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Table of Contents
Vol. 135, No. 3-4, 2011
Issue release date: December 2011
Cytogenet Genome Res 2011;135:241–250
(DOI:10.1159/000334065)

From Karyotyping to Array-CGH in Prenatal Diagnosis

Lichtenbelt K.D. · Knoers N.V.A.M. · Schuring-Blom G.H.
Division of Biomedical Genetics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

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Abstract

Conventional karyotyping detects chromosomal anomalies in up to 35% of pregnancies with fetal ultrasound anomalies, depending on the number and type of these anomalies. Extensive experience gained in the past decades has shown that prenatal karyotyping is a robust technique which can detect the majority of germline chromosomal anomalies. For most of these anomalies the phenotype is known. In postnatal diagnosis of patients with congenital anomalies and intellectual disability, array-CGH/SNP array has become the first-tier investigation. The higher abnormality detection yield and its amenability to automation renders array-CGH also suitable for prenatal diagnosis. As both findings of unclear significance and unexpected findings may be detected, studies on the outcome of array-CGH in prenatal diagnosis were initially performed retrospectively. Recently, prospective application of array-CGH in pregnancies with ultrasound anomalies, and to a lesser extent in pregnancies referred for other reasons, was studied. Array-CGH showed an increased diagnostic yield compared to karyotyping, varying from 1–5%, depending on the reason for referral. Knowledge of the spectrum of array-CGH anomalies detected in the prenatal setting will increase rapidly in the years to come, thus facilitating pre- and posttest counseling. Meanwhile, new techniques like non-invasive prenatal diagnosis are emerging and will claim their place. In this review, we summarize the outcome of studies on prenatal array-CGH, the clinical relevance of differences in detection rate and range as compared to standard karyotyping, and reflect on the future integration of new molecular techniques in the workflow of prenatal diagnosis.



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References

  1. ACOG Committee No. 446: Array comparative genomic hybridization in prenatal diagnosis. Obstet Gynecol 114:1161–1163 (2009).
  2. Akolekar R, Farkas DH, VanAgtmael AL, Bombard AT, Nicolaides KH: Fetal sex determination using circulating cell-free fetal DNA (ccffDNA) at 11 to 13 weeks of gestation. Prenat Diagn 30:918–923 (2010).
  3. Aston E, Whitby H, Maxwell T, Glaus N, Cowley B, et al: Comparison of targeted and whole genome analysis of postnatal specimens using a commercially available array based comparative genomic hybridisation (aCGH) microarray platform. J Med Genet 5:268–274 (2008).

    External Resources

  4. Ballif BC, Rorem EA, Sundin K, Lincicum M, Gaskin S et al: Detection of low-level mosaicism by array CGH in routine diagnostic specimens. Am J Med Genet A 140:2757–2767 (2006).
  5. Benn PA, Chapman AR: Ethical challenges in providing noninvasive prenatal diagnosis. Curr Opin Obstet Gynecol 22:128–134 (2010).
  6. Benn PA, Egan JFX, Fang M, Smith-Bindman R: Changes in the utilization of prenatal diagnosis. Obstet Gynecol 103:1255–1260 (2004).
  7. Bi W, Breman AM, Venable SF, Eng PA, Sahoo T, et al: Rapid prenatal diagnosis using uncultured amniocytes and oligonucleotide array CGH. Prenat Diagn 28:943–949 (2008).
  8. Bianchi DW: Fetal cells in the maternal circulation: feasibility for prenatal diagnosis. Br J Haemat 105:574–583 (1999).
  9. Bianchi DW, Mahr A, Zickwolf GK, Houseal TW, Flint AF, et al: Detection of fetal cells with 47,XY,+21 karyotype in maternal peripheral blood. Hum Genet 90:911–917 (1992).

    External Resources

  10. Bui TH, Vetro A, Zuffardi O, Shaffer LG: Current controversies in prenatal diagnosis 3: is conventional chromosome analysis necessary in the post-array CGH era? Prenat Diagn 31:235–243 (2011).
  11. Caine A, Maltby AE, Parkin CA, Waters JJ, Crolla JA: Prenatal detection of Down’s syndrome by rapid aneuploidy testing for chromosomes 13, 18, and 21 by FISH or PCR without a full karyotype: a cytogenetic risk assessment. Lancet 366:123–128 (2005).
  12. Carbone JF, Tuuli MG, Dicke JF, Macones GA, Odibo A: Revisiting the risk for aneuploidy in fetuses with isolated pyelectasis. Prenat Diagn 31:566–570 (2011).
  13. Cheung SW, Shaw CA, Scott DA, Patel A, Sahoo T et al: Microarray-based CGH detects chromosomal mosaicism not revealed by conventional cytogenetics. Am J Med Genet A 143A:1679–1686 (2007).
  14. Chiu RW, Akolekar R, Zheng YW, Leung TY, Sun H, et al: Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study. BMJ 342:c7401 (2011).
  15. Christensen B, Philip J, Kølvraa S, Lykke-Hansen L, Hromadnikova I, et al: Fetal cells in maternal blood: a comparison of methods for cell isolation and identification. Fetal Diagn Ther 20:106–112 (2005).
  16. Coppinger J, Alliman S, Lamb AN, Torchia BS, Bejjani BA, et al: Whole-genome microarray analysis in prenatal specimens identifies clinically significant chromosome alterations without increase in results of unclear significance compared to targeted microarray. Prenat Diagn 29:1156–1166 (2009).
  17. Cremer T, Landegent J, Bruckner A, Scholl HP, Schardin M, et al: Detection of chromosome aberrations in the human interphase nucleus by visualization of specific target DNAs with radioactive and non-radioactive in situ hybridization techniques: diagnosis of trisomy 18 with probe L1.84. Hum Genet 74:346–352 (1986).
  18. Crolla JA: FISH and molecular studies of autosomal supernumerary marker chromosomes excluding those derived from chromosome 15: II. Review of the literature. Am J Med Genet 75:367–381 (1998).
  19. D’Amours G, Kibar Z, Mathonnet G, Fetni R, Tihy F, et al: Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype. Clin Genet (2011) [Epub ahead of print].
  20. Daniel A, Athayde N, Ogle R, George AM, Michael J, et al: Prospective ranking of the sonographic markers for aneuploidy: Data of 2143 prenatal cytogenetic diagnosis referred for abnormalities on ultrasound. Aust N Z J Obstet Gynaecol 43:16–26 (2003).
  21. de Ravel TJ, Devriendt K, Fryns JP, Vermeesch JR: What’s new in karyotyping? The move towards array comparative genomic hybridisation (CGH). Eur J Pediatr 166:637–643 (2007).
  22. Faas BH, van der Burgt I, Kooper AJ, Pfundt R, Hehir-Kwa JY, et al: Identification of clinically significant, submicroscopic chromosome alterations and UPD in fetuses with ultrasound anomalies using genome-wide 250k SNP array analysis. J Med Genet 47:586–594 (2010).
  23. Faas BH, Cirigliano V, Bui TH: Rapid methods for targeted prenatal diagnosis of common chromosome aneuploidies. Semin Fetal Neonatal Med 16:81–87 (2011).
  24. Filges I, Kang A, Klug V, Wenzel F, Heinimann K, et al: aCGH on chorionic villi mirrors the complexity of fetoplacental mosaicism in prenatal diagnosis. Prenat Diagn 31:473–478 (2011).
  25. Forrester MB, Merz RD: Epidemiology of triploidy in a population-based birth defects registry, Hawaii, 1986–1999. Am J Med Genet 119A:319–323 (2003).
  26. Gall JG, Pardue ML: Molecular hybridization of radioactive DNA to the DNA of cytological preparations. Proc Natl Acad Sci USA 64:600–604 (1969).
  27. Gänshirt-Ahlert D, Börjesson-Stoll R, Burschyk M, Dohr A, Garritsen HS, et al: Detection of fetal trisomies 21 and 18 from maternal blood using triple gradient and magnetic cell sorting. Am J Reprod Immunol 30:194–201 (1993).
  28. Ginsburg C, Fokstuen S, Schinzel AA: The contribution of uniparental disomy to congenital development defects in children born to mothers at advanced childbearing age. Am J Med Genet 5:454–460 (2000).

    External Resources

  29. Go AT, van Vugt JM, Oudejans CB: Non-invasive aneuploidy detection using free fetal DNA and RNA in maternal plasma: recent progress and future possibilities. Hum Reprod Update 17:372–382 (2011).
  30. Hahn S, Lapaire O, Tercanli S, Kolla V, Hösli I: Determination of fetal chromosome aberrations from fetal DNA in maternal blood: has the challenge finally been met? Expert Rev Mol Med 13:e16 (2011).
  31. Hillman SC, Pretlove S, Coomarasamy A, McMullan DJ, Favison EV, et al: Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 37:6–14 (2011).
  32. Hills A, Donaghue C, Waters J, Waters K, Sullivan C, et al: QF-PCR as a stand-alone test for prenatal samples: the first 2 years’ experience in the London region. Prenat Diagn 30:509–517 (2010).
  33. Hopman AH, Wiegant J, Raap AK, Landegent JE, van der Ploeg M, et al: Bi-color detection of two target DNAs by non-radioactive in situ hybridization. Histochemistry 85:1–4 (1986).
  34. Huang B, Solomon S, Thangavelu M, Peters K, Bhatt S: Supernumerary marker chromosomes detected in 100,000 prenatal diagnoses: molecular cytogenetic studies and clinical significance. Prenat Diagn 26:1142–1150 (2006).
  35. Hultén MA, Dhanjal S, Pertl B: Rapid and simple prenatal diagnosis of common chromosome disorders: advantages and disadvantages of the molecular methods FISH and QF-PCR. Reproduction 126:279–297 (2003).
  36. Hsu LY, Yu MT, Richkind KE, Van Dyke DL, Crandall BF, et al: Incidence and significance of chromosome mosaicism involving an autosomal structural abnormality diagnosed prenatally through amniocentesis: a collaborative study. Prenat Diagn 16:1–28 (1996).
  37. Kantarci S, Ragge NK, Thomas NS, Robinson DO, Noonan KM, et al: Donnai-Barrow syndrome (DBS/FOAR) in a child with a homozygous LRP2 mutation due to complete chromosome 2 paternal isodisomy. Am J Med Genet 146A:1842–1847 (2008).
  38. Kotzot D: Prenatal testing for uniparental disomy: indications and clinical relevance. Ultrasound Obstet Gynecol 31:100–105 (2008).
  39. Le Caignec C, Boceno M, Saugier-Veber P, Jacquemont S, Joubert M, et al: Detection of genomic imbalances by array based comparative genomic hybridisation in fetuses with multiple malformations. J Med Genet 42:121–128 (2005).
  40. Leschot NJ, Wolf H, Van Prooijen-Knegt AC, van Asperen CJ, Verjaal M, et al: Cytogenetic findings in 1250 chorionic villus samples obtained in the first trimester with clinical follow-up of the first 1000 pregnancies. Br J Obstet Gynaecol 96:663–670 (1989).
  41. Leschot NL, Schuring-Blom GH, van Prooijen-Knegt AC, Verjaal M, Hansson K, et al: The outcome of pregnancies with confined placental chromosome mosaicism in cytotrophoblast cells. Prenat Diagn 16:705–712 (1996).
  42. Leung TY, Vogel I, Lau TK, Chong W, Hyett JA, et al: Identification of submicroscopic chromosomal aberrations in fetuses with increased nuchal translucency and an apparently normal karyotype. Ultrasound Obstet Gynecol (2011).
  43. Lichtenbelt KD, Alizadeh BZ, Scheffer PG, Stoutenbeek P, Schielen PC, et al: Trends in the utilization of invasive prenatal diagnosis in The Netherlands during 2000–2009. Prenat Diagn 31:756–772 (2011).

    External Resources

  44. Liehr T, Weise A: Frequency of small supernumerary marker chromosomes in prenatal, newborn, developmentally retarded and infertility diagnostics. Int J Mol Med 19:719–731 (2007).
  45. Liehr T, Karamysheva T, Merkas M, Brecevic L, Hamis AB, et al: Somatic mosaicism in cases with small supernumerary marker chromosomes. Curr Genomics 11:432–439 (2010).
  46. Lim TH, Tan AS, Goh VH: Relationship between gestational age and frequency of fetal trophoblasts and nucleated erythrocytes in maternal peripheral blood. Prenat Diagn 21:14–21 (2001).
  47. Lo YM, Corbetta N, Chamberlain PF, Rai V, Sargent IL, et al: Presence of fetal DNA in maternal plasma and serum. Lancet 350:485–487 (1997).
  48. Lu X, Shaw CA, Patel A, Li J, Cooper ML, et al: Clinical implementation of chromosomal microarray analysis: summary of 2513 postnatal cases. PLoS One 2:e327 (2007).
  49. Machado IN, Heinrich JK, Barini R, Peralta CF: Copy number imbalances detected with a BAC-bases array comparative genomic hybridization platform in congenital diaphragmatic hernia fetuses. Genet Mol Res 10:261–267 (2011).
  50. Maya I, Davidov B, Gershovitz L, Zalzstein Y, Taub E, et al: Diagnostic utility of array-based comparative genomic hybridization (aCGH) in a prenatal setting. Prenat Diagn 30:1131–1137 (2010).
  51. McWeeney DT, Munné S, Miller RC, Cekleniak NA, Contag SA, et al: Pregnancy complicated by triploidy: a comparison of the three karyotypes. Am J Perinatol 26:641–645 (2009).
  52. Menten B, Swerts K, Delle Chiaie B, Janssens S, Buysse K, et al: Array comparative genomic hybridization and flow cytometry analysis of spontaneous abortions and mors in utero samples. BMC Med Genet 10:89 (2009).
  53. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, et al: Consensus statement: Chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 86:749–764 (2010).
  54. Mohr J: Fetal genetic diagnosis: Development of techniques for early sampling of fetal cells. Acta Pathol Microbiol Scand 73:73–77 (1968).
  55. Papageorgiou EA, Karagrigoriou A, Tsaliki E, Velissariou V, Carter NP, Patsalis PC: Fetal-specific DNA methylation ratio permits noninvasive prenatal diagnosis of trisomy 21. Nat Med 17:510–513 (2011).
  56. Park JH, Woo JH, Shim SH, Yang SJ, Choi YM, et al: Application of a target array comparative genomic hybridization to prenatal diagnosis. BMC Med Genet 11:102 (2010).
  57. Pittalis MC, Dalpra L, Torricelli F, Rizzo N, Nocera G, et al: The predictive value of cytogenetic diagnosis after CVS based on 4860 cases with both direct and culture methods. Prenat Diagn 14:267–278 (1994).
  58. Rickman L, Fiegler H, Carter NP, Bobrow M: Prenatal diagnosis by array-CGH. Eur J Med Genet 48:232–240 (2005).
  59. Rickman L, Fiegler H, Shaw-Smith C, Nash R, Cirigliano V, et al: Prenatal detection of unbalanced chromosomal rearrangements by array CGH. J Med Genet 43:353–361 (2006).
  60. Rizzo N, Pittalis MC, Pilu G, et al: Distribution of abnormal karyotypes among malformed fetuses detected by ultrasound throughout gestation. Prenat Diagn 16:159–163 (1996).
  61. Robberecht C, Schuddinck V, Fryns JP, Vermeesch JR: Diagnosis of miscarriages by molecular karyotyping: Benefits and pitfalls. Genet Med 11:646–654 (2009).
  62. Robinson WP: Mechanisms leading to uniparental disomy and their clinical consequences. Bioessays 22:452–459 (2000).
  63. Savage MS, Mourad MJ, Wapner RJ: Evolving applications of microarray analysis in prenatal diagnosis. Curr Opin Obstet Gynecol 23:103–108 (2011).
  64. Sahoo T, Cheung SW, Ward P, Darilek S, Patel A, et al: Prenatal diagnosis of chromosomal abnormalities using array-based comparative genomic hybridization. Genet Med 8:719–727 (2006).
  65. Schaeffer AJ, Chung J, Heretis K, Wong A, Ledbetter DH: Comparative genomic hybridization-array analysis enhances the detection of aneuploidies and submicroscopic imbalances in spontaneous miscarriages. Am J Hum Genet 74:1168–1174 (2004).
  66. Scott SA, Cohen N, Brandt T, Toruner G, Desnick RJ, et al: Detection of low-level mosaicism and placental mosaicism by oligonucleotide array comparative genomic hybridization. Genet Med 12:85–92 (2010).
  67. Shaffer LG, Bui T-H: Molecular cytogenetic and rapid aneuploidy detection methods in prenatal diagnosis. Am J Med Genet Part C Semin Med Genet 145C:87–98 (2007).
  68. Shaffer LG, Bejjani BA, Torchia B, Kirkpatrick S, Coppinger J, et al: The identification of microdeletion syndromes and other chromosome abnormalities: cytogenetic methods of the past, new technologies for the future. Am J Med Genet C Semin Med Genet 145C:335–345 (2007).
  69. Shaffer LG, Coppinger J, Alliman S, Torchia BA, Theisen A, et al: Comparison of microarray-based detection rates for cytogenetic abnormalities in prenatal and neonatal specimens. Prenat Diagn 28:789–795 (2008).
  70. Shinawi M, Liu P, Kang SH, Shen J, Belmont JW, et al: Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet 47:332–341 (2010).
  71. Shuster E: Microarray genetic screening: a prenatal roadblock for life? Lancet 369:526–529 (2007).
  72. Simoni G, Brambati B, Danesio C, Rossella F, Terzoli GL, et al: Efficient direct chromosome analyses and enzyme determinations from chorionic villi samples in the first trimester of pregnancy. Hum Genet 63:349–357 (1983).
  73. Simoni G, Gimelli G, Cuoco C, Romitti L, Terzoli GL, et al: Discordance between prenatal cytogenetic diagnosis after chorionic villi sampling and chromosomal constitution of the fetus, in Fraccaro M, Simoni G, Brambati B (eds): First Trimester Fetal Diagnosis, pp. 137–143 (Springer Verlag, Berlin 1985).
  74. South ST, Chen Z, Brothman AR: Genomic medicine in prenatal diagnosis. Clin Obstet Gynecol 51:62–73 (2008).
  75. Speevak MD, Dolling J, Terespolsky D, Blumenthal A, Farrell SA: An algorithm for the prenatal detection of chromosome anomalies by QF-PCR and G-banded analysis. Prenat Diagn 13:1221–1226 (2008).

    External Resources

  76. Speevak MD, McGowan-Jordan J, Chun K: The detection of chromosome anomalies by QF-PCR and residual risks as compared to G-banded analysis. Prenat Diagn 31:454–458 (2011).
  77. Stankiewicz P, Beaudet AL: Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev 17:182–192 (2007).
  78. Steele MW, Breg WR: Chromosome analysis of human amniotic fluid cells. Lancet 1:383–385 (1966).
  79. Tietung Hospital of Anshan Iron and Steel Co., Anshan, Dept of Obstet Gynecol: Fetal sex prediction by sex chromatin of chorionic villi cells during early pregnancy. Chin Med J 1:117–126 (1975).
  80. Tyreman M, Abbott KM, Willatt LR, Nash R, Lees C, et al: High resolution array analysis: diagnosing pregnancies with abnormal ultrasound findings. J Med Genet 46:531–541 (2009).
  81. Valduga M, Philippe C, Segura PB, Thiebaugeorges O, Miton A, et al: A retrospective study by oligonucleotide array-CGH analysis in 50 fetuses with multiple malformations. Prenat Diagn 30:333–341 (2010).
  82. Van den Veyver IB, Beaudet AL: Comparative genomic hybridization and prenatal diagnosis. Curr Opin Obstet Gynecol 18:185–191 (2006).
  83. Van den Veyver IB, Patel A, Shaw CA, Pursley AN, Kang SH, et al: Clinical use of array comparative genomic hybridization (aCGH) for prenatal diagnosis in 300 cases. Prenat Diagn 29:29–39 (2009).
  84. Van Zwieten MC, Willems DL, Litjens LL, Schuring-Blom GH, Leschot N: How unexpected are unexpected findings in prenatal cytogenetic diagnosis? A literature review. Eur J Obstet Gynecol Reprod Biol 120:15–21 (2005).
  85. Voelderking KV, Lyon E: Digital fetal aneuploidy diagnosis by next-generation sequencing. Clin Chem 56:336–338 (2010).
  86. Warburton D: De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. Am J Hum Genet 49:995–1013 (1991).
  87. Wilson RD, Chitayat D, McGillicray BC: Fetal ultrasound abnormalities: correlation with fetal karyotype, autopsy findings and postnatal outcome – five year prospective study. Am J Med Genet 44:586–590 (1992).
  88. Wimalasundera RC, Gardiner HM: Congenital heart disease and aneuploidy. Prenat Diagn 24:1116–1122 (2004).


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