Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.
Warwick Medical School at the University of Warwick, Coventry, United Kingdom.
Am J Obstet Gynecol. 2019 Nov;221(5):493.e1-493.e11. doi: 10.1016/j.ajog.2019.06.007. Epub 2019 Jun 14.
Microdeletions and microduplications can occur in any pregnancy independent of maternal age. The spectrum and features of pathogenic copy number variants including the size, genomic distribution, and mode of inheritance are not well studied. These characteristics have important clinical implications regarding expanding noninvasive prenatal screening for microdeletions and microduplications.
The aim was to investigate the spectrum and characteristics of pathogenic copy number variants in prenatal genetic diagnosis and to provide recommendations for expanding the scope of noninvasive prenatal screening for microdeletions and microduplications.
This was a retrospective study of 1510 pregnant women who underwent invasive prenatal diagnostic testing by chromosomal microarray analysis. Prenatal samples were retrieved by amniocentesis or chorionic villus sampling and sent to our prenatal genetic diagnosis laboratory for chromosomal microarray analysis. The risk of carrying a fetus with pathogenic copy number variants is stratified by the patients' primary indication for invasive testing. We searched the literature for published prenatal chromosomal microarray data to generate a large cohort of 23,865 fetuses. The characteristics and spectrum of pathogenic copy number variants including the type of aberrations (gains or losses), genomic loci, sizes, and the mode of inheritance were studied.
Overall, 375 of 23,865 fetuses (1.6%) carried pathogenic copy number variants for any indication for invasive testing, and 44 of them (11.7%) involve 2 or more pathogenic copy number variants. A total of 428 pathogenic copy number variants were detected in these fetuses, of which 280 were deletions and 148 were duplications. Three hundred sixty (84.1%) were less than 5 Mb in size and 68 (15.9%) were between 5 and 10 Mb. The incidence of carrying a pathogenic copy number variant in the high-risk group is 1 in 36 and the low-risk group is 1 in 125. Parental inheritance study results were available for 311 pathogenic copy number variants, 71 (22.8%) were maternally inherited, 36 (11.6%) were paternally inherited, and 204 (65.6%) occurred de novo.
Collectively, pathogenic copy number variants are common in pregnancies. High-risk pregnancies should be offered invasive testing with chromosomal microarray analysis for the most comprehensive investigation. Detection limits on size, parental inheritance, and genomic distribution should be carefully considered before implementing copy number variant screening in expanded noninvasive prenatal screening.
微缺失和微重复可在任何妊娠中发生，与母体年龄无关。致病性拷贝数变异的谱和特征，包括大小、基因组分布和遗传方式，尚未得到很好的研究。这些特征对于扩展微缺失和微重复的无创性产前筛查具有重要的临床意义。
旨在研究产前遗传诊断中致病性拷贝数变异的谱和特征，并为扩展微缺失和微重复的无创性产前筛查范围提供建议。
这是一项回顾性研究，纳入了 1510 名接受染色体微阵列分析的有创产前诊断检测的孕妇。通过羊膜穿刺术或绒毛取样获取产前样本，并送至我们的产前遗传诊断实验室进行染色体微阵列分析。根据患者有创性检测的主要指征，对携带致病性拷贝数变异胎儿的风险进行分层。我们检索了文献中已发表的产前染色体微阵列数据，以生成一个包含 23865 例胎儿的大队列。研究了致病性拷贝数变异的特征和谱，包括畸变类型（增益或缺失）、基因组位置、大小和遗传方式。
总体而言，375 例（1.6%）有创性检测指征的胎儿携带致病性拷贝数变异，其中 44 例（11.7%）涉及 2 种或以上致病性拷贝数变异。这些胎儿共检出 428 种致病性拷贝数变异，其中 280 种为缺失，148 种为重复。360 种（84.1%）小于 5Mb，68 种（15.9%）为 5-10Mb。高危组携带致病性拷贝数变异的发生率为 1/36，低危组为 1/125。311 种致病性拷贝数变异的父母遗传研究结果可用，其中 71 种（22.8%）为母系遗传，36 种（11.6%）为父系遗传，204 种（65.6%）为新生性遗传。
总体而言，致病性拷贝数变异在妊娠中很常见。高危妊娠应提供染色体微阵列分析的有创性检测，以进行最全面的检查。在扩展无创性产前筛查中进行拷贝数变异筛查之前，应仔细考虑大小、父母遗传和基因组分布的检测限制。
