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

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。

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

ObjectiveTo 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). MethodsA 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. ResultsCMA 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. ConclusionsCMA 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.