SNP-Based Chromosomal Microarray Analysis for Detecting DNA Copy Number Variations in Fetuses with a Thickened Nuchal Fold

The aim of the study was to assess the diagnostic potential of SNP-based chromosomal microarray analysis for detecting pathogenic copies number variations (CNVs) in fetuses with a normal karyotype, in which an increase in the nuchal translucence of >2.5 mm was detected by ultrasound at a gestational age of 11 weeks to 13 weeks 6 days.

Materials and Methods. The study included 225 pregnant women who underwent invasive prenatal diagnostic procedures following the detection of an isolated thickening of the fetal nuchal fold. The fetal material obtained was examined using a cytogenetic test; if a normal karyotype was confirmed, chromosomal microarray analysis was performed as a second-line test.

Results. Pathogenic CNVs were detected in 22 of 225 fetuses (9.8%) with a normal karyotype. Of these 22 fetuses, pathogenic CNVs not classified as syndromes were detected in 14 cases (63.6%), and those previously described as syndromes — in 8 cases (36.4%). In 9 fetuses (41%), CNVs in two non-homologous chromosomes were determined; these findings indicated a high likelihood of carrying balanced translocations in the parents. Indeed, when analyzing the parent’s karyotype, in 8 out of 9 couples, balanced translocations were found in one of the parents.

Conclusion. Using chromosomal microarray analysis in fetuses with a thickened nuchal fold makes it possible to increase the ability to detect chromosomal imbalances, including those caused by pathological meiotic segregation of parental reciprocal translocation.

1. Nicolaides K.H. A model for a new pyramid of prenatal care based on the 11 to 13 weeks’ assessment. Prenat Diagn 2011; 31(1): 3–6, https://doi.org/10.1002/pd.2685.
2. Medvedev M.V., Altynnik N.A. Osnovy ul’trazvukovogo skrininga v 11–14 nedel’ beremennosti [The basics of ultrasound screening at 11–14 weeks of gestation]. Moscow: Real’noe vremya; 2014; p. 128.
3. Zolotukhina T.V., Yudina Ye.V., Shilova N.V., Minzhenkova M.E., Kozlova Yu.O., Markova Zh.G. Range of the rare chromosomal abnormalities diagnosed prenatally at fetuses with increased nuchal translucency. Zurnal akuserstva i zenskih boleznej 2013; 62(2): 88–92, https://doi.org/10.17816/jowd62288-92.
4. Kudryavtseva E.V., Kovalev V.V., Kanivets I.V., Kiyevskaia J.K., Korostelev S.A. The use of chromosomal micromatric analysis in prenatal diagnosis in Russia. Uralskij medicinskij zurnal 2017; 11: 12–15.
5. Dugoff L., Norton M.E., Kuller J.A. The use of chromosomal microarray for prenatal diagnosis. Am J Obstet Gynecol 2016; 215(4): B2–B9, https://doi.org/10.1016/j.ajog.2016.07.016.
6. Souka A.P., Krampl E., Bakalis S., Heath V., Nicolaides K.H. Outcome of pregnancy in chromosomally normal fetuses with increased nuchal translucency in the first trimester. Ultrasound Obstet Gynecol 2001; 18(1): 9–17, https://doi.org/10.1046/j.1469-0705.2001.00454.x.
7. Srebniak M.I., Diderich K.E.M., Joosten M., Govaerts L.C.P., Knijnenburg J., de Vries F.A.T., Boter M., Lont D., Knapen M.F.C.M., de Wit M.C., Go A.T.J.I., Galjaard R.J.H., Van Opstal D. Prenatal SNP array testing in 1000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs. Eur J Hum Genet 2016; 24(5): 645–651, https://doi.org/10.1038/ejhg.2015.193.
8. Hillman S.C., McMullan D.J., Hall G., Togneri F.S., James N., Maher E.J., Meller C.H., Williams D., Wapner R.J., Maher E.R., Kilby M.D. Use of prenatal chromosomal microarray: prospective cohort study and systematic review and meta-analysis. Ultrasound Obstet Gynecol 2013; 41(6): 610–620, https://doi.org/10.1002/uog.12464.
9. Äyräs O., Tikkanen M., Eronen M., Paavonen J., Stefanovic V. Increased nuchal translucency and pregnancy outcome: retrospective study of 1063 consecutive singleton pregnancies in a single referral institution. Prenat Diagn 2013; 33(9): 856–862, https://doi.org/10.1002/pd.4143.
10. Souka A.P., von Kaisenberg C.S., Hyett J.A., Sonek J.D., Nicolaides K.H. Increased nuchal translucency with normal karyotype. Am J Obstet Gynecol 2005; 192(4): 1005–1021, https://doi.org/10.1016/j.ajog.2004.12.093.
11. Shilova N.V., Minzhenkova M.E. Interpretation of clinically significant variations in the number of DNA copies. Medicinskaa genetika 2018; 17(10): 15–19.
12. Tsyvian P.B., Kovalev V.V., Kosovtsova N.V. Ultrasound markers of genetic pathology and early hemodynamic changes in human embryo. Hum Physiol 2014; 40(3): 340–343, https://doi.org/10.1134/s0362119714030189.
13. Cai M., Lin N., Su L., Wu X., Xie X., Li Y., Lin Y., Xu L., Huang H. Copy number variations in ultrasonically abnormal late pregnancy fetuses with normal karyotypes. Sci Rep 2020; 10(1): 15094, https://doi.org/10.1038/s41598-020-72157-6.
14. Callaway J.L., Shaffer L.G., Chitty L.S., Rosenfeld J.A., Crolla J.A. The clinical utility of microarray technologies applied to prenatal cytogenetics in the presence of a normal conventional karyotype: a review of the literature. Prenat Diagn 2013; 33(12): 1119–1123, https://doi.org/10.1002/pd.4209.
15. American College of Obstetricians and Gynecologists. Prenatal diagnostic testing for genetic disorders. Practice Bulletin No.162. Obstet Gynecol 2016; 127(5): e108–e122, https://doi.org/10.1097/aog.0000000000001405.
16. Yao R., Zhang C., Yu T., Li N., Hu X., Wang X., Wang J., Shen Y. Evaluation of three read-depth based CNV detection tools using whole-exome sequencing data. Mol Cytogenet 2017; 10: 30, https://doi.org/10.1186/s13039-017-0333-5.

Kievskaya J.K., Shilova N.V., Kanivets I.V., Kudryavtseva E.V., Pyankov D.V., Korostelev S.A. SNP-Based Chromosomal Microarray Analysis for Detecting DNA Copy Number Variations in Fetuses with a Thickened Nuchal Fold. Sovremennye tehnologii v medicine 2021; 13(6): 72, https://doi.org/10.17691/stm2021.13.6.08