Prenatal detection of copy number variants in fetuses with detected congenital devolpmental disordes, from 2015 to 2020 by Multiplex Ligation-Dependent Probe Amplification and microarray analysis
Authors:
A. Štefeková 1; P. Čapková 1; V. Curtisová 1; E. Mracká 1; H. Filipová 1; Z. Spurná 1; Martin Procházka 1; M. Ľubušký 2; Radovan Pilka 2; R. Vrtěl 1
Authors‘ workplace:
Ústav lékařské genetiky, LF UP a FN Olomouc
1; Porodnicko-gynekologická klinika LF UP a FN Olomouc
2
Published in:
Ceska Gynekol 2023; 88(3): 162-171
Category:
Original Article
doi:
https://doi.org/10.48095/cccg2023162
Overview
Objective: Analysis of prenatal samples from 2015 to 2020. Comparison detection rates of clinically relevant variants by cytogenetic karyotype analysis and cytogenomic MLPA (Multiplex Ligation-Depent Probe Amplification) and microarray methods (CMA – chromosomal microarray). Material and method: 1,029 prenatal samples were analyzed by cytogenetic karyotyping (N = 1,029), cytogenomic methods – MLPA (N = 144) and CMA (N = 111). All unbalanced changes were confirmed by MLPA or CMA. Results: From the analyzed set of fetuses, after subtraction of aneuploidies – 107 (10.40%, N = 1,029), 22 structural aberrations (2.39%, N = 922) – nine unbalanced changes (0.98%), 10 balanced changes (1.08%), one case of unclear mosaicism (0.09%), one case of presence of a marker chromosome (0.09%) and one case of sex discordance (0.09%) – were detected by karyotype analysis. A total of eight (7.21%, N = 111) pathological variants were detected by CMA in 255 samples with physiological karyotype indicated for cytogenomic examination. Five (3.47%, N = 144) of eight pathogenic variants were detected by MLPA method. The total capture of pathogenic variants by MLPA and CMA methods was 14 (5.14%) and 17 (6.25%) (N = 272), including confirmatory pathological karyotype testing. Detection of pathological variants in the isolated disorders group was lower than in the multiple disorders group (5.08 vs. 21.42%). Conclusion: A higher success rate for the detection of pathological copy number variation variants by the microarray method than by the MLPA method was confirmed.
Keywords:
MLPA – congenital developmental disorders – CMA – copy number variants
Sources
1. Feldkamp ML, Carey JC, Byrne JL et al. Etiology and clinical presentation of birth defects: population based study. BMJ 2017; 357: j2249. doi: 10.1136/bmj.j2249.
2. Roztočil et al. Moderní porodnictví. Praha: Grada Publishing a. s. 2017: 136–140.
3. Šípek A, Gregor V, Šípek A jr et al. Vrozené vady u dětí narozených v České republice v období 1994–2015. Čas Lék čes 2019; 158: 9–14.
4. van der Linde D, Konings EE, Slager MA et al. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis. J Am Coll Cardiol 2011; 58 (21): 2241–2247. doi: 10.1016/j.jacc.2011.08.025.
5. Šípek A, Gregor V, Šípek A jr. et al. Vrozené vady v České republice v období 1994–2007. Ceska Gynekol 2009; 74 (1): 31–44.
6. Pavlíček J, Klásková E, Doležálková E et al. Vývoj prenatální diagnostiky vrozených srdečních vad, zisk z jednotlivých ultrazvukových projekcí. Ceska Gynekol 2018; 83 (1): 17–23.
7. Jia CW, Wang L, Lan YL et al. Aneuploidy in early miscarriage and its related factors. Chin Med J (Engl) 2015; 128 (20): 2772–2776. doi: 10.4103/0366-6999.167352.
8. Zhang H, Xu Z, Chen Q et al. Comparison of the combined use of CNV-seq and karyotyping or QF-PCR in prenatal diagnosis: a retrospective study. Sci Rep 2023; 13 (1): 1862. doi: 10.1038/s41598-023-29053-6.
9. Rodriguez-Revenga L, Madrigal I, Borrell A et al. Chromosome microarray analysis should be offered to all invasive prenatal diagnostic testing following a normal rapid aneuploidy test result. Clin Genet 2020; 98 (4): 379–383. doi: 10.1111/cge.13810.
10. South ST, Lee C, Lamb AN et al. 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 (11): 901–909. doi: 10.1038/gim.2013. 129.
11. Martin CL, Warburton D. Detection of chromosomal aberrations in clinical practice: from karyotype to genome sequence. Annu Rev Genomics Hum Genet 2015; 16: 309–326. doi: 10.1146/annurev-genom-090413-025346.
12. Lord J, McMullan DJ, Eberhardt RY et al. Prenatal Assessment of Genomes and Exomes Consortium. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet 2019; 393 (10173): 747–757. doi: 10.1016/S0140-6736 (18) 31940-8.
13. Castleman JS, Wall E, Allen S et al. The prenatal exome – a door to prenatal diagnostics? Expert Rev Mol Diagn 2021; 21 (5): 465–474. doi: 10.1080/14737159.2021.1920398.
14. Koumbaris G, Achilleos A, Nicolaou M et al. Targeted capture enrichment followed by NGS: development and validation of a single comprehensive NIPT for chromosomal aneuploidies, microdeletion syndromes and monogenic diseases. Mol Cytogenet 2019; 12: 48. doi: 10.1186/s13039-019-0459-8.
15. Zarrei M, MacDonald JR, Merico D et al. A copy number variation map of the human genome. Nat Rev Genet 2015; 16 (3): 172–183. doi: 10.1038/nrg3871.
16. Rice AM, McLysaght A. Dosage sensitivity is a major determinant of human copy number variant pathogenicity. Nat Commun 2017; 8: 14366. doi: 10.1038/ncomms14366.
17. Torres F, Barbosa M, Maciel P. Recurrent copy number variations as risk factors for neurodevelopmental disorders: critical overview and analysis of clinical implications. J Med Genet 2016; 53 (2): 73–90. doi: 10.1136/jmed genet-2015-103366.
18. Dap M, Gicquel F, Lambert L et al. Utility of chromosomal microarray analysis for the exploration of isolated and severe fetal growth restriction diagnosed before 24 weeks’ gestation. Prenat Diagn 2022; 42 (10): 1281–1287. doi: 10.1002/pd.6149.
19. Meng X, Jiang L. Prenatal detection of chromosomal abnormalities and copy number variants in fetuses with congenital gastrointestinal obstruction. BMC Pregnancy Childbirth 2022; 22 (1): 50. doi: 10.1186/s12884-022-04401-y.
20. Normand EA, Braxton A, Nassef S et al. Clinical exome sequencing for fetuses with ultrasound abnormalities and a suspected Mendelian disorder. Genome Med 2018; 10 (1): 74. doi: 10.1186/s13073-018-0582-x.
21. Vora NL, Gilmore K, Brandt A et al. An approach to integrating exome sequencing for fetal structural anomalies into clinical practice. Genet Med 2020; 22 (5): 954–961. doi: 10.1038/s41436-020-0750-4.
22. Diderich KE, Romijn K, Joosten M et al. The potential diagnostic yield of whole exome sequencing in pregnancies complicated by fetal ultrasound anomalies. Acta Obstet Gynecol Scand 2021; 100 (6): 1106–1115. doi: 10.1111/aogs.14053.
23. Wilch ES, Morton CC. Historical and clinical perspectives on chromosomal translocations. Adv Exp Med Biol 2018; 1044: 1–14. doi: 10.1007/978-981-13-0593-1_1.
24. Zhang Y, Zhong M, Zheng D. Chromosomal mosaicism detected by karyotyping and chromosomal microarray analysis in prenatal diagnosis. J Cell Mol Med 2021; 25 (1): 358–366. doi: 10.1111/jcmm.16080.
25. Christofolini DM, Bevilacqua LB, Mafra FA et al. Genetic analysis of products of conception. Should we abandon classic karyotyping methodology? Einstein (Sao Paulo) 2021; 19: eAO5945. doi: 10.31744/einstein_journal/2021AO5945.
26. Srebniak MI, Diderich KE, Joosten M et al. Prenatal SNP array testing in 1000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs. Eur J Hum Genet 2016; 24 (5): 645–651. doi: 10.1038/ejhg.2015.193.
27. Chau MH, Cao Y, Kwok YK et al. Characteristics and mode of inheritance of pathogenic copy number variants in prenatal diagnosis. Am J Obstet Gynecol 2019; 221 (5): 493.e1–493.e11. doi: 10.1016/j.ajog.2019.06.007.
28. Lou J, Sun M, Zhao Y et al. Analysis of tissue from pregnancy loss and aborted fetus with ultrasound anomaly using subtelomeric MLPA and chromosomal array analysis. J Matern Fetal Neonatal Med 2022; 35 (16): 3064–3069. doi: 10.1080/14767058.2020.1808612.
29. Wang Y, Li Y, Chen Y et al. Systematic analysis of copy-number variations associated with early pregnancy loss. Ultrasound Obstet Gynecol 2020; 55 (1): 96–104. doi: 10.1002/uog.20412.
30. Xia M, Yang X, Fu J et al. Application of chromosome microarray analysis in prenatal diagnosis. BMC Pregnancy Childbirth 2020; 20 (1): 696. doi: 10.1186/s12884-020-03368-y.
31. Westerfield L, Darilek S, van den Veyver IB. Counseling challenges with variants of uncertain significance and incidental findings in prenatal genetic screening and diagnosis. J Clin Med 2014; 3 (3): 1018–1032. doi: 10.3390/jcm3031018.
32. von der Lippe C, Rustad C, Heimdal K et al. 15q11.2 microdeletion – seven new patients with delayed development and/or behavioural problems. Eur J Med Genet 2011; 54 (3): 357–360. doi: 10.1016/j.ejmg.2010.12.008.
33. Burnside RD, Pasion R, Mikhail FM et al. Microdeletion/microduplication of proximal 15q11.2 between BP1 and BP2: a susceptibility region for neurological dysfunction including developmental and language delay. Hum Genet 2011; 130 (4): 517–528. doi: 10.1007/s00439-011-0970-4.
34. Jønch AE, Douard E, Moreau C et al. 15q11.2 Working Group. Estimating the effect size of the 15Q11.2 BP1-BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice. J Med Genet 2019; 56 (10): 701–710. doi: 10.1136/jmedgenet-2018-105879.
35. Maya I, Perlman S, Shohat M et al. Should we report 15q11.2 BP1-BP2 deletions and duplications in the prenatal setting? J Clin Med 2020; 9 (8): 2602. doi: 10.3390/jcm9082602.
36. Štolfa M, Zůnová H, Slámová Z et al. „High--frequency low-penetrant variants“ Nový klasifikační stupeň pro hodnocení rekurentních variant genomu s vysokou frekvencí, ale nízkou penetrance? Celostátní sjezd Společkosti lékařské genetiky a genomiky ČLS JEP a 55. Výroční cytogenetické conference, Praha 2022.
37. Liu N, Li H, Li M et al. Prenatally diagnosed 16p11.2 copy number variations by SNP array: a retrospective case series. Clin Chim Acta 2023; 538: 15–21. doi: 10.1016/j.cca.2022.10.016.
Labels
Paediatric gynaecology Gynaecology and obstetrics Reproduction medicineArticle was published in
Czech Gynaecology
![Issue 3](https://www.prolekare.cz/media/cache/resolve/journal_issue/media/image_pdf/7deaa1b250d4f5aeb251f8350a50f3dc.jpg)
2023 Issue 3
Most read in this issue
- Pelvic pain in women after childbirth and physiotherapy
- Physiotherapy in a patient with diastasis of the rectus abdominis muscle after childbirth
- Prevention of intrauterine adhesions
- Obesity and assisted reproduction