Background

Chromosomal microarray analysis detects a clinically significant amount of copy number variants in approximately 1% of low-risk pregnancies. As the constantly growing use of noninvasive prenatal screening has facilitated the detection of chromosomal aberrations, defining the rate of abnormal chromosomal microarray analysis findings following normal noninvasive prenatal screening is of importance for making informed decisions regarding prenatal testing and screening options.

Objective

To calculate the residual risk for clinically significant copy number variants following theoretically normal noninvasive prenatal screening.

Study Design

The chromosomal microarray results of all pregnancies undergoing amniocentesis between the years 2013 and 2021 in a large hospital-based laboratory were collected. Pregnancies with sonographic anomalies, abnormal maternal serum screening, or multiple fetuses were excluded. Clinically significant (pathogenic and likely pathogenic) copy number variants were divided into the following: 3-noninvasive prenatal screening–detectable (trisomies 13, 18, and 21), 5- noninvasive prenatal screening–detectable (including sex chromosome aberrations), 5-noninvasive prenatal screening and common microdeletion-detectable (including 1p36.3–1p36.2, 4p16.3–4p16.2, 5p15.3–5p15.1, 15q11.2–15q13.1, and 22q11.2 deletions), and genome-wide noninvasive prenatal screening–detectable (including variants >7 Mb). The theoretical residual risk for clinically significant copy number variants was calculated following the exclusion of noninvasive prenatal screening–detectable findings.

Results

Of the 7235 pregnancies, clinically significant copy number variants were demonstrated in 87 cases (1.2%). The residual risk following theoretically normal noninvasive prenatal screening was 1.07% (1/94) for 3-noninvasive prenatal screening, 0.78% (1/129) for 5- noninvasive prenatal screening, 0.74% (1/136) for 5- noninvasive prenatal screening including common microdeletions, and 0.68% (1/147) for genome-wide noninvasive prenatal screening. In the subgroup of 4048 pregnancies with advanced maternal age, the residual risk for clinically significant copy number variants following theoretically normal noninvasive prenatal screening ranged from 1.36% (1/73) for 3- noninvasive prenatal screening to 0.82% (1/122) for genome-wide noninvasive prenatal screening. In 3187 pregnancies of women <35 years, this residual risk ranged from 0.69% (1/145) for 3- noninvasive prenatal screening to 0.5% (1/199) for genome-wide noninvasive prenatal screening.

Conclusion

The residual risk of clinically significant copy number variants in pregnancies without structural sonographic anomalies is appreciable and depends on the noninvasive prenatal screening extent and maternal age. This knowledge is important for the patients, obstetricians, and genetic counselors to facilitate informed decisions regarding prenatal testing and screening options.

中文翻译：

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排除无创产前筛查可检测结果后，低风险妊娠中临床显着拷贝数变异的残留风险

背景

染色体微阵列分析在大约 1% 的低风险妊娠中检测到临床上显着数量的拷贝数变异。由于无创产前筛查的不断增长的使用促进了染色体畸变的检测，因此确定正常无创产前筛查后异常染色体微阵列分析结果的发生率对于做出有关产前检测和筛查选项的明智决策非常重要。

客观的

计算理论上正常的无创产前筛查后具有临床意义的拷贝数变异的剩余风险。

学习规划

收集了 2013 年至 2021 年间在一家大型医院实验室接受羊膜穿刺术的所有妊娠的染色体微阵列结果。排除超声检查异常、母体血清筛查异常或多胎妊娠的妊娠。临床显着（致病性和可能致病性）拷贝数变异分为以下几类：3-无创产前筛查-可检测（13、18 和 21 三体）、5-无创产前筛查-可检测（包括性染色体畸变）、5-无创产前筛查和可检测到的常见微缺失（包括 1p36.3–1p36.2、4p16.3–4p16.2、5p15.3–5p15.1、15q11.2–15q13.1 和 22q11.2 缺失），以及全基因组无创产前筛查 - 可检测（包括 >7 Mb 的变异）。

结果

在 7235 例妊娠中，有 87 例（1.2%）证实了具有临床意义的拷贝数变异。理论上正常无创产前筛查后的残余风险为：3 次无创产前筛查为 1.07% (1/94)，5 次无创​​产前筛查为 0.78% (1/129)，5 次无创​​产前筛查为 0.74% (1/136)筛查包括常见的微缺失，以及 0.68% (1/147) 的全基因组无创产前筛查。在 4048 名高龄孕妇的亚组中，理论上正常的无创产前筛查后临床显着拷贝数变异的残留风险范围从 3-无创产前筛查的 1.36% (1/73) 到 3-无创产前筛查的 0.82% (1/122)全基因组无创产前筛查。在 3187 名 35 岁以下的孕妇中，该残留风险范围为 0。

结论

在没有结构超声异常的妊娠中，临床上显着的拷贝数变异的残余风险是可观的，并且取决于无创产前筛查的范围和母亲的年龄。这些知识对于患者、产科医生和遗传咨询师来说非常重要，可以帮助他们做出有关产前检测和筛查选择的知情决定。