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

      Background

      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.

      Objectives

      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.

      Results

      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.

      Conclusion

      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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      References

        • American College of Obstetricians and Gynecologists
        Microarray and next-generation sequencing technology: the use of advanced genetic diagnostic tools in obstetrics and gynaecology. ACOG Committee Opinion No. 682.
        Obstet Gynecol. 2016; 128: e262-e268
        • Lupski J.R.
        Genomic disorders ten years on.
        Genom Med. 2009; 1: 42
        • Gregg A.R.
        • Skotko B.G.
        • Benkendorf J.L.
        • et al.
        Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics.
        Genet Med. 2016; 18: 1056-1065
        • Lo K.K.
        • Karampetsou E.
        • Boustred C.
        • et al.
        Limited clinical utility of non-invasive prenatal testing for subchromosomal abnormalities.
        Am J Hum Genet. 2016; 98: 34-44
        • Yu S.C.Y.
        • Jiang P.
        • Choy K.W.
        • et al.
        Noninvasive prenatal molecular karyotyping from maternal plasma.
        PLoS One. 2013; 8: e60968
        • Liang D.
        • C D.S.
        • Tan H.
        • et al.
        Clinical utility of noninvasive prenatal screening for expanded chromosome disease syndromes.
        Genet Med. 2019; 21: 1998-2006
        • Li R.
        • Wan J.
        • Zhang Y.
        • Fu F.
        • et al.
        Detection of fetal copy number variants by non-invasive prenatal testing for common aneuploidies.
        Ultrasound Obstet Gynecol. 2016; 47: 53-57
        • Kearney H.M.
        • Thorland E.C.
        • Brown K.K.
        • Quintero-Rivera F.
        • South S.T.
        a working group of the American College of Medical Genetics Laboratory Quality Assurance Committee. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants.
        Genet Med. 2011; 13: 680-685
        • South S.T.
        • Lee C.
        • Lamb A.N.
        • Higgins A.W.
        • Kearney H.M.
        Working Group for the American College of Medical Genetics and Genomics Laboratory Quality Assurance Committee. ACMG standards and guidelines for constitutional cytogenomic microarray analysis, including postnatal and prenatal applications: revision 2013.
        Genet Med. 2013; 15: 901-909
        • Riggs E.R.
        • Church D.M.
        • Hanson K.
        • et al.
        Towards an evidence-based process for the clinical interpretation of copy number variations.
        Clin Genet. 2012; 81: 403-412
        • Wapner R.J.
        • Martin C.L.
        • Levy B.
        • et al.
        Chromosomal microarray versus karyotyping for prenatal diagnosis.
        N Engl J Med. 2012; 367: 2175-2184
        • Kan A.S.Y.
        • Lau E.T.
        • Tang W.F.
        • et al.
        Whole-genome array CGH evaluation for replacing prenatal karyotyping in Hong Kong.
        PLOS One. 2014; 9: e87988
        • Papoulidis I.
        • Sotiriadis A.
        • Siomou E.
        • et al.
        Routine use of array comparative genomic hybridization (aCGH) as standard approach for prenatal diagnosis of chromosomal abnormalities. Clinical experience of 1763 prenatal cases.
        Prenat Diagn. 2015; 35: 1269-1277
        • Lee C.N.
        • Lin S.Y.
        • Lin C.H.
        • Shih J.C.
        • Lin T.H.
        • Su Y.N.
        Clinical utility of array comparative genomic hybridization for prenatal diagnosis: a cohort study of 3171 pregnancies.
        BJOG. 2012; 119: 614-625
        • Armengol L.
        • Nevado J.
        • Serra-Juhé C.
        • et al.
        Clinical utility of chromosomal microarray analysis in invasive prenatal diagnosis.
        Hum Genet. 2012; 131: 513-523
        • Van Opstal D.
        • de Vries F.
        • Govaerts L.
        • et al.
        Benefits and burdens of using SNP array in pregnancies at increased risk for the common aneuploidies.
        Hum Mutat. 2015; 36: 319-326
        • Maya I.
        • Davidov B.
        • Gershovitz L.
        • et al.
        Diagnostic utility of array-based comparative genomic hybridization (aCGH) in a prenatal setting.
        Prenat Diagn. 2010; 30: 1131-1137
        • Oneda B.
        • Baldinger R.
        • Reissmann R.
        • et al.
        High-resolution chromosomal microarrays in prenatal diagnosis significantly increase diagnostic power.
        Prenat Diagn. 2014; 34: 525-533
        • Fiorentino F.
        • Napoletano S.
        • Caiazzo F.
        • et al.
        Chromosomal microarray analysis as a first-line test in pregnancies with a priori low risk for the detection of submicroscopic chromosomal abnormalities.
        Eur J Hum Genet. 2013; 21: 725-730
        • Wu Y.
        • Wang Y.
        • Tao J.
        • et al.
        The clinical use of chromosomal microarray analysis in detection of fetal chromosomal rearrangements: a study from China Mainland.
        Eur J Obstet Gynecol Reprod Biol. 2017; 212: 44-50
        • Coppinger J.
        • Alliman S.
        • Lamb A.N.
        • Torchia B.S.
        • Bejjani B.A.
        • Shaffer L.G.
        Whole-genome microarray analysis in prenatal specimens identifies clinically significant chromosome alterations without increase in results of unclear significance compared to targeted microarray.
        Prenat Diagn. 2009; 29: 1156-1166
        • Scott F.
        • Murphy K.
        • Carey L.
        • et al.
        Prenatal diagnosis using combined quantitative fluorescent polymerase chain reaction and array comparative genomic hybridization analysis as a first-line test: results from over 1000 consecutive cases.
        Ultrasound Obstet Gynecol. 2013; 41: 500-507
        • Konialis C.
        • Pangalos C.
        Dilemmas in prenatal chromosomal diagnosis revealed through a single center’s 30 years’ experience and 90,000 cases.
        Fetal Diagn Ther. 2015; 38: 218-232
        • Sotiriadis A.
        • Papoulidis
        • Siomou E.
        • et al.
        Non-invasive prenatal screening versus prenatal diagnosis by array comparative genomic hybridization: a comparative retrospective study.
        Prenat Diagn. 2017; 37: 583-592
        • Newcombe R.G.
        Interval estimation for the difference between independent proportions: comparison of eleven methods.
        Stat Med. 1998; 17: 873-890
        • Rosenfeld J.A.
        • Coe B.P.
        • Eichler E.E.
        • et al.
        Estimates of penetrance for recurrent pathogenic copy-number variations.
        Genet Med. 2013; 15: 478-481
        • Yu S.
        • Fiedler S.
        • Stegner A.
        • et al.
        Genomic profile of copy number variants on the short arm of human chromosome 8.
        Eur J Hum Genet. 2010; 18: 1114-1120
        • Wapner R.J.
        • Babiarz J.E.
        • Lev B.
        • et al.
        Expanding the scope of noninvasive prenatal testing: detection of fetal microdeletion syndromes.
        Am J Obstet Gynecol. 2015; 212: 332.e1-332.e9
        • Gross S.J.
        • Stosic M.
        • McDonald-McGinn D.M.
        • et al.
        Clinical experience with single-nucleotide polymorphism-based non-invasive prenatal screening for 22q11.2 deletion syndrome.
        Ultrasound Obstet Gynecol. 2016; 47: 177-183
        • Bianchi D.W.
        From prenatal genomic diagnosis to fetal personalized medicine: progress and challenges.
        Nat Med. 2012; 18: 1041-1051
        • Chitty L.S.
        • Hudgins L.
        • Norton M.E.
        Current controversies in prenatal diagnosis 2: cell-free DNA prenatal screening should be used to identify all chromosome abnormalities.
        Prenat Diagn. 2018; 38: 160-165
        • Snyder M.W.
        • Simmons L.E.
        • Kitzman J.O.
        • et al.
        Copy-number variation and false positive prenatal aneuploidy screening results.
        N Engl J Med. 2015; 372: 1639-1645
        • Carvalho C.M.B.
        • Lupski J.R.
        Mechanisms underlying structural variant formation in genomic disorders.
        Nat Rev Genet. 2016; 17: 224-238
        • Vogel I.
        • Petersen O.B.
        • Christensen R.
        • et al.
        Chromosomal microarray as primary diagnostic genomic tool for pregnancies at increased risk within a population based combined first-trimester screening program.
        Ultrasound Obstet Gynecol. 2018; 51: 480-486
        • Ravi H.
        • McNeill G.
        • Goel S.
        • et al.
        Validation of a SNP-based non-invasive prenatal test to detect the fetal 22q11.2 deletion in maternal plasma samples.
        PLoS One. 2018; 13: e0193476
        • Martin K.
        • Iyengar S.
        • Kalyan A.
        • et al.
        Clinical experience with a single-nucleotide polymorphism-based non-invasive prenatal test for five clinically significant microdeletions.
        Clin Genet. 2018; 93: 293-300
        • Evans M.I.
        • Wapner R.J.
        • Berkowitz R.L.
        Noninvasive prenatal screening or advanced diagnostic testing: caveat emptor.
        Am J Obstet Gynecol. 2016; 215: 298-305
        • Cheng Y.K.Y.
        • Leung W.C.
        • Choy K.W.
        • et al.
        Women’s preference for non-invasive prenatal DNA testing versus chromosomal microarray after screening for Down syndrome: a prospective study.
        BJOG. 2017; 125: 451-459
        • Akolekar R.
        • Beta J.
        • Picciarelli G.
        • Ogilvie C.
        • D’Antonio F.
        Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis.
        Ultrasound Obstet Gynecol. 2015; 45: 16-26
        • Malan V.
        • Bussières L.
        • Winer N.
        • et al.
        Effect of cell-free DNA screening vs direct invasive diagnosis on miscarriage rates in women with pregnancies at high risk of trisomy 21: a randomized clinical trial.
        JAMA. 2018; 320: 557-565
        • Lewis C.
        • Hill M.
        • Silcock C.
        • Daley R.
        • Chitty L.S.
        Non-invasive prenatal testing for trisomy 21: a cross-sectional survey of service users’ views and likely uptake.
        Br J Obstet Gynaecol. 2014; 121: 582-594
        • Lo T.K.
        • Chan K.Y.
        • Kan A.S.
        • So P.L.
        • Kong C.W.
        • Mak S.L.
        • Lee C.N.
        Informed choice and decision making in women offered cell-free DNA prenatal genetic screening.
        Prenat Diagno. 2017; 37: 299-302
        • Evans M.I.
        • Adriole S.
        • Curtis J.
        • Evans S.M.
        • Kessler A.A.
        • Rubenstein A.F.
        The epidemic of abnormal copy number variant cases missed because of reliance upon noninvasive prenatal screening.
        Prenat Diagn. 2018; 38: 730-734
        • Dong Z.
        • Wang H.
        • Chen H.
        • et al.
        Identification of balanced chromosomal rearrangements previously unknown among participants in the 1000 Genomes Project: implications for interpretation of structural variation in genomes and the future of clinical cytogenetics.
        Genet Med. 2018; 20: 697-707
        • Cheung S.W.
        • Bi W.
        Novel applications of array comparative genomic hybridization in molecular diagnostics.
        Exp Rev Mol Diagnost. 2018; 18: 531-542
        • Dong Z.
        • Zhang J.
        • Hu P.
        • et al.
        Low-pass whole-genome sequencing in clinical cytogenetics: a validated approach.
        Genet Med. 2016; 18: 940-948
        • Wang J.C.
        • Radcliff J.
        • Coe S.J.
        • Mahon L.W.
        Effects of platforms, size filter cutoffs, and targeted regions of cytogenomic microarray on detection of copy number variants and uniparental disomy in prenatal diagnosis: results from 5,026 pregnancies.
        Prenat Diagn. 2019; 39: 137-156
        • Grati F.R.
        • Gomes D.M.
        • Ferreira J.C.P.B.
        • et al.
        Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies.
        Prenat Diagn. 2015; 35: 1-9

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        American Journal of Obstetrics & GynecologyVol. 221Issue 6
        • Preview
          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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