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中华诊断学电子杂志 ›› 2022, Vol. 10 ›› Issue (01) : 36 -41. doi: 10.3877/cma.j.issn.2095-655X.2022.01.008

临床研究

染色体微阵列分析联合全外显子组测序在先天性泌尿系统发育异常胎儿诊断中的应用
郑皓宇1, 张慕玲1, 李晨星1, 周晓燕1,()   
  1. 1. 223300 南京医科大学附属淮安第一医院产前诊断中心
  • 收稿日期:2021-04-15 出版日期:2022-02-26
  • 通信作者: 周晓燕
  • 基金资助:
    南京医科大学科技发展基金(NMUB2019354); 吴阶平医学基金会临床科研专项资助基金(320.6755.15016); 淮安市自然科学研究计划基金(HAB202108)

The application of chromosomal microarray analysis combined with whole exome sequencing in the diagnosis of fetuses with congenital anomalies of the kidney and urinary tract

Haoyu Zheng1, Muling Zhang1, Chenxing Li1, Xiaoyan Zhou1,()   

  1. 1. Department of Prenatal Diagnosis Center, The Affiliated Huai′an No.1 People′s Hospital of Nanjing Medical University, Huai′an 223300, China
  • Received:2021-04-15 Published:2022-02-26
  • Corresponding author: Xiaoyan Zhou
引用本文:

郑皓宇, 张慕玲, 李晨星, 周晓燕. 染色体微阵列分析联合全外显子组测序在先天性泌尿系统发育异常胎儿诊断中的应用[J]. 中华诊断学电子杂志, 2022, 10(01): 36-41.

Haoyu Zheng, Muling Zhang, Chenxing Li, Xiaoyan Zhou. The application of chromosomal microarray analysis combined with whole exome sequencing in the diagnosis of fetuses with congenital anomalies of the kidney and urinary tract[J]. Chinese Journal of Diagnostics(Electronic Edition), 2022, 10(01): 36-41.

目的

探讨染色体微阵列分析(CMA)联合全外显子组测序(WES)在先天性泌尿系统发育异常(CAKUT)胎儿遗传学病因诊断中的应用价值。

方法

选择2008年1月至2021年1月南京医科大学附属淮安市第一人民医院产前诊断中心,因产前超声检查胎儿诊断为CAKUT的单胎孕妇127例,采用CMA技术进行遗传学分析,并对CMA检测阴性的孤立性CAKUT样本采用WES分析。

结果

对127例胎儿样本进行CMA检测,结果显示3例(2.36%)染色体非整倍体异常,核型分别为47,XXY、47,XX,+21及47,XX,+18。CMA检出6例致病性拷贝数变异(CNVs),2例可疑致病性CNVs,总检出率为6.30%(8/127)。WES对41例CMA结果未见异常的不明原因孤立性CAKUT胎儿样本进行检测,结果在3例样本中检测到致病性突变,所涉及的基因分别为PKD1、ACTA2、PKHD1,诊断性变异检出率为7.32%(3/41);另外在2例样本中检测到偶发变异,所涉及的基因分别为INF2和PPM1D基因。

结论

CMA是产前CAKUT一线检测手段,WES是CMA检测阴性的补充检查。采取分步检测和排除的方式,可有效提高CAKUT产前遗传学检测效率。

Objective

To explore the application value of chromosome microarray analysis (CMA) combined with whole exome sequencing (WES) in the diagnosis of genetic etiology of fetuses with congenital anomalies of the kidney and urinary tract (CAKUT).

Methods

A total of 127 singleton pregnant women with CAKUT diagnosed by prenatal ultrasonography were selected from the Center of Prenatal Diagnosis of the First People′s Hospital of Huai′an, Nanjing Medical University from January 2008 to January 2021. Genetic analysis was conducted using CMA technique. Isolated CAKUT samples negative for CMA were analyzed by WES.

Results

CMA was performed on 127 cases, identified 3 patients (2.36%) with chromosomal aneuploidy including 47, XXY, 47, XX, + 21 and 47, XX, + 18. Six patients carried pathogenic copy number variations (CNVs) and 2 patients carried likely pathogenic CNVs. The total detection rate of pathogenic and likely pathogenic CNVs was 6.30% (8/127). In 41 fetuses with CMA who were no abnormality, WES identified pathogenic variants in 3 patients (7.32%), and involved genes were PKD1, ACTA2 and PKHD1. In addition, incidental variations were detected in 2 cases, and the involved genes were INF2 and PPM1D.

Conclusions

CMA testing is recommended as a first-tier test for fetuses with CAKUT, and prenatal WES is a supplementary approach for the etiologic diagnosis of unexplained isolated CAKUT with negative CMA. The results show that a step-by-step and elimination approach could effectively improve the efficiency of prenatal CAKUT genetic testing.

表1 3例染色体非整倍体异常CAKUT胎儿的临床特点
表2 8例CAKUT胎儿的致病性及可疑致病性CNVs的临床特点
图1 孤立性CAKUT诊断性变异胎儿及其父母的Sanger测序验证结果图注:a图显示胎儿ACTA2基因突变位点c.536 G>A为新发变异;b图显示胎儿PKHD1基因移码缺失(c.8301del: p.N2768Tfs*18)来源于父亲;c图显示胎儿PKD1基因突变位点c.6571 C>T: p.Arg2191Cys,为新发变异(箭头所示);CAKUT为先天性泌尿系统发育异常
表3 5例孤立性CAKUT胎儿WES检测阳性结果的临床表型及基因型信息
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