SNP-array技术应用于超声检查异常胎儿产前诊断的研究

Application of single nucleotide polymorphism array in prenatal diagnosis for fetuses with abnormal ultrasound findings

目的 分析单核苷酸多态性芯片（SNP-array）技术在超声检查异常胎儿产前诊断中的应用价值。 方法 收集2015年5月至2017年11月于郑州大学第一附属医院就诊、产前超声检查结果异常的胎儿共904例。904例胎儿均接受SNP-array技术检测，其中434例（48.0%，434/904）同时行染色体核型分析。904例胎儿根据异常的超声检查结果类型分为5组：单结构畸形组280例（31.0%），多结构畸形组31例（3.4%），单软指标异常组331例（36.6%），多软指标异常组107例（11.8%），结构畸形合并软指标异常组155例（17.2%），比较5组超声检查异常胎儿的染色体异常率。 结果 （1）总体SNP-array结果：904例胎儿中，SNP-array技术检出染色体异常率18.9%（171/904），发现致病性拷贝数变异（pCNV）27例（3.0%，27/904），临床意义不明确的拷贝数变异（VOUS）71例（7.9%，71/904）。对27例携带VOUS的胎儿进行父母验证，发现7例（26.0%，7/27）为新发突变。（2）5组超声检查异常胎儿的SNP-array结果：单结构畸形组检出染色体异常率为19.3%（54/280）、多结构畸形组为25.8%（8/31）、单软指标异常组为13.9%（46/331）、多软指标异常组为19.6%（21/107）、结构畸形合并软指标异常组为27.1%（42/155），5组比较，差异有统计学意义（P=0.010）；在单软指标异常组胎儿中，脉络丛囊肿、心室强光点、单脐动脉和肾盂增宽者均未检出染色体异常。（3）超声检查异常胎儿检出染色体非整倍体异常率随孕妇年龄增加而升高，但其随孕周的增加而降低（P均〈0.05）；而超声检查异常胎儿pCNV和VOUS的检出率，不随孕妇年龄及孕周的改变而变化（P均〉0.05）。（4）SNP-array与染色体核型分析结果的比较：904例胎儿中，434例胎儿同时接受了染色体核型分析和SNP-array检测，染色体核型分析检出胎儿染色体异常率10.3%（43/419），SNP-array 检出胎儿染色体异常率18.7%（81/434）。 结论SNP-array可作为产前超声检查异常胎儿遗传学诊断的有效方法。对于不同种类的产前超声检查异常胎儿，SNP-array检出的染色体异常率不同。与染色体核型分析比较，SNP-array技术可提高产前超声检查异常胎儿的染色体异常检出率，且能够发现染色体核型分析不能检出的染色体异常，为妊娠提供更合理的建议。

Objective To investigate the value of single nucleotide polymorphism array （SNP- array） for fetuses with abnormal uhrasound findings. Method A total of 904 fetuses with abnormal ultrasound findings were enrolled in this study from May 2015 to November 2017, and 434 （48.0%） cases received conventional karyotyping analysis at the same time. According to different abnormal ultrasound category, 904 cases were divided into 5 groups： 280 cases （31.0%） in single system structural anomalies, 31 cases （3.4%） in multiple system structural anomalies, 331 cases （36.6%） in single ultrasound soft marker abnormalities without structural anomalies, 107 cases （11.8%） in muhiple soft marker abnormalities and 155 cases （17.2%） in structural abnormalities combined with soft markers abnormalities, Abnormal detection rates by SNP-array among 5 groups of abnormal ultrasound category were calculated. Result （1）Total SNP-array results： 171 （19.0%） cases out of 904 cases analyzed by SNP-array, presented chromosomal abnormalities. Pathogenic copy number variants were detected in 27 cases （3.0%） and variants of unknown significance were detected in 81 cases （7.8%）. In addition, 7 cases （26.0%） were found with new mutation by parental validation. （2） SNP-array of 5 groups： among the 5 groups of abnormal ultrasound category, chromosomal abnormalities were identified by SNP-array in 19.3% （54/280） with single system structural abnormalities, 25.8% （8 / 31 ） with multiple system structural abnormalities, 13.9% （46 / 331 ） with single nonstructural anomalies, 19.6% （21 / 107） with multiple nonstructural anomalies and 27.1% （42/155 ） with structural abnormalities combined with nonstructural anomalies. The differences were significant （P= 0.010）. No chromosome abnormalities was identified in single soft marker abnormalities, such as choroid plexus cysts, echogenic foci in the heart, single umbilical artery and pyelectasis. （3）Chromosomal abnormalities： the abnormal detection rate of aneuploidy chromosomal abnormalities by SNP-array increased with the maternal age, decreased with the gestational weeks （all P〈0.05）. However, the pathogenic copy number variants and variants of unknown significance rates did not change with maternal age and gestational weeks （all P〉0.05）. （4） SNP-array and karyotyping： 434 cases were analyzed by conventional karyotyping and SNP-array respectively, 10.3% （43/419） of which presented chromosomal abnormalities by conventional karyotyping and 18.7% （81/434） of which presented chromosomal abnormalities by SNP-array. Conclusions SNP-array could be a useful genetic analysis method in prenatal diagnosis for fetuses with abnormal ultrasound findings. For different abnormal ultrasound category, SNP-array has different detection rate. Compared with conventional karyotyping analysis, SNP-array can improve the detection rates for chromosomal abnormalities and find the chromosome abnormalities which can＇ t be detected by conventional karyotyping analysis. In clinical prenatal genetic counseling, SNP-arrray should be selected rationally in combination with the various abnormal ultrasound category.