Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

Genome wide noninvasive prenatal testing detects microduplication of the distal end of chromosome 15 in a fetus: a case report

Genome wide noninvasive prenatal testing detects microduplication of the distal end of chromosome... 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 disor‑ ders 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 transloca‑ tion carrier versus being a de novo finding. Parental chromosomal analysis provided no evidence of a rearrange ‑ ment 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 effi‑ cient screening method, which might be used to detect a broad range of chromosomal imbalances. Since microdu‑ plications 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. Keywords: Noninvasive prenatal test, 15q26.1‑ qter partial trisomy, Microduplication, Prenatal testing Introduction The use of maternal serum marker screening and *Correspondence: aida@mehmedbasic.ba ultrasound imaging (ultrasonography) to detect chro- Institute for Gynecology, Perinatology, and Infertility “Mehmedbašić”, mosome aneuploidies and other birth defects are tra- 71000 Sarajevo, Bosnia and Herzegovina Full list of author information is available at the end of the article ditional approaches of prenatal care in the first and/ © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 2 of 7 or second trimesters [1]. If these tests indicate that a Clinical course fetus is at an increased risk for a genetic disorder, inva- A 34-year-old pregnant woman, G2P1, gestational age sive methods such as chorionic villus sampling (CVS) 10 weeks and 5 days, came to prenatal clinic for routine or amniocentesis are recommended for diagnostic test- prenatal care. Patient elected to screen for the common ing. More recently, large systemic review reported sig- fetal chromosomal aneuploidies using NIFTY standard nificantly lower procedure related risks of pregnancy panel. Routine first trimester ultrasound examination complications, including miscarriage [2]. The use of did not indicate any fetal abnormalities. No history of non-invasive prenatal screening test (NIPT) has grown spontaneous abortions was reported. Family history rapidly, leading to a simultaneous reduction in the was remarkable, no chromosomal anomalies or other application of traditional analyte screening tests and genetic disorders were reported. invasive diagnostic procedures [3]. Clinical translation of NIPT technologies has revo- lutionized prenatal care. NIPT measures and evaluates Materials and methods small fragments of placental DNA that are circulating in Noninvasive prenatal screening a pregnant woman’s blood. The cell-free DNA (cfDNA) Noninvasive screening test was performed at NIFTY in maternal plasma reflects the genetic makeup of the (powered by Geneplanet, Ljubljana,  Slovenia). A blood developing fetus. Commercially available NIPT is used sample required (minimum of 10  ml) for NIPT testing as a prenatal screening technique allowing for detection was drawn at > 10  weeks of gestation. NIFTY standard of the most common autosomal and sex chromosome panel screens for the common autosomal aneuploidies aneuploidies. Further advances in NIPT technology have and sex chromosome aneuploidies. shown that micropulications and microdeletions can be detected. Many professional societies currently rec- ommend that NIPT be used as a screening tool, not a Genomic microarray analysis definitive diagnostic test; therefore, when cell-free DNA Genomic microarray analysis on isolated DNA from results are at high risk, the diagnosis requires subsequent amniotic fluid cells was performed at Life Code Labo - follow-up testing by means of genetic analysis of samples ratories (Athens, Greece). Briefly, genomic DNA from collected invasively. NIPT provides high sensitivity (true amniotic fluid was extracted using NucleoSpin blood positive rate) and specificity (true negative rate), making extraction kit by Macherey–Nagel. CytoScan Optima it an attractive alternative to the serum screens and inva- Array by Affymetrix (Santa Clara, CA, USA) was used sive diagnostics currently in use [4, 5]. for the detection of copy number variations (CNV) and A normal human cell is made up of 46 chromosomes loss of heterozygosity (LOH), according to manufac- that are grouped into 24 different types and arranged turer’s instructions. Results were analyzed using Chro- in 23 homologous pairs. Of those 23 pairs, 22 are auto- mosome Analysis Suite (ChAS). Additional databases somes, and the remaining pair is comprised of the two referenced for the analysis included: Decipher, DGV, different types of two sex chromosomes, which specify ClinVar, OMIM, NetAffyx, UCSC, and Ensemble. gender (XX for female and XY for male) [6]. Each chro- mosomal homologous pair consists of one maternal and one paternal chromosome that pair up with each other Chromosomal karyotype analysis inside a cell during meiosis [7]. Chromosomal disor- Cytogenetic analysis on long-term cultured amniocytes ders mostly fall into two main categories: numerical and was performed using standard cytogenetic techniques structural abnormalities [8]. Chromosomal anomalies or according to specimen specific protocols, in accord - aneuploidies, represented primarily by numerical change, ance with the European Society of Human Genetics are the single greatest contributor to prenatal morbid- (ESHG) and European Cytogenetics Association (E.C.A) ity and mortality [9]. Karyotyping, fluorescence in  situ guidelines. Chromosomes were aged and banded using hybridization (FISH), quantitative fluorescence polymer - G-bands by pancreatin and Giemsa staining technique. ase chain reaction (QF-PCR), chromosomal microarray To investigate the total number and structure of the (CMA), and the next-generation sequencing (NGS) are chromosomes, twenty metaphase cells were visualized the common methods used for prenatal diagnostics [10]. and analyzed by qualified cytogenetics technologist using Herein, we present a clinical prenatal case in which Zeiss microscope Axioskop2 plus (Zeiss, Jena, Germany) NIPT testing detected a 10.34  Mb gain (duplication) of with the assistance of the Metasystems imaging sys- the long arm of chromosome 15. Clinical value of NIPT tem. Furthermore, to rule out a balanced chromosomal finding was further confirmed by microarray analysis in rearrangement, involving chromosome 15, parental conjunction with karyotyping and FISH analysis. S ahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 3 of 7 chromosome analysis from a stimulated peripheral blood reported by noninvasive prenatal testing as an incidental lymphocytes was performed. finding. Reported fetal cfDNA was 10.66%. Amniocen - tesis was performed under the guidance of ultrasound, Fluorescence in situ hybridization (FISH) where approximately 18  ml of amniotic fluid was with - Fluorescence In  Situ Hybridization (FISH) was per- drawn by syringe for diagnostic studies. formed at the Klinikum rechts der Isar laboratories (Munich, Germany). FISH analysis was performed using Microarray analysis commercial Vysis sub-telomeric probes for chromosome The results of the chromosomal microarray analysis con - 15 (D15Z1, D15S936) and 18 (D18S552, VIJyRM2050). firmed the presence of a pathogenic 10.66  Mb gain of All specimen types were subjected to standard FISH the distal end of chromosome 15, chromosomal region pretreatment, hybridization, and fluorescence micros - 15q26.1q26.3. More specifically, the duplicated seg - copy according to the manufacturer’s specifications and ment includes the chromosomal region between bases standard specimen specific laboratory protocols. The 91,763,147 and 102,429,112, encompassing 22 OMIM results of genetic testing were described and reported in genes (NCBI Build 37/hg19) (Fig.  1A and B). No other accordance with the International Standing Committee copy number variants were detected, using laboratory’s on Human Cytogenetic Nomenclature [11]. evaluation criteria. To further characterize this observa- tion, additional studies were completed using G-banding Results analysis. Noninvasive prenatal testing Professional and detailed genetic counseling regard- Amniotic fluid karyotype analysis ing the NIPT screening, purpose, significance, accuracy, Upon analysis of G-banded karyotype obtained from limitations, and other screening and diagnostic testing amniotic fluid, it was determined that chromosome 15 options was provided. Informed consent for genetic test- does not contain any obvious abnormalities. However, ing was obtained. A duplication of 10.34  Mb of the long the banding pattern on the long arm of chromosome arm of chromosome 15, specifically 15q26.1-q26.3 was 18 had an atypical appearance and was suggestive of Fig. 1 Microarray profile depicting gain (partial trisomy) of the distal long arm of chromosome 15. Representative microarray profile of the fetus showing copy number state and Log2 ratio (A‑top panel) and the whole genome view (B‑lower panel) are shown for chromosome 15 (arrows) Sahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 4 of 7 Parental karyotype analysis additional chromatin present on the distal end of the long No structural or numerical chromosomal anomalies were arm. These findings indicated that the additional chro - detected in parental chromosome analysis (Fig.  3 A and matin probably originated from the long arm of chro- B). mosome 15 (Fig.  2A). The chromosomal morphology/ banding of the cells was compromised, precluding our Parental FISH analysis ability to fully characterize the abnormalities present. In Parental metaphase FISH analysis showed the expected an attempt to better characterize structural abnormali- number of probes (2 signals for each probe) present, and ties involving chromosomes 15 and 18 observed in the the probes were localized to their anticipated sub-telom- G-banded karyotype analysis, additional studies were eric bands. There was no evidence for loss or gain of the completed using FISH techniques (Fig. 2B). p or q subtelomeric regions for the chromosomal regions evaluated. Thus, parental FISH studies provided no evi - Amniotic fluid FISH analysis dence for a rearrangement between chromosome 15 and FISH analysis was performed using sub-telomeric probes chromosome 18 (Fig. 3 C and D). for the long arm of chromosomes 15 (green signal) and 18 (red signal). Following hybridization, the probe signal Discussion pattern noted was three signals (trisomic imbalance) for Because of improvements in the safety of invasive proce- chromosome 15q and two signals for chromosome 18q. dures and advances in technology, the most recent sys- Two green signals localized to anticipated chromosome tematic reviews demonstrated pregnancy loss rates for 15q region, the third signal being localized to structur- CVS and amniocentesis to be less than 1.0% [2, 12]. Natu- ally abnormal chromosome 18q, resulting in an unbal- rally, parents-to-be are anxious to have results as early as anced rearrangement indicated by a single fusion signal possible. Cell-free DNA screening takes the advantage of (Fig. 2B). being able to be performed as early as 10 weeks, without Studies for sub-telomeric region of the long arm of the need of an invasive procedure. Noninvasive prenatal chromosome 18, showed two probe signals and the screening test has sensitivities and specificities approach - probes were localized to their anticipated 18q sub-telom- ing 99%. While NIPT detects aneuploidies with a high eric bands. Thus, the FISH studies provided no evidence degree of certainty, it is, so far, less reliable in detecting for a rearrangement or loss of the sub-telomeric region microdeletions and duplications in fetal genomes smaller of chromosome 18. The FISH test confirmed the charac - than 5  Mb [13, 14]. Recently, large number of validation terization of the abnormalities involving chromosomes studies reporting the PPV of NIPT for the detection of 15 and 18 that were noted in both the microarray and CNVs have been published. Gou et al. demonstrated that G-banding analyses. Fig. 2 A Amniotic fluid karyotype analysis showing additional genetic material on the distal end of the long arm of chromosome 18q23 (arrow). B Sequential metaphase FISH analysis utilizing sub‑telomeric probes for chromosome 15 (green) and chromosome 18 (red), showing three green signals: two on the normal 15q, and the yellow signal representing a single fusion located on the distal long arm of chromosome 18 S ahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 5 of 7 Fig. 3 A Parental phytohemagglutinin (PHA) stimulated cultured peripheral blood karyograms showing normal karyotypes: A. Maternal karyotype: 46,XX. B Paternal karyotype: 46,XY. C (maternal) and D (paternal). Metaphase FISH analysis showing the presence of the expected number of probes present and the probes were localized to their anticipated regions: two aqua signals for centromeric region (D15Z1) and two orange signals for sub‑telomeric region (D15S936) of chromosome 15; two green signals for 18p sub ‑telomeric probe (D18S552) and two orange signals for 18q sub‑telomeric region ( VIJyRM2050) the PPV of recurrent CNVs seemed to be higher than region [18–20]. The breakpoints and extent of the dupli - that of rare chromosomal deletions/duplications [15]. cated segment are variable among patients. The clinical Furthermore, a recent study by Rafalko et  al. reported outcome and severity of physical findings varies from higher PPV for complex CNVs (93.9%) compared to iso- case to case, depending on the length and the genes lated CNVs (61.0%) [16]. involved in the duplicated region of the chromosome [19, A concern is that as higher proportions of the genome 21]. Specifically, duplication of type 1 insulin-like growth are analyzed, false positive and false negative results are factor 1 receptor (IGF1R) (OMIM 147,370) gene located expected to increase, which would result in an increase at 15q26.3 is thought to lead to overgrowth, whereas hap- in unnecessary invasive procedures [17]. NIPT is still loinsufficiency of IGF1R can cause growth restriction a screening test. During pre-test counseling, women [19–22]. The majority of cases reported have resulted should be informed about the accuracy, reliability, false from de novo unbalanced translocations, and the second positive, and false negative rates. According to current chromosome involved in the translocation has varied. NIPT guidelines, ACMG strongly recommends all posi- Although many large duplications can be appreciated by tive NIPT findings to be confirm by invasive prenatal routine karyotyping, detection of this duplication gener- diagnostic testing [17]. In addition, diagnostic follow up ally requires analysis by fluorescence in situ hybridization testing with CMA should be offered when NIPT identi - and chromosomal microarray. Abnormalities involving fies a CNV [17]. sub-telomeric regions can be difficult to visualize well Partial trisomy of the distal 15q is a rare chromosomal using conventional cytogenetics methods  (G-banding disorder. In general, the duplication of 15q has been analysis). characterized by prenatal and postnatal overgrowth, Previous study has detected the deletion of 5  Mb in craniosynostosis, distinct facial features, and intellec- fetal chromosome 15q11.2q13.1 and was further con- tual disability, likely reflecting triplosensitivity for one firmed by CNV and karyotype analysis [14]. Our study or more of the several genes that are found within this reports a duplication of about 10  Mb in size detected Sahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 6 of 7 using NIPT. A finding of duplication of a 10.34 Mb frag - approximately 1.7% of all structurally normal pregnancies ment located on 15q26.1q26.3 by NIPT was confirmed [23]. There is a potentially high value in microdeletion/ using various genetic modalities. The existence of dupli - microduplication NIPT testing mainly for CNVs with cation of material from chromosome 15 was established substantial morbidity and mortality such as 22q11.2 syn- and further delineated by microarray, followed by the drome. With the typical ultrasound and screening testing karyotype analysis and FISH. Detection of microdele- many of these cases can go unnoticed or detected late in tions or duplications can be very difficult using G-band - pregnancy. In these terms NIPT screening could offer an ing karyotyping analysis from amniotic fluid. Therefore, early diagnosis, pregnancy intervention, and coordinated to pinpoint the exact location of the duplicated fragment neonatal management. It is a fact that NIPT screening is and to visualize the whole chromosomal complement, still in its infancy, facing a lot of challenges and in need subtelomeric probes for the distal portion of chromo- of further validation, but such difficulties are expected somes 15q and 18q were used. The final karyotype from in the introduction of any new prenatal screening test. amniotic fluid was reported as 46,XX,der(18)t(15;18) Calculation of the test specifications (sensitivity, specific - (q26.1;q23)dn. ity, PPV, NPV) for submicroscopic imbalances are lim- Without molecular cytogenetic testing modalities, a ited due to lack of confirmatory genetic testing and the dup(15)(q26.1q26.3) would have been suggested, but a prevalence of the disease. Having in mind that all screen- derivative chromosome 18 would not have been detected. ing tests have to balance between medical benefits and CNV analyses provide information whether copy number the burden of a false-positive or uncertain finding, NIPT gains and losses are present but not whether they have could evolve in another complementary screening tool been translocated from their normal position(s) in the for early detection of many known syndromes. genome. Thus, confirmation of suspected chromosome abnormalities by FISH and chromosome analysis may be Abbreviations necessary to determine the nature of an abnormality. NIPT: Noninvasive prenatal test; FISH: Fluorescence in situ hybridization; The pregnancy reported in this paper ended in an CVS: Chorionic villus sampling; QF‑PCR: Quantitative fluorescence polymer ‑ ase chain reaction; CMA: Chromosomal microarray; NGS: Next‑ generation elective interruption of pregnancy. Since unbalanced sequencing; CNV: Copy number variations; LOH: Loss of heterozygosity; ChAS: translocations can result from either de novo event or Chromosome Analysis Suite; ESGH: European Society of Human Genetics; the malsegregation of a balanced parental translocation, E.C.A.: European Cytogenetics Association; cfDNA: Cell‑free DNA; ACMG: American College of Medical Genetics; IGF1R: Insulin‑like growth factor 1 parental chromosomal studies were completed to see receptor; OMIM: Online Mendelian Inheritance in Man; PPV: Positive predicted if either of them is a balanced carrier of a translocation value; NPV: Negative predicted value. involving chromosome 15 and 18. Due to lack of precise Acknowledgements and targeted genomic testing done in Bosnia and Her- We thank the family for participating in this study. zegovina, diagnostic follow up testing was done in col- laboration with laboratories in Greece and Germany. Authors’ contributions H.S. contributed with figure designs and assisted in writing and formatting the Parental karyotype and FISH analysis were normal with manuscript. A.D. and F.I. performed, interpreted, and reported microarray anal‑ no genetic aberrations. The couple has another healthy ysis. S.LF. and S.A. performed all the FISH testing and parental chromosomal child with unknown karyotype. The de novo origin of the analyses and interpretation. S.M. provided guidance, performed ultrasounds and amniocenteses. A.C. selected, directed, and collected reported data. All 15q duplication is consistent with the fact that there is authors read and approved the final version of the manuscript. no prior history of spontaneous abortions and no family history of chromosomal anomalies or genetic disorders. Funding This research did not receive any specific grant from funding agencies in the Moreover, it is important to note that negative results in public, commercial, or non‑for ‑profit sectors. both parents cannot exclude the possibility of parental gonadal mosaicism, thus leading to minor recurrence risk Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or in subsequent pregnancies. analyzed during the current study. Conclusion Declarations In conclusion, this case report shows that the resolution of current NIPT technology has the potential to detect Ethics approval and consent to participate No ethics committee approval was required, because this was a clinical case submicroscopic aberrations. The clinical application of report of a single patient. Patient consent to participate was obtained. NIPT screening can be second best choice when patients refuse invasive diagnostic testing, especially for those Consent for publication Consent for publication was obtained. with no ultrasound findings and no family history. It is clear that NIPT can potentially detect clinically signifi - Competing interests cant unbalanced chromosomal abnormalities present in The authors declare no competing interests. S ahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 7 of 7 Author details 21. Tatton‑Brown K, Pilz DT, Örstavik KH, Patton M, Barber JCK, Collinson MN, Department of Clinical Studies, University of Ostrava, 70300 Ostrava, Czech et al. 15q overgrowth syndrome: a newly recognized phenotype associ‑ Republic. Institute of Human Genetics, Klinikum Rechts Der Isar, Technical ated with overgrowth, learning difficulties, characteristic facial appear ‑ University of Munich, 81675 Munich, Germany. LIFE CODE Private Diagnos‑ ance, renal anomalies and increased dosage of distal chromosome 15q. tic Laboratory, Medical Ltd., 11523 Athens, Greece. Institute for Gynecol‑ Am J Med Genet Part A. 2009;149(2):147–54. ogy, Perinatology, and Infertility “Mehmedbašić”, 71000 Sarajevo, Bosnia 22. Okubo Y, Siddle K, Firth H, O’Rahilly S, Wilson LC, Willatt L, et al. Cell and Herzegovina. 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 Received: 7 November 2021 Accepted: 15 March 2022 and a tall child with three copies of the IGF1R gene. J Clin Endocrinol Metab. 2003;88(12):5981–8. 23. Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175–84. References Publisher’s Note 1. Norem CT, Schoen EJ, Walton DL, Krieger RC, O’Keefe J, To TT, et al. Rou‑ Springer Nature remains neutral with regard to jurisdictional claims in pub‑ tine ultrasonography compared with maternal serum alpha‑fetoprotein lished maps and institutional affiliations. for neural tube defect screening. Obstet Gynecol. 2005;106(4):747–52. 2. 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):442–51. 3. Norwitz ER, Levy B. Noninvasive prenatal testing: the future is now. Rev Obstet Gynecol. 2013;6(2):48–62. 4. Hartwig TS, Ambye L, Sørensen S, Jørgensen FS. Discordant non‑ invasive prenatal testing (NIPT )—a systematic review. Prenat Diagn. 2017;37(6):527–39. 5. Dello Russo C, Cesta A, Longo S, et al. Validation of extensive next‑ gener‑ ation sequencing method for monogenic disorder analysis on cell‑free fetal DNA: noninvasive prenatal diagnosis. J Mol Diagn. 2019;21(4):572–9. 6. Tjio JH, Levan A. The chromosome number of man. Hereditas. 1956;42(1–2):1–6. 7. Ford CE, Hamerton JL. The chromosomes of man. Nature. 1956;178(4541):1020–3. 8. MIkkelsen M, Brondum‑Nielsen K. Karyotype analysis and chromosome disorders. Prenat diagnosis screening London Churchill Livingstone. 1992;99–125. 9. Schonberg SA. Cytogenetic analysis in prenatal diagnosis. West J Med. 1993;159(3):360–5. 10. Shaffer LG, Bui TH. Molecular cytogenetic and rapid aneuploidy detec‑ tion methods in prenatal diagnosis. Am J Med Genet Part C Semin Med Genet. 2007;145(1):87–98. 11. McGowan‑ Jordan J, Hastings RJ, Moore S, editors. ISCN 2020: an interna‑ tional system for human cytogenomic nomenclature. Basel: Karger; 2020. 12. Beta J, Lesmes‑Heredia C, Bedetti C, Akolekar R. Risk of miscarriage follow‑ ing amniocentesis and chorionic villus sampling: a systematic review of the literature. Minerva Ginecol. 2018;70(2):215–9. 13. 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):167–76. 14. 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):13–7. 15. 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. 16. Rafalko J, Soster E, Caldwell S, et al. Genome‑ wide cell‑free DNA screen‑ ing: a focus on copy‑number variants. Genet Med. 2021;23(10):1847–53. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : 17. Gregg AR, Skotko BG, Benkendorf JL, et al. Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of fast, convenient online submission the American College of Medical Genetics and Genomics. Genet Med. thorough peer review by experienced researchers in your field 2016;18(10):1056–65. 18. Leffler M, Puusepp S, Žilina O, et al. Two familial microduplications of rapid publication on acceptance 15q26.3 causing overgrowth and variable intellectual disability with support for research data, including large and complex data types normal copy number of IGF1R. Eur J Med Genet. 2016;59(4):257–62. • gold Open Access which fosters wider collaboration and increased citations 19. Chen CP, Lin YH, Au HK, et al. Chromosome 15q overgrowth syndrome: maximum visibility for your research: over 100M website views per year prenatal diagnosis, molecular cytogenetic characterization, and perinatal • findings in a fetus with dup(15)(q26.2q26.3). Taiwan J Obstet Gynecol. 2011;50(3):359–65. At BMC, research is always in progress. 20. Faivre L, Gosset P, Cormier‑Daire V, et al. Overgrowth and trisomy 15q26.1‑ Learn more biomedcentral.com/submissions qter including the IGF1 receptor gene: report of two families and review of the literature. Eur J Hum Genet. 2002;10(11):699–706. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Molecular Cytogenetics Springer Journals

Genome wide noninvasive prenatal testing detects microduplication of the distal end of chromosome 15 in a fetus: a case report

Download PDF
7 pages

Loading next page...
 
/lp/springer-journals/genome-wide-noninvasive-prenatal-testing-detects-microduplication-of-i5ELiUTMii

References (21)

Publisher
Springer Journals
Copyright
Copyright © The Author(s) 2022
eISSN
1755-8166
DOI
10.1186/s13039-022-00592-3
Publisher site
See Article on Publisher Site

Abstract

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 disor‑ ders 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 transloca‑ tion carrier versus being a de novo finding. Parental chromosomal analysis provided no evidence of a rearrange ‑ ment 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 effi‑ cient screening method, which might be used to detect a broad range of chromosomal imbalances. Since microdu‑ plications 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. Keywords: Noninvasive prenatal test, 15q26.1‑ qter partial trisomy, Microduplication, Prenatal testing Introduction The use of maternal serum marker screening and *Correspondence: aida@mehmedbasic.ba ultrasound imaging (ultrasonography) to detect chro- Institute for Gynecology, Perinatology, and Infertility “Mehmedbašić”, mosome aneuploidies and other birth defects are tra- 71000 Sarajevo, Bosnia and Herzegovina Full list of author information is available at the end of the article ditional approaches of prenatal care in the first and/ © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 2 of 7 or second trimesters [1]. If these tests indicate that a Clinical course fetus is at an increased risk for a genetic disorder, inva- A 34-year-old pregnant woman, G2P1, gestational age sive methods such as chorionic villus sampling (CVS) 10 weeks and 5 days, came to prenatal clinic for routine or amniocentesis are recommended for diagnostic test- prenatal care. Patient elected to screen for the common ing. More recently, large systemic review reported sig- fetal chromosomal aneuploidies using NIFTY standard nificantly lower procedure related risks of pregnancy panel. Routine first trimester ultrasound examination complications, including miscarriage [2]. The use of did not indicate any fetal abnormalities. No history of non-invasive prenatal screening test (NIPT) has grown spontaneous abortions was reported. Family history rapidly, leading to a simultaneous reduction in the was remarkable, no chromosomal anomalies or other application of traditional analyte screening tests and genetic disorders were reported. invasive diagnostic procedures [3]. Clinical translation of NIPT technologies has revo- lutionized prenatal care. NIPT measures and evaluates Materials and methods small fragments of placental DNA that are circulating in Noninvasive prenatal screening a pregnant woman’s blood. The cell-free DNA (cfDNA) Noninvasive screening test was performed at NIFTY in maternal plasma reflects the genetic makeup of the (powered by Geneplanet, Ljubljana,  Slovenia). A blood developing fetus. Commercially available NIPT is used sample required (minimum of 10  ml) for NIPT testing as a prenatal screening technique allowing for detection was drawn at > 10  weeks of gestation. NIFTY standard of the most common autosomal and sex chromosome panel screens for the common autosomal aneuploidies aneuploidies. Further advances in NIPT technology have and sex chromosome aneuploidies. shown that micropulications and microdeletions can be detected. Many professional societies currently rec- ommend that NIPT be used as a screening tool, not a Genomic microarray analysis definitive diagnostic test; therefore, when cell-free DNA Genomic microarray analysis on isolated DNA from results are at high risk, the diagnosis requires subsequent amniotic fluid cells was performed at Life Code Labo - follow-up testing by means of genetic analysis of samples ratories (Athens, Greece). Briefly, genomic DNA from collected invasively. NIPT provides high sensitivity (true amniotic fluid was extracted using NucleoSpin blood positive rate) and specificity (true negative rate), making extraction kit by Macherey–Nagel. CytoScan Optima it an attractive alternative to the serum screens and inva- Array by Affymetrix (Santa Clara, CA, USA) was used sive diagnostics currently in use [4, 5]. for the detection of copy number variations (CNV) and A normal human cell is made up of 46 chromosomes loss of heterozygosity (LOH), according to manufac- that are grouped into 24 different types and arranged turer’s instructions. Results were analyzed using Chro- in 23 homologous pairs. Of those 23 pairs, 22 are auto- mosome Analysis Suite (ChAS). Additional databases somes, and the remaining pair is comprised of the two referenced for the analysis included: Decipher, DGV, different types of two sex chromosomes, which specify ClinVar, OMIM, NetAffyx, UCSC, and Ensemble. gender (XX for female and XY for male) [6]. Each chro- mosomal homologous pair consists of one maternal and one paternal chromosome that pair up with each other Chromosomal karyotype analysis inside a cell during meiosis [7]. Chromosomal disor- Cytogenetic analysis on long-term cultured amniocytes ders mostly fall into two main categories: numerical and was performed using standard cytogenetic techniques structural abnormalities [8]. Chromosomal anomalies or according to specimen specific protocols, in accord - aneuploidies, represented primarily by numerical change, ance with the European Society of Human Genetics are the single greatest contributor to prenatal morbid- (ESHG) and European Cytogenetics Association (E.C.A) ity and mortality [9]. Karyotyping, fluorescence in  situ guidelines. Chromosomes were aged and banded using hybridization (FISH), quantitative fluorescence polymer - G-bands by pancreatin and Giemsa staining technique. ase chain reaction (QF-PCR), chromosomal microarray To investigate the total number and structure of the (CMA), and the next-generation sequencing (NGS) are chromosomes, twenty metaphase cells were visualized the common methods used for prenatal diagnostics [10]. and analyzed by qualified cytogenetics technologist using Herein, we present a clinical prenatal case in which Zeiss microscope Axioskop2 plus (Zeiss, Jena, Germany) NIPT testing detected a 10.34  Mb gain (duplication) of with the assistance of the Metasystems imaging sys- the long arm of chromosome 15. Clinical value of NIPT tem. Furthermore, to rule out a balanced chromosomal finding was further confirmed by microarray analysis in rearrangement, involving chromosome 15, parental conjunction with karyotyping and FISH analysis. S ahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 3 of 7 chromosome analysis from a stimulated peripheral blood reported by noninvasive prenatal testing as an incidental lymphocytes was performed. finding. Reported fetal cfDNA was 10.66%. Amniocen - tesis was performed under the guidance of ultrasound, Fluorescence in situ hybridization (FISH) where approximately 18  ml of amniotic fluid was with - Fluorescence In  Situ Hybridization (FISH) was per- drawn by syringe for diagnostic studies. formed at the Klinikum rechts der Isar laboratories (Munich, Germany). FISH analysis was performed using Microarray analysis commercial Vysis sub-telomeric probes for chromosome The results of the chromosomal microarray analysis con - 15 (D15Z1, D15S936) and 18 (D18S552, VIJyRM2050). firmed the presence of a pathogenic 10.66  Mb gain of All specimen types were subjected to standard FISH the distal end of chromosome 15, chromosomal region pretreatment, hybridization, and fluorescence micros - 15q26.1q26.3. More specifically, the duplicated seg - copy according to the manufacturer’s specifications and ment includes the chromosomal region between bases standard specimen specific laboratory protocols. The 91,763,147 and 102,429,112, encompassing 22 OMIM results of genetic testing were described and reported in genes (NCBI Build 37/hg19) (Fig.  1A and B). No other accordance with the International Standing Committee copy number variants were detected, using laboratory’s on Human Cytogenetic Nomenclature [11]. evaluation criteria. To further characterize this observa- tion, additional studies were completed using G-banding Results analysis. Noninvasive prenatal testing Professional and detailed genetic counseling regard- Amniotic fluid karyotype analysis ing the NIPT screening, purpose, significance, accuracy, Upon analysis of G-banded karyotype obtained from limitations, and other screening and diagnostic testing amniotic fluid, it was determined that chromosome 15 options was provided. Informed consent for genetic test- does not contain any obvious abnormalities. However, ing was obtained. A duplication of 10.34  Mb of the long the banding pattern on the long arm of chromosome arm of chromosome 15, specifically 15q26.1-q26.3 was 18 had an atypical appearance and was suggestive of Fig. 1 Microarray profile depicting gain (partial trisomy) of the distal long arm of chromosome 15. Representative microarray profile of the fetus showing copy number state and Log2 ratio (A‑top panel) and the whole genome view (B‑lower panel) are shown for chromosome 15 (arrows) Sahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 4 of 7 Parental karyotype analysis additional chromatin present on the distal end of the long No structural or numerical chromosomal anomalies were arm. These findings indicated that the additional chro - detected in parental chromosome analysis (Fig.  3 A and matin probably originated from the long arm of chro- B). mosome 15 (Fig.  2A). The chromosomal morphology/ banding of the cells was compromised, precluding our Parental FISH analysis ability to fully characterize the abnormalities present. In Parental metaphase FISH analysis showed the expected an attempt to better characterize structural abnormali- number of probes (2 signals for each probe) present, and ties involving chromosomes 15 and 18 observed in the the probes were localized to their anticipated sub-telom- G-banded karyotype analysis, additional studies were eric bands. There was no evidence for loss or gain of the completed using FISH techniques (Fig. 2B). p or q subtelomeric regions for the chromosomal regions evaluated. Thus, parental FISH studies provided no evi - Amniotic fluid FISH analysis dence for a rearrangement between chromosome 15 and FISH analysis was performed using sub-telomeric probes chromosome 18 (Fig. 3 C and D). for the long arm of chromosomes 15 (green signal) and 18 (red signal). Following hybridization, the probe signal Discussion pattern noted was three signals (trisomic imbalance) for Because of improvements in the safety of invasive proce- chromosome 15q and two signals for chromosome 18q. dures and advances in technology, the most recent sys- Two green signals localized to anticipated chromosome tematic reviews demonstrated pregnancy loss rates for 15q region, the third signal being localized to structur- CVS and amniocentesis to be less than 1.0% [2, 12]. Natu- ally abnormal chromosome 18q, resulting in an unbal- rally, parents-to-be are anxious to have results as early as anced rearrangement indicated by a single fusion signal possible. Cell-free DNA screening takes the advantage of (Fig. 2B). being able to be performed as early as 10 weeks, without Studies for sub-telomeric region of the long arm of the need of an invasive procedure. Noninvasive prenatal chromosome 18, showed two probe signals and the screening test has sensitivities and specificities approach - probes were localized to their anticipated 18q sub-telom- ing 99%. While NIPT detects aneuploidies with a high eric bands. Thus, the FISH studies provided no evidence degree of certainty, it is, so far, less reliable in detecting for a rearrangement or loss of the sub-telomeric region microdeletions and duplications in fetal genomes smaller of chromosome 18. The FISH test confirmed the charac - than 5  Mb [13, 14]. Recently, large number of validation terization of the abnormalities involving chromosomes studies reporting the PPV of NIPT for the detection of 15 and 18 that were noted in both the microarray and CNVs have been published. Gou et al. demonstrated that G-banding analyses. Fig. 2 A Amniotic fluid karyotype analysis showing additional genetic material on the distal end of the long arm of chromosome 18q23 (arrow). B Sequential metaphase FISH analysis utilizing sub‑telomeric probes for chromosome 15 (green) and chromosome 18 (red), showing three green signals: two on the normal 15q, and the yellow signal representing a single fusion located on the distal long arm of chromosome 18 S ahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 5 of 7 Fig. 3 A Parental phytohemagglutinin (PHA) stimulated cultured peripheral blood karyograms showing normal karyotypes: A. Maternal karyotype: 46,XX. B Paternal karyotype: 46,XY. C (maternal) and D (paternal). Metaphase FISH analysis showing the presence of the expected number of probes present and the probes were localized to their anticipated regions: two aqua signals for centromeric region (D15Z1) and two orange signals for sub‑telomeric region (D15S936) of chromosome 15; two green signals for 18p sub ‑telomeric probe (D18S552) and two orange signals for 18q sub‑telomeric region ( VIJyRM2050) the PPV of recurrent CNVs seemed to be higher than region [18–20]. The breakpoints and extent of the dupli - that of rare chromosomal deletions/duplications [15]. cated segment are variable among patients. The clinical Furthermore, a recent study by Rafalko et  al. reported outcome and severity of physical findings varies from higher PPV for complex CNVs (93.9%) compared to iso- case to case, depending on the length and the genes lated CNVs (61.0%) [16]. involved in the duplicated region of the chromosome [19, A concern is that as higher proportions of the genome 21]. Specifically, duplication of type 1 insulin-like growth are analyzed, false positive and false negative results are factor 1 receptor (IGF1R) (OMIM 147,370) gene located expected to increase, which would result in an increase at 15q26.3 is thought to lead to overgrowth, whereas hap- in unnecessary invasive procedures [17]. NIPT is still loinsufficiency of IGF1R can cause growth restriction a screening test. During pre-test counseling, women [19–22]. The majority of cases reported have resulted should be informed about the accuracy, reliability, false from de novo unbalanced translocations, and the second positive, and false negative rates. According to current chromosome involved in the translocation has varied. NIPT guidelines, ACMG strongly recommends all posi- Although many large duplications can be appreciated by tive NIPT findings to be confirm by invasive prenatal routine karyotyping, detection of this duplication gener- diagnostic testing [17]. In addition, diagnostic follow up ally requires analysis by fluorescence in situ hybridization testing with CMA should be offered when NIPT identi - and chromosomal microarray. Abnormalities involving fies a CNV [17]. sub-telomeric regions can be difficult to visualize well Partial trisomy of the distal 15q is a rare chromosomal using conventional cytogenetics methods  (G-banding disorder. In general, the duplication of 15q has been analysis). characterized by prenatal and postnatal overgrowth, Previous study has detected the deletion of 5  Mb in craniosynostosis, distinct facial features, and intellec- fetal chromosome 15q11.2q13.1 and was further con- tual disability, likely reflecting triplosensitivity for one firmed by CNV and karyotype analysis [14]. Our study or more of the several genes that are found within this reports a duplication of about 10  Mb in size detected Sahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 6 of 7 using NIPT. A finding of duplication of a 10.34 Mb frag - approximately 1.7% of all structurally normal pregnancies ment located on 15q26.1q26.3 by NIPT was confirmed [23]. There is a potentially high value in microdeletion/ using various genetic modalities. The existence of dupli - microduplication NIPT testing mainly for CNVs with cation of material from chromosome 15 was established substantial morbidity and mortality such as 22q11.2 syn- and further delineated by microarray, followed by the drome. With the typical ultrasound and screening testing karyotype analysis and FISH. Detection of microdele- many of these cases can go unnoticed or detected late in tions or duplications can be very difficult using G-band - pregnancy. In these terms NIPT screening could offer an ing karyotyping analysis from amniotic fluid. Therefore, early diagnosis, pregnancy intervention, and coordinated to pinpoint the exact location of the duplicated fragment neonatal management. It is a fact that NIPT screening is and to visualize the whole chromosomal complement, still in its infancy, facing a lot of challenges and in need subtelomeric probes for the distal portion of chromo- of further validation, but such difficulties are expected somes 15q and 18q were used. The final karyotype from in the introduction of any new prenatal screening test. amniotic fluid was reported as 46,XX,der(18)t(15;18) Calculation of the test specifications (sensitivity, specific - (q26.1;q23)dn. ity, PPV, NPV) for submicroscopic imbalances are lim- Without molecular cytogenetic testing modalities, a ited due to lack of confirmatory genetic testing and the dup(15)(q26.1q26.3) would have been suggested, but a prevalence of the disease. Having in mind that all screen- derivative chromosome 18 would not have been detected. ing tests have to balance between medical benefits and CNV analyses provide information whether copy number the burden of a false-positive or uncertain finding, NIPT gains and losses are present but not whether they have could evolve in another complementary screening tool been translocated from their normal position(s) in the for early detection of many known syndromes. genome. Thus, confirmation of suspected chromosome abnormalities by FISH and chromosome analysis may be Abbreviations necessary to determine the nature of an abnormality. NIPT: Noninvasive prenatal test; FISH: Fluorescence in situ hybridization; The pregnancy reported in this paper ended in an CVS: Chorionic villus sampling; QF‑PCR: Quantitative fluorescence polymer ‑ ase chain reaction; CMA: Chromosomal microarray; NGS: Next‑ generation elective interruption of pregnancy. Since unbalanced sequencing; CNV: Copy number variations; LOH: Loss of heterozygosity; ChAS: translocations can result from either de novo event or Chromosome Analysis Suite; ESGH: European Society of Human Genetics; the malsegregation of a balanced parental translocation, E.C.A.: European Cytogenetics Association; cfDNA: Cell‑free DNA; ACMG: American College of Medical Genetics; IGF1R: Insulin‑like growth factor 1 parental chromosomal studies were completed to see receptor; OMIM: Online Mendelian Inheritance in Man; PPV: Positive predicted if either of them is a balanced carrier of a translocation value; NPV: Negative predicted value. involving chromosome 15 and 18. Due to lack of precise Acknowledgements and targeted genomic testing done in Bosnia and Her- We thank the family for participating in this study. zegovina, diagnostic follow up testing was done in col- laboration with laboratories in Greece and Germany. Authors’ contributions H.S. contributed with figure designs and assisted in writing and formatting the Parental karyotype and FISH analysis were normal with manuscript. A.D. and F.I. performed, interpreted, and reported microarray anal‑ no genetic aberrations. The couple has another healthy ysis. S.LF. and S.A. performed all the FISH testing and parental chromosomal child with unknown karyotype. The de novo origin of the analyses and interpretation. S.M. provided guidance, performed ultrasounds and amniocenteses. A.C. selected, directed, and collected reported data. All 15q duplication is consistent with the fact that there is authors read and approved the final version of the manuscript. no prior history of spontaneous abortions and no family history of chromosomal anomalies or genetic disorders. Funding This research did not receive any specific grant from funding agencies in the Moreover, it is important to note that negative results in public, commercial, or non‑for ‑profit sectors. both parents cannot exclude the possibility of parental gonadal mosaicism, thus leading to minor recurrence risk Availability of data and materials Data sharing is not applicable to this article as no datasets were generated or in subsequent pregnancies. analyzed during the current study. Conclusion Declarations In conclusion, this case report shows that the resolution of current NIPT technology has the potential to detect Ethics approval and consent to participate No ethics committee approval was required, because this was a clinical case submicroscopic aberrations. The clinical application of report of a single patient. Patient consent to participate was obtained. NIPT screening can be second best choice when patients refuse invasive diagnostic testing, especially for those Consent for publication Consent for publication was obtained. with no ultrasound findings and no family history. It is clear that NIPT can potentially detect clinically signifi - Competing interests cant unbalanced chromosomal abnormalities present in The authors declare no competing interests. S ahinbegovic et al. Molecular Cytogenetics (2022) 15:16 Page 7 of 7 Author details 21. Tatton‑Brown K, Pilz DT, Örstavik KH, Patton M, Barber JCK, Collinson MN, Department of Clinical Studies, University of Ostrava, 70300 Ostrava, Czech et al. 15q overgrowth syndrome: a newly recognized phenotype associ‑ Republic. Institute of Human Genetics, Klinikum Rechts Der Isar, Technical ated with overgrowth, learning difficulties, characteristic facial appear ‑ University of Munich, 81675 Munich, Germany. LIFE CODE Private Diagnos‑ ance, renal anomalies and increased dosage of distal chromosome 15q. tic Laboratory, Medical Ltd., 11523 Athens, Greece. Institute for Gynecol‑ Am J Med Genet Part A. 2009;149(2):147–54. ogy, Perinatology, and Infertility “Mehmedbašić”, 71000 Sarajevo, Bosnia 22. Okubo Y, Siddle K, Firth H, O’Rahilly S, Wilson LC, Willatt L, et al. Cell and Herzegovina. 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 Received: 7 November 2021 Accepted: 15 March 2022 and a tall child with three copies of the IGF1R gene. J Clin Endocrinol Metab. 2003;88(12):5981–8. 23. Wapner RJ, Martin CL, Levy B, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367(23):2175–84. References Publisher’s Note 1. Norem CT, Schoen EJ, Walton DL, Krieger RC, O’Keefe J, To TT, et al. Rou‑ Springer Nature remains neutral with regard to jurisdictional claims in pub‑ tine ultrasonography compared with maternal serum alpha‑fetoprotein lished maps and institutional affiliations. for neural tube defect screening. Obstet Gynecol. 2005;106(4):747–52. 2. 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):442–51. 3. Norwitz ER, Levy B. Noninvasive prenatal testing: the future is now. Rev Obstet Gynecol. 2013;6(2):48–62. 4. Hartwig TS, Ambye L, Sørensen S, Jørgensen FS. Discordant non‑ invasive prenatal testing (NIPT )—a systematic review. Prenat Diagn. 2017;37(6):527–39. 5. Dello Russo C, Cesta A, Longo S, et al. Validation of extensive next‑ gener‑ ation sequencing method for monogenic disorder analysis on cell‑free fetal DNA: noninvasive prenatal diagnosis. J Mol Diagn. 2019;21(4):572–9. 6. Tjio JH, Levan A. The chromosome number of man. Hereditas. 1956;42(1–2):1–6. 7. Ford CE, Hamerton JL. The chromosomes of man. Nature. 1956;178(4541):1020–3. 8. MIkkelsen M, Brondum‑Nielsen K. Karyotype analysis and chromosome disorders. Prenat diagnosis screening London Churchill Livingstone. 1992;99–125. 9. Schonberg SA. Cytogenetic analysis in prenatal diagnosis. West J Med. 1993;159(3):360–5. 10. Shaffer LG, Bui TH. Molecular cytogenetic and rapid aneuploidy detec‑ tion methods in prenatal diagnosis. Am J Med Genet Part C Semin Med Genet. 2007;145(1):87–98. 11. McGowan‑ Jordan J, Hastings RJ, Moore S, editors. ISCN 2020: an interna‑ tional system for human cytogenomic nomenclature. Basel: Karger; 2020. 12. Beta J, Lesmes‑Heredia C, Bedetti C, Akolekar R. Risk of miscarriage follow‑ ing amniocentesis and chorionic villus sampling: a systematic review of the literature. Minerva Ginecol. 2018;70(2):215–9. 13. 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):167–76. 14. 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):13–7. 15. 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. 16. Rafalko J, Soster E, Caldwell S, et al. Genome‑ wide cell‑free DNA screen‑ ing: a focus on copy‑number variants. Genet Med. 2021;23(10):1847–53. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : 17. Gregg AR, Skotko BG, Benkendorf JL, et al. Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of fast, convenient online submission the American College of Medical Genetics and Genomics. Genet Med. thorough peer review by experienced researchers in your field 2016;18(10):1056–65. 18. Leffler M, Puusepp S, Žilina O, et al. Two familial microduplications of rapid publication on acceptance 15q26.3 causing overgrowth and variable intellectual disability with support for research data, including large and complex data types normal copy number of IGF1R. Eur J Med Genet. 2016;59(4):257–62. • gold Open Access which fosters wider collaboration and increased citations 19. Chen CP, Lin YH, Au HK, et al. Chromosome 15q overgrowth syndrome: maximum visibility for your research: over 100M website views per year prenatal diagnosis, molecular cytogenetic characterization, and perinatal • findings in a fetus with dup(15)(q26.2q26.3). Taiwan J Obstet Gynecol. 2011;50(3):359–65. At BMC, research is always in progress. 20. Faivre L, Gosset P, Cormier‑Daire V, et al. Overgrowth and trisomy 15q26.1‑ Learn more biomedcentral.com/submissions qter including the IGF1 receptor gene: report of two families and review of the literature. Eur J Hum Genet. 2002;10(11):699–706.

Journal

Molecular Cytogenetics – Springer Journals

Published: Apr 2, 2022

Keywords: Noninvasive prenatal test; 15q26.1-qter partial trisomy; Microduplication; Prenatal testing

There are no references for this article.