Skip to main content
PMC home page
Journal of Medical Genetics logoLink to Journal of Medical Genetics
. 2005 Feb;42(2):121–128. doi: 10.1136/jmg.2004.025478

Detection of genomic imbalances by array based comparative genomic hybridisation in fetuses with multiple malformations

C Le Caignec 1, M Boceno 1, P Saugier-Veber 1, S Jacquemont 1, M Joubert 1, A David 1, T Frebourg 1, J Rival 1
PMCID: PMC1735978  PMID: 15689449

Abstract

Background: Malformations are a major cause of morbidity and mortality in full term infants and genomic imbalances are a significant component of their aetiology. However, the causes of defects in many patients with multiple congenital malformations remain unexplained despite thorough clinical examination and laboratory investigations.

Methods: We used a commercially available array based comparative genomic hybridisation method (array CGH), able to screen all subtelomeric regions, main microdeletion syndromes, and 201 other regions covering the genome, to detect submicroscopic chromosomal imbalances in 49 fetuses with three or more significant anomalies and normal karyotype.

Results: Array CGH identified eight genomic rearrangements (16.3%), all confirmed by quantitative multiplex PCR of short fluorescent fragments. Subtelomeric and interstitial deletions, submicroscopic duplications, and a complex genomic imbalance were identified. In four de novo cases (15qtel deletion, 16q23.1–q23.3 deletion, 22q11.2 deletion, and mosaicism for a rearranged chromosome 18), the genomic imbalance identified clearly underlay the pathological phenotype. In one case, the relationship between the genotype and phenotype was unclear, since a subtelomeric 6q deletion was detected in a mother and her two fetuses bearing multiple malformations. In three cases, a subtelomeric 10q duplication, probably a genomic polymorphism, was identified.

Conclusions: The detection of 5/49 causative chromosomal imbalances (or 4/49 if the 6qtel deletion is not considered as causative) suggests wide genome screening when standard chromosome analysis is normal and confirms that array CGH will have a major impact on pre and postnatal diagnosis as well as providing information for more accurate genetic counselling.

Full Text

The Full Text of this article is available as a PDF (316.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albertson D. G., Ylstra B., Segraves R., Collins C., Dairkee S. H., Kowbel D., Kuo W. L., Gray J. W., Pinkel D. Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene. Nat Genet. 2000 Jun;25(2):144–146. doi: 10.1038/75985. [DOI] [PubMed] [Google Scholar]
  2. Biesecker Leslie G. The end of the beginning of chromosome ends. Am J Med Genet. 2002 Feb 1;107(4):263–266. doi: 10.1002/ajmg.10160. [DOI] [PubMed] [Google Scholar]
  3. Bruder C. E., Hirvelä C., Tapia-Paez I., Fransson I., Segraves R., Hamilton G., Zhang X. X., Evans D. G., Wallace A. J., Baser M. E. High resolution deletion analysis of constitutional DNA from neurofibromatosis type 2 (NF2) patients using microarray-CGH. Hum Mol Genet. 2001 Feb 1;10(3):271–282. doi: 10.1093/hmg/10.3.271. [DOI] [PubMed] [Google Scholar]
  4. Buckley Patrick G., Mantripragada Kiran K., Benetkiewicz Magdalena, Tapia-Páez Isabel, Diaz De Ståhl Teresita, Rosenquist Magnus, Ali Haider, Jarbo Caroline, De Bustos Cecilía, Hirvelä Carina. A full-coverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications. Hum Mol Genet. 2002 Dec 1;11(25):3221–3229. doi: 10.1093/hmg/11.25.3221. [DOI] [PubMed] [Google Scholar]
  5. Callen D. F., Eyre H., Lane S., Shen Y., Hansmann I., Spinner N., Zackai E., McDonald-McGinn D., Schuffenhauer S., Wauters J. High resolution mapping of interstitial long arm deletions of chromosome 16: relationship to phenotype. J Med Genet. 1993 Oct;30(10):828–832. doi: 10.1136/jmg.30.10.828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Charbonnier F., Raux G., Wang Q., Drouot N., Cordier F., Limacher J. M., Saurin J. C., Puisieux A., Olschwang S., Frebourg T. Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments. Cancer Res. 2000 Jun 1;60(11):2760–2763. [PubMed] [Google Scholar]
  7. Charbonnier Françoise, Olschwang Sylviane, Wang Qing, Boisson Cécile, Martin Cosette, Buisine Marie-Pierre, Puisieux Alain, Frebourg Thierry. MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer. Cancer Res. 2002 Feb 1;62(3):848–853. [PubMed] [Google Scholar]
  8. De Galan-Roosen A. E., Kuijpers J. C., Meershoek A. P., van Velzen D. Contribution of congenital malformations to perinatal mortality. A 10 years prospective regional study in The Netherlands. Eur J Obstet Gynecol Reprod Biol. 1998 Sep;80(1):55–61. doi: 10.1016/s0301-2115(98)00085-2. [DOI] [PubMed] [Google Scholar]
  9. De Vries B. B. A., Winter R., Schinzel A., van Ravenswaaij-Arts C. Telomeres: a diagnosis at the end of the chromosomes. J Med Genet. 2003 Jun;40(6):385–398. doi: 10.1136/jmg.40.6.385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Delafontaine P. Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc Res. 1995 Dec;30(6):825–834. [PubMed] [Google Scholar]
  11. Devriendt K., Moerman P., Van Schoubroeck D., Vandenberghe K., Fryns J. P. Chromosome 22q11 deletion presenting as the Potter sequence. J Med Genet. 1997 May;34(5):423–425. doi: 10.1136/jmg.34.5.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Harada N., Hatchwell E., Okamoto N., Tsukahara M., Kurosawa K., Kawame H., Kondoh T., Ohashi H., Tsukino R., Kondoh Y. Subtelomere specific microarray based comparative genomic hybridisation: a rapid detection system for cryptic rearrangements in idiopathic mental retardation. J Med Genet. 2004 Feb;41(2):130–136. doi: 10.1136/jmg.2003.014639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Ishkanian Adrian S., Malloff Chad A., Watson Spencer K., DeLeeuw Ronald J., Chi Bryan, Coe Bradley P., Snijders Antoine, Albertson Donna G., Pinkel Daniel, Marra Marco A. A tiling resolution DNA microarray with complete coverage of the human genome. Nat Genet. 2004 Feb 15;36(3):299–303. doi: 10.1038/ng1307. [DOI] [PubMed] [Google Scholar]
  14. Jacquet Hélène, Raux Grégory, Thibaut Florence, Hecketsweiler Bernadette, Houy Emmanuelle, Demilly Caroline, Haouzir Sadeq, Allio Gabrielle, Fouldrin Gael, Drouin Valérie. PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. Hum Mol Genet. 2002 Sep 15;11(19):2243–2249. doi: 10.1093/hmg/11.19.2243. [DOI] [PubMed] [Google Scholar]
  15. Kallioniemi A., Kallioniemi O. P., Sudar D., Rutovitz D., Gray J. W., Waldman F., Pinkel D. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science. 1992 Oct 30;258(5083):818–821. doi: 10.1126/science.1359641. [DOI] [PubMed] [Google Scholar]
  16. Kalter H., Warkany J. Congenital malformations (second of two parts). N Engl J Med. 1983 Mar 3;308(9):491–497. doi: 10.1056/NEJM198303033080904. [DOI] [PubMed] [Google Scholar]
  17. Kalter H., Warkany J. Medical progress. Congenital malformations: etiologic factors and their role in prevention (first of two parts). N Engl J Med. 1983 Feb 24;308(8):424–431. doi: 10.1056/NEJM198302243080804. [DOI] [PubMed] [Google Scholar]
  18. Kirchhoff M., Rose H., Lundsteen C. High resolution comparative genomic hybridisation in clinical cytogenetics. J Med Genet. 2001 Nov;38(11):740–744. doi: 10.1136/jmg.38.11.740. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Knight S. J., Lese C. M., Precht K. S., Kuc J., Ning Y., Lucas S., Regan R., Brenan M., Nicod A., Lawrie N. M. An optimized set of human telomere clones for studying telomere integrity and architecture. Am J Hum Genet. 2000 Jun 22;67(2):320–332. doi: 10.1086/302998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Knight S. J., Regan R., Nicod A., Horsley S. W., Kearney L., Homfray T., Winter R. M., Bolton P., Flint J. Subtle chromosomal rearrangements in children with unexplained mental retardation. Lancet. 1999 Nov 13;354(9191):1676–1681. doi: 10.1016/S0140-6736(99)03070-6. [DOI] [PubMed] [Google Scholar]
  21. Krassikoff N., Sekhon G. S. Terminal deletion of 6q and Fryns syndrome: a microdeletion/syndrome pair? Am J Med Genet. 1990 Jul;36(3):363–364. doi: 10.1002/ajmg.1320360327. [DOI] [PubMed] [Google Scholar]
  22. Kriek M., White S. J., Bouma M. C., Dauwerse H. G., Hansson K. B. M., Nijhuis J. V., Bakker B., van Ommen G-J B., den Dunnen J. T., Breuning M. H. Genomic imbalances in mental retardation. J Med Genet. 2004 Apr;41(4):249–255. doi: 10.1136/jmg.2003.014308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Le Caignec C., Winer N., Boceno M., Delnatte C., Podevin G., Liet J. M., Quere M. P., Joubert M., Rival J. M. Prenatal diagnosis of sacrococcygeal teratoma with constitutional partial monosomy 7q/trisomy 2p. Prenat Diagn. 2003 Dec 15;23(12):981–984. doi: 10.1002/pd.742. [DOI] [PubMed] [Google Scholar]
  24. Liu J. P., Baker J., Perkins A. S., Robertson E. J., Efstratiadis A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell. 1993 Oct 8;75(1):59–72. [PubMed] [Google Scholar]
  25. Locke D. P., Segraves R., Nicholls R. D., Schwartz S., Pinkel D., Albertson D. G., Eichler E. E. BAC microarray analysis of 15q11-q13 rearrangements and the impact of segmental duplications. J Med Genet. 2004 Mar;41(3):175–182. doi: 10.1136/jmg.2003.013813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Monaghan K. G., Van Dyke D. L., Wiktor A., Feldman G. L. Cytogenetic and clinical findings in a patient with a deletion of 16q23.1: first report of bilateral cataracts and a 16q deletion. Am J Med Genet. 1997 Dec 12;73(2):180–183. doi: 10.1002/(sici)1096-8628(1997)73:2<180::aid-ajmg13>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  27. Nelson K., Holmes L. B. Malformations due to presumed spontaneous mutations in newborn infants. N Engl J Med. 1989 Jan 5;320(1):19–23. doi: 10.1056/NEJM198901053200104. [DOI] [PubMed] [Google Scholar]
  28. Ness Gro Oddveig, Lybaek Helle, Houge Gunnar. Usefulness of high-resolution comparative genomic hybridization (CGH) for detecting and characterizing constitutional chromosome abnormalities. Am J Med Genet. 2002 Nov 22;113(2):125–136. doi: 10.1002/ajmg.10593. [DOI] [PubMed] [Google Scholar]
  29. Pinkel D., Segraves R., Sudar D., Clark S., Poole I., Kowbel D., Collins C., Kuo W. L., Chen C., Zhai Y. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet. 1998 Oct;20(2):207–211. doi: 10.1038/2524. [DOI] [PubMed] [Google Scholar]
  30. Roback E. W., Barakat A. J., Dev V. G., Mbikay M., Chrétien M., Butler M. G. An infant with deletion of the distal long arm of chromosome 15 (q26.1----qter) and loss of insulin-like growth factor 1 receptor gene. Am J Med Genet. 1991 Jan;38(1):74–79. doi: 10.1002/ajmg.1320380117. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rosenberg M. J., Killoran C., Dziadzio L., Chang S., Stone D. L., Meck J., Aughton D., Bird L. M., Bodurtha J., Cassidy S. B. Scanning for telomeric deletions and duplications and uniparental disomy using genetic markers in 120 children with malformations. Hum Genet. 2001 Sep;109(3):311–318. doi: 10.1007/s004390100559. [DOI] [PubMed] [Google Scholar]
  32. Rosenberg M. J., Vaske D., Killoran C. E., Ning Y., Wargowski D., Hudgins L., Tifft C. J., Meck J., Blancato J. K., Rosenbaum K. Detection of chromosomal aberrations by a whole-genome microsatellite screen. Am J Hum Genet. 2000 Feb;66(2):419–427. doi: 10.1086/302743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Saugier-Veber P., Drouot N., Lefebvre S., Charbonnier F., Vial E., Munnich A., Frébourg T. Detection of heterozygous SMN1 deletions in SMA families using a simple fluorescent multiplex PCR method. J Med Genet. 2001 Apr;38(4):240–243. doi: 10.1136/jmg.38.4.240. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Schaeffer Anthony J., Chung June, Heretis Konstantina, Wong Andrew, Ledbetter David H., Lese Martin Christa. Comparative genomic hybridization-array analysis enhances the detection of aneuploidies and submicroscopic imbalances in spontaneous miscarriages. Am J Hum Genet. 2004 May 4;74(6):1168–1174. doi: 10.1086/421250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Schoumans J., Anderlid B-M, Blennow E., Teh B. T., Nordenskjöld M. The performance of CGH array for the detection of cryptic constitutional chromosome imbalances. J Med Genet. 2004 Mar;41(3):198–202. doi: 10.1136/jmg.2003.013920. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Shaw-Smith C., Redon R., Rickman L., Rio M., Willatt L., Fiegler H., Firth H., Sanlaville D., Winter R., Colleaux L. Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. J Med Genet. 2004 Apr;41(4):241–248. doi: 10.1136/jmg.2003.017731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Siebler T., Lopaczynski W., Terry C. L., Casella S. J., Munson P., De Leon D. D., Phang L., Blakemore K. J., McEvoy R. C., Kelley R. I. Insulin-like growth factor I receptor expression and function in fibroblasts from two patients with deletion of the distal long arm of chromosome 15. J Clin Endocrinol Metab. 1995 Dec;80(12):3447–3457. doi: 10.1210/jcem.80.12.8530582. [DOI] [PubMed] [Google Scholar]
  38. Slavotinek A., Rosenberg M., Knight S., Gaunt L., Fergusson W., Killoran C., Clayton-Smith J., Kingston H., Campbell R. H., Flint J. Screening for submicroscopic chromosome rearrangements in children with idiopathic mental retardation using microsatellite markers for the chromosome telomeres. J Med Genet. 1999 May;36(5):405–411. [PMC free article] [PubMed] [Google Scholar]
  39. Snijders A. M., Nowak N., Segraves R., Blackwood S., Brown N., Conroy J., Hamilton G., Hindle A. K., Huey B., Kimura K. Assembly of microarrays for genome-wide measurement of DNA copy number. Nat Genet. 2001 Nov;29(3):263–264. doi: 10.1038/ng754. [DOI] [PubMed] [Google Scholar]
  40. Solinas-Toldo S., Lampel S., Stilgenbauer S., Nickolenko J., Benner A., Döhner H., Cremer T., Lichter P. Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer. 1997 Dec;20(4):399–407. [PubMed] [Google Scholar]
  41. Turleau C., de Grouchy J. Trisomy 18qter and trisomy mapping of chromosome 18. Clin Genet. 1977 Dec;12(6):361–371. doi: 10.1111/j.1399-0004.1977.tb00955.x. [DOI] [PubMed] [Google Scholar]
  42. Tönnies H., Schulze I., Hennies H., Neumann L. M., Keitzer R., Neitzel H. De novo terminal deletion of chromosome 15q26.1 characterised by comparative genomic hybridisation and FISH with locus specific probes. J Med Genet. 2001 Sep;38(9):617–621. doi: 10.1136/jmg.38.9.617. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Veltman Joris A., Fridlyand Jane, Pejavar Sunanda, Olshen Adam B., Korkola James E., DeVries Sandy, Carroll Peter, Kuo Wen-Lin, Pinkel Daniel, Albertson Donna. Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Cancer Res. 2003 Jun 1;63(11):2872–2880. [PubMed] [Google Scholar]
  44. Veltman Joris A., Schoenmakers Eric F. P. M., Eussen Bert H., Janssen Irene, Merkx Gerard, van Cleef Brigitte, van Ravenswaaij Conny M., Brunner Han G., Smeets Dominique, van Kessel Ad Geurts. High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization. Am J Hum Genet. 2002 Apr 9;70(5):1269–1276. doi: 10.1086/340426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Vissers Lisenka E. L. M., de Vries Bert B. A., Osoegawa Kazutoyo, Janssen Irene M., Feuth Ton, Choy Chik On, Straatman Huub, van der Vliet Walter, Huys Erik H. L. P. G., van Rijk Anke. Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. Am J Hum Genet. 2003 Nov 18;73(6):1261–1270. doi: 10.1086/379977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Werner W., Kraft S., Callen D. F., Bartsch O., Hinkel G. K. A small deletion of 16q23.1-->16q24.2 [del(16)(q23.1q24.2).ish del(16)(q23.1q24.2)(D16S395+, D16S348-, P5432+)] in a boy with iris coloboma and minor anomalies. Am J Med Genet. 1997 Jun 27;70(4):371–376. [PubMed] [Google Scholar]
  47. Wilhelm Mónica, Veltman Joris A., Olshen Adam B., Jain Ajay N., Moore Dan H., Presti Joe C., Jr, Kovacs Gyula, Waldman Frederic M. Array-based comparative genomic hybridization for the differential diagnosis of renal cell cancer. Cancer Res. 2002 Feb 15;62(4):957–960. [PubMed] [Google Scholar]
  48. Yu Wei, Ballif Blake C., Kashork Catherine D., Heilstedt Heidi A., Howard Leslie A., Cai Wei-Wen, White Lisa D., Liu Wenbin, Beaudet Arthur L., Bejjani Bassem A. Development of a comparative genomic hybridization microarray and demonstration of its utility with 25 well-characterized 1p36 deletions. Hum Mol Genet. 2003 Jul 15;12(17):2145–2152. doi: 10.1093/hmg/ddg230. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

[Tables and Figures of Figure 1]
jmedgene_42_2_121__index.html (2.5KB, html)
jmedgene_42_2_121__1.pdf (139.5KB, pdf)
jmedgene_42_2_121__422121Fetus17.jpg (36.8KB, jpg)
jmedgene_42_2_121__422121Fetus21.jpg (34.2KB, jpg)
jmedgene_42_2_121__422121Fetus27.jpg (35.8KB, jpg)
jmedgene_42_2_121__422121Fetus41.jpg (36.7KB, jpg)
jmedgene_42_2_121__422121Fetus52.jpg (71.9KB, jpg)
jmedgene_42_2_121__422121Fetus20.jpg (37KB, jpg)

Articles from Journal of Medical Genetics are provided here courtesy of BMJ Publishing Group

RESOURCES