1例肾脏发育不全或缺如3型胎儿产前超声表型及遗传学分析

Prenatal ultrasound phenotype and genetic analysis of a fetus with renal hypodysplasia/aplasia-3

目的分析1例GREB1L基因突变所致肾脏发育不全或缺如(RHDA)3型胎儿的产前超声表型和遗传学特征。方法2023年2月6日郑州大学第一附属医院诊治1例因产前超声异常行妊娠期遗传咨询的25岁孕妇,收集引产胎儿皮肤组织及夫妇双方外周静脉血,进行全外显子组测序,应用HGMD、ClinVar、ExAC、1000Genomes和gnomAD等数据库对基因突变位点进行检索;参照《遗传变异分类标准与指南》及美国医学遗传学和基因组学学会(ACMG)指南进行突变致病性评级;应用Uniprot数据库预测该基因编码蛋白质结构。收集夫妇双方及胎儿临床资料,分析胎儿产前超声表型和遗传学特征。结果孕妇经遗传咨询后引产1男胎。产前超声提示胎儿颈背部皱褶厚度增厚,双肾缺如,无膀胱和羊水,胃泡体积小和少量心包积液。胎儿携带GREB1L基因c.5429_5442dupGGCC(p.Ile1815fs)移码突变,父母均未携带该突变,属于新发突变,该突变未见文献报道,HGMD和ClinVar数据库未见收录。该突变导致氨基酸编码异常,引起蛋白质功能改变(PVS1);在ExAC、1000Genomes和gnomAD数据库均未发现(PM2_Supporting);为经双亲验证的新发突变(PS2);初步判定为致病性突变(PVS1+PM2_Supporting+PS2)。结论GREB1L基因c.5429_5442dupGGCC移码突变为新发突变,是导致该家系胎儿RHDA3型的遗传学病因,产前超声主要表现为双肾缺如。

Objective To analyze the prenatal ultrasound phenotype and genetic features of a fetus with renal hypodysplasia/aplasia-3(RHDA3)due to GREB1L gene mutation.Methods A 25-year-old pregnant woman underwent genetic counseling during pregnancy due to abnormal prenatal ultrasound in the First Affiliated Hospital of Zhengzhou University on February 6,2023.The skin tissue of the aborted fetus and peripheral venous blood of the couple were collected to perform whole exome sequencing,and gene mutation site was retrieved in databases as HGMD,ClinVar,ExAC,1000 Genomes and gnomAD.The pathogenicity of variants was rated with reference to the Criteria and Guidelines for Classification of Genetic Variants and The American College of Medical Genetics and Genomics(ACMG).Uniprot database was used to predict the protein structure of this gene code.The clinical data of the couple and the fetus were collected,and the prenatal ultrasound phenotype and genetic features of the fetus were analyzed.Results One male fetus was induced after genetic counseling.Prenatal ultrasound indicated thickening of the neck and back folds,absence of both kidneys,absence of bladder and amniotic fluid,small magenblase volume and a small amount of pericardial effusion.The fetus carried the frameshift mutation of GREB1L gene c.5429_5442dupGGCC(p.Ile1815fs),and neither parents carried the mutation.This variant has not been reported in the literature,and has not been included in the HGMD and ClinVar databases,which is a noval variant.This mutation led to abnormal amino acid coding and changes in protein function(PVS1).This mutation was not found in ExAC,1000 Genomes and gnomAD databases(PM2_Supporting).The mutation was a novel mutation verified by both parents(PS2).In summary,the mutation was preliminarily determined to be pathogenic(PVS1+PM2_Supporting+PS2).Conclusion The frameset mutation of GREB1L gene c.5429_5442dupGGCC is a noval mutation,which is the genetic cause of RHDA3 type in the fetus of this family,and the main manifestation of prenatal ultrasound is double kidney absence.