Characteristics and mode of inheritance of pathogenic copy number variants in prenatal diagnosis


      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.

      Study Design

      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.

      Key words

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        American Journal of Obstetrics & GynecologyVol. 221Issue 6
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          We thank Xu et al for their interest in our paper and their support of our opinion that noninvasive prenatal screening (NIPS) will miss some pathogenic copy number variants (pCNVs), especially those <5 Mb, in high-risk pregnancies that chromosomal microarray can detect.1 Figure 1 illustrates the frequency of pCNV detected relative to aberration size and potentially what NIPS would miss.
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      • Clinical utility of noninvasive prenatal screening for pathogenic copy number variants
        American Journal of Obstetrics & GynecologyVol. 221Issue 6
        • Preview
          Chau et al1 investigated the spectrum and characteristics of pathogenic copy number variants (pCNVs) in prenatal genetic diagnosis. In 23,865 fetuses for any indication for invasive testing, they found that 375 (1.6%) carried pCNVs. Of 428 pCNVs detected, 360 (84.1%) were <5 Mb in size and 68 (15.9%) were between 5 and 10 Mb.
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