystic kidney disease who visited the Obstetrics clinic of the First Medical Center of Chinese PLA General Hospital in April 2021 and her family members.Methods High-throughput sequencing was used to conduct genetic testing of the previously induced labor fetus.The peripheral blood samples of these family members were harvested for DNA extraction.Long-range PCR combined with nested PCR was used to verify these family members,and the genotypes of the pregnant woman and her eldest daughter,her father and her husband were determined before prenatal diagnosis of the amniotic fluid.Results High-throughput sequencing results indicated that there were heterozygous and nonsense mutations of c.7214G>A(p.Trp2405Ter)and missense mutations of c.9884A>G(p.Asn3295Ser)in PKD1 gene of the previously induced labor fetus.The pregnant woman had heterozygous nonsense mutation of c.7214G>A(p.Trp2405Ter),her husband had heterozygous missense mutation of c.9884A>G(p.Asn3295Ser),her father had heterozygous nonsense mutation of c.7214G>A(p.Trp2405Ter).The genetic results of the pregnant woman’s eldest daughter and the induced labor fetus were consistent.Prenatal diagnosis in amniotic fluid specimen found that there were both c.7214G>A(p.Trp2405Ter)heterozygous nonsense mutation and c.9884A>G(p.Asn3295Ser)heterozygous missense mutation in PKD1 gene.Conclusion In this study,it is speculated that the heterozygous mutation of c.7214G>A(p.Trp2405Ter)is a pathogenic mutation site in the family,and the pregnant woman is recommended to undergo detailed fetal kidney ultrasound examination during pregnancy to prevent the birth of child with renal abnormality.