Genomic Arrays in Prenatal Diagnosis


Prenatal diagnosis (PND) is being applied to high‐risk pregnancies in order to identify possible genetic disorders in an unborn foetus or embryo. Through the application of various techniques, genetic disorders can be detected. As chromosomal abnormalities are one of the major causes of childhood intellectual disability and first trimester intrauterine deaths, PND is often suggested to exclude genetic disorders caused by chromosomal abnormalities. Currently, chromosomal analysis is the method of choice in PND, but with the emerging technologies, its substitution to array comparative genomic hybridisation (array‐CGH), is being considered. Challenges such as, interpretation issues, limitations of the method and lack of a dedicated database for prenatal samples that correlates ultrasound findings to copy number changes, need to be overcome before conventional karyotyping can be replaced by array‐CGH in PND.

Key Concepts

  • Prenatal diagnosis is applied to high‐risk pregnancies.
  • Invasive prenatal diagnosis is required to exclude genetic disorders in the foetus.
  • Chromosomal analysis, a whole genome testing, is used to detect chromosomal abnormalities in prenatal diagnosis.
  • Noninvasive prenatal screening tests can be offered to all pregnant women.
  • Complementary methods to chromosomal analysis can be applied to offer rapid prenatal testing for certain conditions.
  • Array‐CGH, a whole genome diagnostic test can be offered to add diagnostic value to chromosomal analysis.

Keywords: array comparative genomic hybridisation (array‐CGH); chromosomal analysis; karyotype; prenatal diagnosis; copy number variation (CNV)

Figure 1. A normal male G‐Banded karyotype from an amniotic fluid at between 550‐850 bands per haploid set resolution.
Figure 2. Array‐CGH analysis of a prenatal case presented with tetralogy of Fallot, showing a causative de novo copy number loss on the short arm of chromosome 19 at 19p13.3. Representation of the chromosomal and genomic location region [113,447–1,035,371 (GRCh37,hg19)] in the Database of Genomic Variants is shown. The loss of 700–950 Kb in size is marked by the red arrows, and it encompasses several RefSeq genes; four OMIM disease genes included in the deletion are represented by the orange bracket namely BSG, ELANE, CFD, KISS1R.


Akolekar R, Beta J, Picciarelli G, Ogilvie C and D'Antonio F (2015) Procedure‐related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta‐analysis. Ultrasound in Obstetrics and Gynecology 45 (1): 16–26.

American College of Obstetricians and Gynecologists Committee on Genetics (2013) Committee Opinion No. 581: the use of chromosomal microarray analysis in prenatal diagnosis. Obstetrics and Gynecology 122 (6): 1374–1377.

Bashiardes S, Kousoulidou L, van Bokhoven H, et al. (2009) A new chromosome x exon‐specific microarray platform for screening of patients with X‐linked disorders. Journal of Molecular Diagnostics 11 (6): 562–568.

Bateman MS, Mehta SG, Willatt L, et al. (2010) A de novo 4q34 interstitial deletion of at least 9.3 Mb with no discernible phenotypic effect. American Journal of Medical Genetics Part A 152A (7): 1764–1769.

Bejjani BA and Shaffer LG (2005) Use of targeted array‐based CGH for the clinical diagnosis of chromosomal imbalance: is less more? American Journal of Medical Genetics Part A 134 (3): 259–267.

Bejjani BA and Shaffer LG (2006) Application of array‐based comparative genomic hybridization to clinical diagnostics. Journal of Molecular Diagnostics 8 (5): 528–533.

Bui TH, Vetro A, Zuffardi O and Shaffer LG (2011) Current controversies in prenatal diagnosis 3: is conventional chromosome analysis necessary in the post‐array CGH era? Prenatal Diagnosis 31 (3): 235–243.

Burgess T, Downie L, Pertile MD, et al. (2014) Monosomy 21 seen in live born is unlikely to represent true monosomy 21: a case report and review of the literature. Case Reports in Genetics 2014: 965401.

Chiu RW and Lo YM (2011) Non‐invasive prenatal diagnosis by fetal nucleic acid analysis in maternal plasma: the coming of age. Seminars in Fetal and Neonatal Medicine 16 (2): 88–93.

Cicero S, Sacchini C, Rembouskos G and Nicolaides KH (2003) Sonographic markers of fetal aneuploidy—a review. Placenta 24 (Suppl B): S88–S98.

Di Gregorio E, Savin E, Biamino E, et al. (2014) Large cryptic genomic rearrangements with apparently normal karyotypes detected by array‐CGH. Molecular Cytogenetics 7 (1): 82.

Eisenberg B and Wapner RJ (2002) Clinical procedures in prenatal diagnosis. Best Practice & Research. Clinical Obstetrics & Gynaecology 16 (5): 611–627.

Evangelidou P, Alexandrou A, Moutafi M, et al. (2013) Implementation of high resolution whole genome array CGH in the prenatal clinical setting: advantages, challenges, and review of the literature. BioMed Research International 2013: 346762.

Evangelidou P, Sismani C, Ioannides M, et al. (2010) Clinical application of whole‐genome array CGH during prenatal diagnosis: study of 25 selected pregnancies with abnormal ultrasound findings or apparently balanced structural aberrations. Molecular Cytogenetics 3: 24.

Fiegler H, Redon R, Andrews D, et al. (2006) Accurate and reliable high‐throughput detection of copy number variation in the human genome. Genome Research 16 (12): 1566–1574.

Filges I, Röthlisberger B, Noppen C, et al. (2009) Familial 14.5 Mb interstitial deletion 13q21.1‐13q21.33: clinical and array‐CGH study of a benign phenotype in a three‐generation family. American Journal of Medical Genetics Part A 149A (2): 237–241.

Fiorentino F, Napoletano S, Caiazzo F, et al. (2013) Chromosomal microarray analysis as a first‐line test in pregnancies with a priori low risk for the detection of submicroscopic chromosomal abnormalities. European Journal of Human Genetics 21 (7): 725–730.

Firouzabadi SG, Kariminejad R, Vameghi R, et al. (2016) Copy number variants in patients with autism and additional clinical features: report of VIPR2 duplication and a novel microduplication syndrome. Molecular Neurobiology. DOI: 10.1007/s12035-016-0202-y.

Friedman JM, Baross A, Delaney AD, et al. (2006) Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation. American Journal of Human Genetics 79 (3): 500–513.

Fritz B, Hallermann C, Olert J, et al. (2001) Cytogenetic analyses of culture failures by comparative genomic hybridisation (CGH)‐re‐evaluation of chromosome aberration rates in early spontaneous abortions. European Journal of Human Genetics 9 (7): 539–547.

Gregg AR, Skotko BG, Benkendorf JL, et al. (2016) Noninvasive prenatal screening for fetal aneuploidy, 2016 update: a position statement of the American College of Medical Genetics and Genomics. Genetics in Medicine 18 (10): 1056–1065.

Hastings RJ, Nisbet DL, Waters K, et al. (1999) Prenatal detection of extra structurally abnormal chromosomes (ESACs): new cases and a review of the literature. Prenatal Diagnosis 19 (5): 436–445.

Hillman SC, Pretlove S, Coomarasamy A, et al. (2011) Additional information from array comparative genomic hybridization technology over conventional karyotyping in prenatal diagnosis: a systematic review and meta‐analysis. Ultrasound in Obstetrics and Gynecology 37 (1): 6–14.

Jacobs PA (1974) Correlation between euploid structural chromosome rearrangements and mental subnormality in humans. Nature 249 (453): 164–165.

Kan AS, Lau ET, Tang WF, et al. (2014) Whole‐genome array CGH evaluation for replacing prenatal karyotyping in Hong Kong. PLoS One 9 (2): e87988.

Kang SH, Shaw C, Ou Z, et al. (2010) Insertional translocation detected using FISH confirmation of array‐comparative genomic hybridization (aCGH) results. American Journal of Medical Genetics Part A 152A (5): 1111–1126.

Kleeman L, Bianchi D, Shaffer L, et al. (2009) Use of array comparative genomic hybridization for prenatal diagnosis of fetuses with sonographic anomalies and normal metaphase karyotype. Prenatal Diagnosis 29 (13): 1213–1217.

Lo YM, Corbetta N, Chamberlain PF, et al. (1997) Presence of fetal DNA in maternal plasma and serum. Lancet 350 (9076): 485–487.

Medical Research Council (1991) Medical Research Council European trial of chorion villus sampling. MRC working party on the evaluation pf chorion villus sampling. Lancet 337 (8756): 1491–1499.

Miller DT, Adam MP, Aradhya S, et al. (2010) Consensus statement: chromosomal microarray is a first‐tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. American Journal of Human Genetics 86 (5): 749–764.

Naqvi M, Goldfarb IT, Hanmer KJ, et al. (2016) Chromosomal microarray use among women undergoing invasive prenatal diagnosis. Prenatal Diagnosis 36 (7): 656–661.

Rauch A, Hoyer J, Guth S, et al. (2006) Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. American Journal of Medical Genetics Part A 140 (19): 2063–2074.

Rooney DEC and Czepulkowski BH (1992) Human Cytogenetics. A Practical Approach. Oxford, UK: IRL Press.

Sachs ES, Van Hemel JO, Den Hollander JC, et al. (1987) Marker chromosomes in a series of 10,000 prenatal diagnoses. Cytogenetic and follow‐up studies. Prenatal Diagnosis 7 (2): 81–89.

Sahoo T, Cheung SW, Ward P, et al. (2006) Prenatal diagnosis of chromosomal abnormalities using array‐based comparative genomic hybridization. Genetics in Medicine 8 (11): 719–727.

Scott F, Murphy K, Carey L, et al. (2013) Prenatal diagnosis using combined quantitative fluorescent polymerase chain reaction and array comparative genomic hybridization analysis as a first‐line test: results from over 1000 consecutive cases. Ultrasound in Obstetrics and Gynecology 41 (5): 500–507.

Shaffer LG, Coppinger J, Alliman S, et al. (2008) Comparison of microarray‐based detection rates for cytogenetic abnormalities in prenatal and neonatal specimens. Prenatal Diagnosis 28 (9): 789–795.

Sharp AJ (2009) Emerging themes and new challenges in defining the role of structural variation in human disease. Human Mutation 30 (2): 135–144.

Shiefa S, Amargandhi M, Bhupendra J, et al. (2013) First trimester maternal serum screening using biochemical markers PAPP‐A and free beta‐hCG for Down syndrome, Patau syndrome and Edward syndrome. Indian Journal of Clinical Biochemistry 28 (1): 3–12.

Sismani C, Kitsiou‐Tzeli S, Ioannides M, et al. (2008) Cryptic genomic imbalances in patients with de novo or familial apparently balanced translocations and abnormal phenotype. Molecular Cytogenetics 1: 15.

Slavotinek AM (2008) Novel microdeletion syndromes detected by chromosome microarrays. Human Genetics 124 (1): 1–17.

Srebniak MI, Diderich KE, Joosten M, et al. (2016) Prenatal SNP array testing in 1000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs. European Journal of Human Genetics 24 (5): 645–651.

Srebniak MI, Mout L, Van Opstal D and Galjaard RJ (2013) 0.5 Mb array as a first‐line prenatal cytogenetic test in cases without ultrasound abnormalities and its implementation in clinical practice. Human Mutation 34 (9): 1298–1303.

Tyreman M, Abbott KM, Willatt LR, et al. (2009) High resolution array analysis: diagnosing pregnancies with abnormal ultrasound findings. Journal of Medical Genetics 46 (8): 531–541.

Van den Veyver IB (2016) Recent advances in prenatal genetic screening and testing. F1000Res 5: 2591.

Vermeesch JR, Brady PD, Sanlaville D, et al. (2012) Genome‐wide arrays: quality criteria and platforms to be used in routine diagnostics. Human Mutation 33 (6): 906–915.

Wapner RJ (2005) Invasive prenatal diagnostic techniques. Seminars in Perinatology 29 (6): 401–404.

Wapner RJ, Martin CL, Levy B, et al. (2012) Chromosomal microarray versus karyotyping for prenatal diagnosis. New England Journal of Medicine 367 (23): 2175–2184.

Warburton D (1991) De novo balanced chromosome rearrangements and extra marker chromosomes identified at prenatal diagnosis: clinical significance and distribution of breakpoints. American Journal of Human Genetics 49 (5): 995–1013.

Zhu H, Lin S, Huang L, et al. (2016a) Application of chromosomal microarray analysis in prenatal diagnosis of fetal growth restriction. Prenatal Diagnosis 36 (7): 686–692.

Zhu X, Li J, Ru T, et al. (2016b) Identification of copy number variations associated with congenital heart disease by chromosomal microarray analysis and next‐generation sequencing. Prenatal Diagnosis 36 (4): 321–327.

Further Reading

Benn PA and Tantravahi U (2001) Chromosome staining and banding techniques. In: Rooney DE (ed.) Human Cytogenetics: Constitutional Analysis, A Practical Approach, 3rd edn, pp. 99–127. New York, NY: Oxford University Press.

Boyle T and Griffin D (2001) The cytogenetics of pregnancy. In: Rooney DE (ed.) Human Cytogenetics: Constitutional Analysis, A Practical Approach, 3rd edn, pp. 55–97. New York, NY: Oxford University Press.

Clouston HJ (2001) Lymphocyte culture. In: Rooney DE (ed.) Human Cytogenetics: Constitutional Analysis, A Practical Approach, 3rd edn, pp. 33–53. New York, NY: Oxford University Press.

Evangelidou P, Patsalis CP and Sismani C (2015) Array in prenatal diagnosis. In: Henderson A (ed.) Prenatal and Maternal Diagnosis, Screening and Infant Development Implications, pp. 53–107. New York, NY: Nova Science Publishers, Inc.

Kearney L and Buckle VJ (2001) The application of fluorescence in situ hybridization to chromosome analysis. In: Rooney DE (ed.) Human Cytogenetics: Constitutional Analysis, A Practical Approach, 3rd edn, pp. 175–207. New York, NY: Oxford University Press.

Mann K, Donaghue C, Fox SP, et al (2004) Strategies for the rapid prenatal diagnosis of chromosome aneuploidy. European Journal of Human Genetics 12: 907–915.

McKinlay Gardner RJ, Sutherland GR and Shaffer LG (2012) Chromosome Abnormalities and Genetic Counselling. New York, NY: Oxford University Press.

Wolstenholme J and Cross I (2001) An introduction to human chromosomes and their analysis. In: Rooney DE (ed.) Human Cytogenetics: Constitutional Analysis, A Practical Approach, 3rd edn, pp. 1–31. New York, NY: Oxford University Press.

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Evangelidou, Paola, and Sismani, Carolina(Mar 2017) Genomic Arrays in Prenatal Diagnosis. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026715]