BACKGROUND: Noninvasive prenatal testing (NIPT) is the most recent modality widely used in prenatal diagnostics. Commercially available NIPT has high sensitivity and specificity for the common fetal chromosomal aneuploidies. As future advancements in NIPT sequencing technology are becoming promising and more reliable, the ability to detect beyond aneuploidies and to expand detection of submicroscopic genomic alterations, as well as single-gene disorders might become possible. CASE PRESENTATION: Here we present a case of a 34-year-old pregnant woman, G2P1, who had NIPT screening which detected a terminal microduplication of 10.34 Mb on the long arm of chromosome 15 (15q26.1q26.3). Subsequent prenatal diagnostic testing including karyotype, microarray and fluorescence in situ hybridization (FISH) analyses were performed. Microarray testing confirmed and particularized a copy number gain of 10.66 Mb of the distal end of the long arm of chromosome 15. The G-banding cytogenetic studies yielded results consistent with unbalanced translocation between chromosome 15 and 18. To further characterize the abnormality involving the long arm of chromosome 18 and to map the genomic location of the duplicated 15q more precisely, FISH analysis using specific sub-telomeric probes was performed. FISH analysis confirmed that the extra duplicated segment of chromosome 15 is translocated onto the distal end of the long arm of chromosome 18 at band 18q23. Parental karyotype and FISH studies were performed to see if this unbalanced rearrangement was inherited from a healthy balanced translocation carrier versus being a de novo finding. Parental chromosomal analysis provided no evidence of a rearrangement between chromosome 15 and chromosome 18. The final fetal karyotype was reported as 46,XX,der(18)t(15;18)(q26.2;q23)dn. CONCLUSIONS: In this case study, the microduplication of fetal chromosome 15q26.1q26.3 was accurately detected using NIPT. Our results suggest that further refinements in NIPT have the potential to evolve to a powerful and efficient screening method, which might be used to detect a broad range of chromosomal imbalances. Since microduplications and microdeletions are a potential reportable result with NIPT, this must be included in pre-test counseling. Prenatal diagnostic testing of such findings is strongly recommended.

Department of Clinical Studies University of Ostrava 70300 Ostrava Czech Republic

Institute for Gynecology Perinatology and Infertility Mehmedbašić 71000 Sarajevo Bosnia and Herzegovina

Institute of Human Genetics Klinikum Rechts Der Isar Technical University of Munich 81675 Munich Germany

LIFE CODE Private Diagnostic Laboratory Medical Ltd 11523 Athens Greece

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Norem CT, Schoen EJ, Walton DL, Krieger RC, O’Keefe J, To TT, et al. Routine ultrasonography compared with maternal serum alpha-fetoprotein for neural tube defect screening. Obstet Gynecol. 2005;106(4):747–752. doi: 10.1097/01.AOG.0000178780.63956.3b. PubMed DOI

Salomon LJ, Sotiriadis A, Wulff CB, Odibo A, Akolekar R. Risk of miscarriage following amniocentesis or chorionic villus sampling: systematic review of literature and updated meta-analysis. Ultrasound Obstet Gynecol. 2019;54(4):442–451. doi: 10.1002/uog.20353. PubMed DOI

Norwitz ER, Levy B. Noninvasive prenatal testing: the future is now. Rev Obstet Gynecol. 2013;6(2):48–62. PubMed PMC

Hartwig TS, Ambye L, Sørensen S, Jørgensen FS. Discordant non-invasive prenatal testing (NIPT)—a systematic review. Prenat Diagn. 2017;37(6):527–539. doi: 10.1002/pd.5049. PubMed DOI

Dello Russo C, Cesta A, Longo S, et al. Validation of extensive next-generation sequencing method for monogenic disorder analysis on cell-free fetal DNA: noninvasive prenatal diagnosis. J Mol Diagn. 2019;21(4):572–579. doi: 10.1016/j.jmoldx.2019.02.010. PubMed DOI

Tjio JH, Levan A. The chromosome number of man. Hereditas. 1956;42(1–2):1–6.

Ford CE, Hamerton JL. The chromosomes of man. Nature. 1956;178(4541):1020–1023. doi: 10.1038/1781020a0. PubMed DOI

MIkkelsen M, Brondum-Nielsen K. Karyotype analysis and chromosome disorders. Prenat diagnosis screening London Churchill Livingstone. 1992;99–125.

Schonberg SA. Cytogenetic analysis in prenatal diagnosis. West J Med. 1993;159(3):360–365. PubMed PMC

Shaffer LG, Bui TH. Molecular cytogenetic and rapid aneuploidy detection methods in prenatal diagnosis. Am J Med Genet Part C Semin Med Genet. 2007;145(1):87–98. doi: 10.1002/ajmg.c.30114. PubMed DOI

McGowan-Jordan J, Hastings RJ, Moore S, editors. ISCN 2020: an international system for human cytogenomic nomenclature. Basel: Karger; 2020. PubMed

Beta J, Lesmes-Heredia C, Bedetti C, Akolekar R. Risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review of the literature. Minerva Ginecol. 2018;70(2):215–219. PubMed

Srinivasan A, Bianchi DW, Huang H, Sehnert AJ, Rava RP. Noninvasive detection of fetal subchromosome abnormalities via deep sequencing of maternal plasma. Am J Hum Genet. 2013;92(2):167–176. doi: 10.1016/j.ajhg.2012.12.006. PubMed DOI PMC

Yin L, Tang Y, Lu Q, Shi M, Pan A, Chen D. Noninvasive prenatal testing detects microdeletion abnormalities of fetal chromosome 15. J Clin Lab Anal. 2019;33(6):13–17. doi: 10.1002/jcla.22911. PubMed DOI PMC

Gou L, Suo F, Wang Y, et al. Clinical value for the detection of fetal chromosomal deletions/duplications by noninvasive prenatal testing in clinical practice. Mol Genet Genomic Med. 2021;9(6):e1687. doi: 10.1002/mgg3.1687. PubMed DOI PMC

Rafalko J, Soster E, Caldwell S, et al. Genome-wide cell-free DNA screening: a focus on copy-number variants. Genet Med. 2021;23(10):1847–1853. doi: 10.1038/s41436-021-01227-5. PubMed DOI PMC

Gregg AR, Skotko BG, Benkendorf JL, 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(10):1056–1065. doi: 10.1038/gim.2016.97. PubMed DOI

Leffler M, Puusepp S, Žilina O, et al. Two familial microduplications of 15q26.3 causing overgrowth and variable intellectual disability with normal copy number of IGF1R. Eur J Med Genet. 2016;59(4):257–262. doi: 10.1016/j.ejmg.2015.12.002. PubMed DOI

Chen CP, Lin YH, Au HK, et al. Chromosome 15q overgrowth syndrome: prenatal diagnosis, molecular cytogenetic characterization, and perinatal findings in a fetus with dup(15)(q26.2q26.3) Taiwan J Obstet Gynecol. 2011;50(3):359–365. doi: 10.1016/j.tjog.2011.07.004. PubMed DOI

Faivre L, Gosset P, Cormier-Daire V, et al. Overgrowth and trisomy 15q26.1-qter including the IGF1 receptor gene: report of two families and review of the literature. Eur J Hum Genet. 2002;10(11):699–706. doi: 10.1038/sj.ejhg.5200879. PubMed DOI

Tatton-Brown K, Pilz DT, Örstavik KH, Patton M, Barber JCK, Collinson MN, et al. 15q overgrowth syndrome: a newly recognized phenotype associated with overgrowth, learning difficulties, characteristic facial appearance, renal anomalies and increased dosage of distal chromosome 15q. Am J Med Genet Part A. 2009;149(2):147–154. doi: 10.1002/ajmg.a.32534. PubMed DOI

Okubo Y, Siddle K, Firth H, O’Rahilly S, Wilson LC, Willatt L, et al. Cell proliferation activities on skin fibroblasts from a short child with absence of one copy of the type 1 insulin-like growth factor receptor (IGF1R) gene and a tall child with three copies of the IGF1R gene. J Clin Endocrinol Metab. 2003;88(12):5981–5988. doi: 10.1210/jc.2002-021080. PubMed DOI

Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175–2184. doi: 10.1056/NEJMoa1203382. PubMed DOI PMC