Skip to main content
SpringerLink
Log in

BACs-on-Beads Assay for the Prenatal Diagnosis of Microdeletion and Microduplication Syndromes

  • Original Research Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Objective

To evaluate the clinical value of BACs-on-Beads (BoBs) assay in detection of microdeletion and microduplication syndromes.

Methods

A total of 6,814 cases of amniotic fluid cells collected from January 2015 to July 2020 in our hospital were analyzed by chromosomal karyotyping and BoBs assay. Fluorescence in situ hybridization (FISH) or chromosomal microarray analysis (CMA) provided further validation for the cases of microdeletion and microduplication.

Results

Thirty microdeletion and microduplication syndromes were identified by BoBs with an incidence of ~1/227, including 22q11.2 microduplication (0.044%, 3/6814), DiGeorge I syndrome (0.044%, 3/6814), 17p11.2 microduplication (0.015%, 1/6814), Smith–Magenis syndrome (0.015%, 1/6814), 17p11.2p11.3 microduplication (0.015%, 1/6814), Williams–Beuren syndrome (0.088%, 6/6814), 7q11.2 microduplication (0.029%, 2/6814), DiGeorge II syndrome (0.015%, 1/6814), 18p11.32p11.21 microduplication (0.015%, 1/6814), Wolf–Hirschhorn syndrome (0.029%, 2/6814), 4p16.3 microduplication (0.015%, 1/6814), Langer–Giedion syndrome (0.015%, 1/6814), Miller–Dieker syndrome (0.015%, 1/6814), Cri du Chat syndrome (0.015%, 1/6814), Xp22.31 microdeletion (0.059%, 4/6814), Prader–Willi syndrome (0.015%, 1/6814). High concordance was obtained between BoBs and FISH or CMA. However, only four cases were detected by chromosomal karyotyping.

Conclusion

BoBs assay can rapidly detect microdeletion and microduplication syndromes, which compensates the shortcomings of conventional chromosomal karyotyping and greatly improves the efficiency and accuracy of prenatal diagnosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Rosano A, Botto LD, Botting B, Mastroiacovo P. Infant mortality and congenital anomalies from 1950 to 1994: an international perspective. J Epidemiol Community Health. 2000;54(9):660–6. https://doi.org/10.1136/jech.54.9.660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Li C, Chen B, Zheng J, Cheng L, Song T, Guo F, et al. Prenatal diagnosis of BACs-on-beads assay in 3647 cases of amniotic fluid cells. Reprod Sci. 2019;26(7):1005–12. https://doi.org/10.1177/1933719118804416.

    Article  CAS  PubMed  Google Scholar 

  3. Smajlagic D, Lavrichenko K, Berland S, Helgeland O, Knudsen GP, Vaudel M, et al. Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents. Eur J Hum Genet. 2020. https://doi.org/10.1038/s41431-020-00707-7.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Romano C, Ferranti S, Mencarelli MA, Longo I, Renieri A, Grosso S. 17p13.3 microdeletion including YWHAE and CRK genes: towards a clinical characterization. Neurol Sci. 2020;41(8):2259–62. https://doi.org/10.1007/s10072-020-04424-3.

    Article  PubMed  Google Scholar 

  5. Liang B, Wang Y, Lin N, Huang H, Chen L, Chen M, et al. Single nucleotide polymorphism array analysis of 102 patients with developmental delay and/or intellectual disability from Fujian, China. Clin Chim Acta. 2020. https://doi.org/10.1016/j.cca.2020.08.032.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gross SJ, Bajaj K, Garry D, Klugman S, Karpel BM, Roe AM, et al. Rapid and novel prenatal molecular assay for detecting aneuploidies and microdeletion syndromes. Prenat Diagn. 2011;31(3):259–66. https://doi.org/10.1002/pd.2674.

    Article  PubMed  Google Scholar 

  7. Xu L, Zhang M, Huang H, Wang Y, Chen L, Chen M, et al. The comprehensive comparison of BACs-on-Beads assay and copy number variation sequencing in prenatal diagnosis of Southern Chinese women. J Mol Diagn. 2020. https://doi.org/10.1016/j.jmoldx.2020.07.005.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Farra C, Nassar AH, Mirza F, Abdouni L, Souaid M, Awwad J. BACs-on-Beads assay, a rapid aneuploidy test, improves the diagnostic yield of conventional karyotyping. Mol Biol Rep. 2020;47(1):169–77. https://doi.org/10.1007/s11033-019-05117-7.

    Article  CAS  PubMed  Google Scholar 

  9. Wang Y, Zhang M, Chen L, Huang H, Xu L. Prenatal diagnosis of BACs-on-Beads assay in 1520 cases from Fujian Province, China. Mol Genet Genomic Med. 2020;8:e1446. https://doi.org/10.1002/mgg3.1446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Tao H, Shi J, Wang J, Zhao L, Ding J, Yang L. Rapid prenatal aneuploidy detection of BACs-on-Beads assay in 4961 cases of amniotic fluid samples. J Matern Fetal Neonatal Med. 2019. https://doi.org/10.1080/14767058.2019.1704248.

    Article  PubMed  Google Scholar 

  11. Huang H, Zhang M, Wang Y, Lin N, He D, Chen M, et al. Application of the BACs-on-Beads assay for rapid prenatal detection application of BoBs for PND of aneuploidies and microdeletions. Mol Reprod Dev. 2018;85(2):146–54. https://doi.org/10.1002/mrd.22945.

    Article  CAS  PubMed  Google Scholar 

  12. Grati FR, Molina Gomes D, Ferreira JC, Dupont C, Alesi V, Gouas L, et al. Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies. Prenat Diagn. 2015;35(8):801–9. https://doi.org/10.1002/pd.4613.

    Article  PubMed  Google Scholar 

  13. Choy KW, Kwok YK, Cheng YK, Wong KM, Wong HK, Leung KO, et al. Diagnostic accuracy of the BACs-on-Beads assay versus karyotyping for prenatal detection of chromosomal abnormalities: a retrospective consecutive case series. BJOG. 2014;121(10):1245–52. https://doi.org/10.1111/1471-0528.12873.

    Article  CAS  PubMed  Google Scholar 

  14. Zhuang J, Chen C, Jiang Y, Luo Q, Zeng S, Lv C, et al. Application of the BACs-on-Beads assay for the prenatal diagnosis of chromosomal abnormalities in Quanzhou, China. BMC Pregnancy Childbirth. 2021;21(1):94. https://doi.org/10.1186/s12884-021-03589-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ma W, Mao J, Wang X, Duan L, Song Y, Lian X, et al. Novel microdeletion in the X chromosome leads to Kallmann syndrome, ichthyosis, obesity, and strabismus. Front Genet. 2020;11:596. https://doi.org/10.3389/fgene.2020.00596.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Takeichi T, Akiyama M. Inherited ichthyosis: non-syndromic forms. J Dermatol. 2016;43(3):242–51. https://doi.org/10.1111/1346-8138.13243.

    Article  PubMed  Google Scholar 

  17. Jung PS, Won HS, Cho IJ, Hyun MK, Shim JY, Lee PR, et al. A case report of prenatally diagnosed tetrasomy 18p. Obstet Gynecol Sci. 2013;56(3):190–3. https://doi.org/10.5468/ogs.2013.56.3.190.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Plaiasu V, Ochiana D, Motei G, Georgescu A. A rare chromosomal disorder—isochromosome 18p syndrome. Maedica (Bucur). 2011;6(2):132–6.

    PubMed  PubMed Central  Google Scholar 

  19. Sebold C, Roeder E, Zimmerman M, Soileau B, Heard P, Carter E, et al. Tetrasomy 18p: report of the molecular and clinical findings of 43 individuals. Am J Med Genet A. 2010;152A(9):2164–72. https://doi.org/10.1002/ajmg.a.33597.

    Article  PubMed  Google Scholar 

  20. O’Donnell L, Soileau BT, Sebold C, Gelfond J, Hale DE, Cody JD. Tetrasomy 18p: report of cognitive and behavioral characteristics. Am J Med Genet A. 2015;167(7):1474–82. https://doi.org/10.1002/ajmg.a.37036.

    Article  PubMed  Google Scholar 

  21. Slimani W, Ben Khelifa H, Dimassi S, Chioukh FZ, Jelloul A, Kammoun M, et al. Clinical and molecular findings in nine new cases of tetrasomy 18p syndrome: FISH and array CGH characterization. Mol Cytogenet. 2019;12:5. https://doi.org/10.1186/s13039-019-0414-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Abbas E, Cox DM, Smith T, Butler MG. The 7q112.3 microduplication syndrome: a clinical report with review of literature. J Pediatr Genet. 2016;5(3):129–40. https://doi.org/10.1055/s-0036-1584361.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dixit A, McKee S, Mansour S, Mehta SG, Tanteles GA, Anastasiadou V, et al. 7q112.3 Microduplication: a recognizable phenotype. Clin Genet. 2013;83(2):155–61. https://doi.org/10.1111/j.1399-0004.2012.01862.x.

    Article  CAS  PubMed  Google Scholar 

  24. Depienne C, Heron D, Betancur C, Benyahia B, Trouillard O, Bouteiller D, et al. Autism, language delay and mental retardation in a patient with 7q11 duplication. J Med Genet. 2007;44(7):452–8. https://doi.org/10.1136/jmg.2006.047092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yu A, Turbiville D, Xu F, Ray JW, Britt AD, Lupo PJ, et al. Genotypic and phenotypic variability of 22q11.2 microduplications: an institutional experience. Am J Med Genet A. 2019;179(11):2178–89. https://doi.org/10.1002/ajmg.a.61345.

    Article  CAS  PubMed  Google Scholar 

  26. Ribeiro-Bicudo LA, de Campos LC, Gamba BF, Candido Sandri RM, Richieri-Costa A. Cognitive deficit, learning difficulties, severe behavioral abnormalities and healed cleft lip in a patient with a 1.2-mb distal microduplication at 22q11.2. Mol Syndromol. 2013;4(6):292–6. https://doi.org/10.1159/000354095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. de La Rochebrochard C, Joly-Helas G, Goldenberg A, Durand I, Laquerriere A, Ickowicz V, et al. The intrafamilial variability of the 22q11.2 microduplication encompasses a spectrum from minor cognitive deficits to severe congenital anomalies. Am J Med Genet A. 2006;140(14):1608–13. https://doi.org/10.1002/ajmg.a.31227.

    Article  CAS  Google Scholar 

  28. Rosenfeld JA, Coe BP, Eichler EE, Cuckle H, Shaffer LG. Estimates of penetrance for recurrent pathogenic copy-number variations. Genet Med. 2013;15(6):478–81. https://doi.org/10.1038/gim.2012.164.

    Article  CAS  PubMed  Google Scholar 

  29. Daw SC, Taylor C, Kraman M, Call K, Mao J, Schuffenhauer S, et al. A common region of 10p deleted in DiGeorge and velocardiofacial syndromes. Nat Genet. 1996;13(4):458–60. https://doi.org/10.1038/ng0896-458.

    Article  CAS  PubMed  Google Scholar 

  30. Van Esch H, Groenen P, Fryns JP, Van de Ven W, Devriendt K. The phenotypic spectrum of the 10p deletion syndrome versus the classical DiGeorge syndrome. Genet Couns. 1999;10(1):59–65.

    PubMed  Google Scholar 

  31. Lindstrand A, Malmgren H, Verri A, Benetti E, Eriksson M, Nordgren A, et al. Molecular and clinical characterization of patients with overlapping 10p deletions. Am J Med Genet A. 2010;152A(5):1233–43. https://doi.org/10.1002/ajmg.a.33366.

    Article  PubMed  Google Scholar 

  32. Melis D, Genesio R, Boemio P, Del Giudice E, Cappuccio G, Mormile A, et al. Clinical description of a patient carrying the smallest reported deletion involving 10p14 region. Am J Med Genet A. 2012;158A(4):832–5. https://doi.org/10.1002/ajmg.a.34133.

    Article  CAS  PubMed  Google Scholar 

  33. Van Esch H, Groenen P, Nesbit MA, Schuffenhauer S, Lichtner P, Vanderlinden G, et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature. 2000;406(6794):419–22. https://doi.org/10.1038/35019088.

    Article  CAS  PubMed  Google Scholar 

  34. Hasegawa T, Hasegawa Y, Aso T, Koto S, Nagai T, Tsuchiya Y, et al. HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10)(p13). Am J Med Genet. 1997;73(4):416–8. https://doi.org/10.1002/(sici)1096-8628(19971231)73:4%3c416::aid-ajmg9%3e3.0.co;2-l.

    Article  CAS  PubMed  Google Scholar 

  35. Schuffenhauer S, Lichtner P, Peykar-Derakhshandeh P, Murken J, Haas OA, Back E, et al. Deletion mapping on chromosome 10p and definition of a critical region for the second DiGeorge syndrome locus (DGS2). Eur J Hum Genet. 1998;6(3):213–25. https://doi.org/10.1038/sj.ejhg.5200183.

    Article  CAS  PubMed  Google Scholar 

  36. Yatsenko SA, Yatsenko AN, Szigeti K, Craigen WJ, Stankiewicz P, Cheung SW, et al. Interstitial deletion of 10p and atrial septal defect in DiGeorge 2 syndrome. Clin Genet. 2004;66(2):128–36. https://doi.org/10.1111/j.1399-0004.2004.00290.x.

    Article  CAS  PubMed  Google Scholar 

  37. Morcel K, Watrin T, Pasquier L, Rochard L, Le Caignec C, Dubourg C, et al. Utero-vaginal aplasia (Mayer-Rokitansky-Kuster-Hauser syndrome) associated with deletions in known DiGeorge or DiGeorge-like loci. Orphanet J Rare Dis. 2011;6:9. https://doi.org/10.1186/1750-1172-6-9.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Chen CP, Wang LK, Chern SR, Wu PS, Chen SW, Wu FT, et al. Wolf-Hirschhorn syndrome: Prenatal diagnosis and molecular cytogenetic characterization of a de novo distal deletion of 4p (4p16.1 --> pter) in a fetus with facial cleft and preaxial polydactyly. Taiwan J Obstet Gynecol. 2020;59(3):425–31. https://doi.org/10.1016/j.tjog.2020.03.016.

    Article  PubMed  Google Scholar 

  39. Zhao Y, Diacou A, Johnston HR, Musfee FI, McDonald-McGinn DM, McGinn D, et al. Complete sequence of the 22q11.2 allele in 1,053 subjects with 22q11.2 deletion syndrome reveals modifiers of conotruncal heart defects. Am J Hum Genet. 2020;106(1):26–40. https://doi.org/10.1016/j.ajhg.2019.11.010.

    Article  CAS  PubMed  Google Scholar 

  40. Li S, Jin Y, Yang J, Yang L, Tang P, Zhou C, et al. Prenatal diagnosis of rearrangements in the fetal 22q11.2 region. Mol Cytogenet. 2020;13:28. https://doi.org/10.1186/s13039-020-00498-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shubina J, Barkov IY, Stupko OK, Kuznetsova MV, Goltsov AY, Kochetkova TO, et al. Prenatal diagnosis of Prader-Willi syndrome due to uniparental disomy with NIPS: Case report and literature review. Mol Genet Genomic Med. 2020. https://doi.org/10.1002/mgg3.1448.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Xu C, Xiang Y, Xu X, Zhou L, Li H, Dong X, et al. Clinical application of chromosomal microarray analysis for fetuses with craniofacial malformations. Mol Cytogenet. 2020;13:38. https://doi.org/10.1186/s13039-020-00502-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Villa R, Fergnani VGC, Silipigni R, Guerneri S, Cinnante C, Guala A, et al. Structural brain anomalies in Cri-du-Chat syndrome: MRI findings in 14 patients and possible genotype-phenotype correlations. Eur J Paediatr Neurol. 2020. https://doi.org/10.1016/j.ejpn.2020.07.002.

    Article  PubMed  Google Scholar 

  44. Hui L, Norton M. What is the real “price” of more prenatal screening and fewer diagnostic procedures? Costs and trade-offs in the genomic era. Prenat Diagn. 2018;38(4):246–9. https://doi.org/10.1002/pd.5228.

    Article  PubMed  Google Scholar 

  45. Harper LM, Sutton AL, Longman RE, Odibo AO. An economic analysis of prenatal cytogenetic technologies for sonographically detected fetal anomalies. Am J Med Genet A. 2014;164A(5):1192–7. https://doi.org/10.1002/ajmg.a.36435.

    Article  PubMed  Google Scholar 

  46. Shaffer LG, Coppinger J, Morton SA, Alliman S, Burleson J, Traylor R, et al. The development of a rapid assay for prenatal testing of common aneuploidies and microdeletion syndromes. Prenat Diagn. 2011;31(8):778–87. https://doi.org/10.1002/pd.2766.

    Article  CAS  PubMed  Google Scholar 

  47. Cheng YK, Wong C, Wong HK, Leung KO, Kwok YK, Suen A, et al. The detection of mosaicism by prenatal BoBs. Prenat Diagn. 2013;33(1):42–9. https://doi.org/10.1002/pd.4006.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge all the pregnant women who provided the information and accepted follow-up for the study.

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Xijing Hospital, The Fourth Military Medical University, 127 West ChangLe Road, Xi’an, 710032, Shaanxi, China

    Chunyan Li, Jianfang Zhang, Jia Li, Guyuan Qiao, Ying Xu & Hong Yang

  2. Department of Obstetrics and Gynecology, 518 Hospital of PLA, Xi’an, 710043, Shaanxi, China

    Ying Zhan

Authors
  1. Chunyan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianfang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guyuan Qiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ying Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hong Yang.

Ethics declarations

Author contributions

HY conceived and designed the study. CL drafted the manuscript. CL, JZ and JL participated in collecting data. GQ and YZ performed the data analysis. CL, and YX revised the manuscript. All authors have read and approved the final article.

Funding

The study was supported by the Key Research and Development Program of Shaanxi Province (2019ZDLSF01-06).

Conflict of interest

Chunyan Li, Jianfang Zhang, Jia Li, Guyuan Qiao, Ying Zhan, Ying Xu, and Hong Yang declare there are no conflicts of interest with regard to the publication of this paper.

Ethics approval

Ethics approval for the study was obtained from Chinese PLA General Hospital Medical Ethics Committee (S2016-120-02).

Data availability

The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, C., Zhang, J., Li, J. et al. BACs-on-Beads Assay for the Prenatal Diagnosis of Microdeletion and Microduplication Syndromes. Mol Diagn Ther 25, 339–349 (2021). https://doi.org/10.1007/s40291-021-00522-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-021-00522-w

Search

Navigation