Skip to main content

Advertisement

SpringerLink
Log in

A novel 5q11.2 deletion detected by microarray comparative genomic hybridisation in a child referred as a case of suspected 22q11 deletion syndrome

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

The 22q11 deletion syndrome (22q11DS) is a developmental syndrome comprising of heart, palate, thymus and parathyroid glands defects. Individuals with 22q11DS usually carry a 1.5- to 3-Mb heterozygous deletion on chromosome 22q11.2. However, there are many patients with features of 22q11DS without a known cause from conventional karyotype and FISH analysis. Six patients with features of 22q11DS, a normal chromosomal and FISH 22q11 analysis, were selected for investigation by microarray genomic comparative hybridisation (array CGH). Array-CGH is a powerful technology enabling detection of submicroscopic chromosome duplications and deletions by comparing a differentially labelled test sample to a control. The samples are co-hybridised to a microarray containing genomic clones and the resulting ratio of fluorescence intensities on each array element is proportional to the DNA copy number difference. No chromosomal changes were detected by hybridisation to a high resolution array representing chromosome 22q. However, one patient was found to have a 6-Mb deletion on 5q11.2 detected by a whole genome 1-Mb array. This deletion was confirmed with fluorescence in-situ hybridisation (FISH) and microsatellite marker analysis. It is the first deletion described in this region. The patient had tetralogy of Fallot, a bifid uvula and velopharyngeal insufficiency, short stature, learning and behavioural difficulties. This case shows the increased sensitivity of array CGH over detailed karyotype analysis for detection of chromosomal changes. It is anticipated that array CGH will improve the clinician’s capacity to diagnose congenital syndromes with an unknown aetiology.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Adham IM, Sallam MA, Steding G, Korabiowska M, Brinck U, Hoyer-Fender S, Oh C, Engel W (2003) Disruption of the pelota gene causes early embryonic lethality and defects in cell cycle progression. Mol Cell Biol 23:1470–1476

    Article  CAS  PubMed  Google Scholar 

  • Bachiller D, Klingensmith J, Shneyder N, Tran U, Anderson R, Rossant J, De Robertis EM (2003) The role of chordin/Bmp signals in mammalian pharyngeal development and DiGeorge syndrome. Development 130:3567–3578

    Article  CAS  PubMed  Google Scholar 

  • Bailey JA, Gu Z, Clark RA, Reinert K, Samonte RV, Schwartz S, Adams MD, Myers EW, Li PW, Eichler EE (2002) Recent segmental duplications in the human genome. Science 297:1003–1007

    Article  CAS  PubMed  Google Scholar 

  • Bijnens AP, Gils A, Jutten B, Faber BC, Heeneman S, Kitslaar PJ, Tordoir JH, de Vries CJ, Kroon AA, Daemen MJ, Cleutjens KB (2003) Vasculin, a novel vascular protein differentially expressed in human atherogenesis. Blood 102:2803–2810

    Article  CAS  PubMed  Google Scholar 

  • Brewer C, Holloway S, Zawalnyski P, Schinzel A, FitzPatrick D (1998) A chromosomal deletion map of human malformations. Am J Hum Genet 63:1153–1159

    Article  CAS  PubMed  Google Scholar 

  • Buckley PG, Mantripragada KK, Benetkiewicz M, Tapia-Paez I, Diaz DS, Rosenquist M, Ali H, Jarbo C, De Bustos C, Hirvela C, Sinder WB, Fransson I, Thyr C, Johnsson BI, Bruder CE, Menzel U, Hergersberg M, Mandahl N, Blennow E, Wedell A, Beare DM, Collins JE, Dunham I, Albertson D, Pinkel D, Bastian BC, Faruqi AF, Lasken RS, Ichimura K, Collins VP, Dumanski JP (2002) A full-coverage, high-resolution human chromosome 22 genomic microarray for clinical and research applications. Hum Mol Genet 11:3221–3229

    Article  CAS  PubMed  Google Scholar 

  • Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5:877–889

    Article  CAS  PubMed  Google Scholar 

  • Carey AH, Kelly D, Halford S, Wadey R, Wilson D, Goodship J, Burn J, Paul T, Sharkey A, Dumanski J, Nordenskjold M, Williamson R, Scambler PJ (1992) Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome. Am J Hum Genet 51:964–970

    CAS  PubMed  Google Scholar 

  • Chen J, Diacovo TG, Grenache DG, Santoro SA, Zutter MM (2002) The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 161:337–344

    CAS  PubMed  Google Scholar 

  • Feijen A, Goumans MJ, van den Eijnden-van Raaij AJ (1994) Expression of activin subunits, activin receptors and follistatin in postimplantation mouse embryos suggests specific developmental functions for different activins. Development 120:3621–3637

    CAS  PubMed  Google Scholar 

  • Fiegler H, Carr P, Douglas EJ, Burford DC, Hunt S, Scott CE, Smith J, Vetrie D, Gorman P, Tomlinson IP, Carter NP (2003) DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones. Genes Chromosomes Cancer 36:361–374

    Article  CAS  PubMed  Google Scholar 

  • Gong W, Gottlieb S, Collins J, Blescia A, Dietz H, Goldmuntz E, McDonald-McGinn DM, Zackai EH, Emanuel BS, Driscoll DA, Budarf ML (2001) Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects. J Med Genet 38:E45

    Article  CAS  PubMed  Google Scholar 

  • Hemmati-Brivanlou A, Kelly OG, Melton DA (1994) Follistatin, an antagonist of activin, is expressed in the Spemann organizer and displays direct neuralizing activity. Cell 77:283–295

    Article  CAS  PubMed  Google Scholar 

  • Iemura S, Yamamoto TS, Takagi C, Uchiyama H, Natsume T, Shimasaki S, Sugino H, Ueno N (1998) Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo. Proc Natl Acad Sci USA 95:9337–9342

    Article  CAS  PubMed  Google Scholar 

  • Jain AN, Tokuyasu TA, Snijders AM, Segraves R, Albertson DG, Pinkel D (2002) Fully automatic quantification of microarray image data. Genome Res 12:325–332

    Article  Google Scholar 

  • Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, Waldman F, Pinkel D (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258:818–821

    CAS  PubMed  Google Scholar 

  • Kirchhoff M, Rose H, Lundsteen C (2001) High resolution comparative genomic hybridisation in clinical cytogenetics. J Med Genet 38:740–744

    Article  CAS  PubMed  Google Scholar 

  • Lee HJ, Adham IM, Schwarz G, Kneussel M, Sass JO, Engel W, Reiss J (2002) Molybdenum cofactor-deficient mice resemble the phenotype of human patients. Hum Mol Genet 11:3309–3317

    Article  CAS  PubMed  Google Scholar 

  • Matzuk MM, Lu N, Vogel H, Sellheyer K, Roop DR, Bradley A (1995) Multiple defects and perinatal death in mice deficient in follistatin. Nature 374:360–363

    Article  CAS  PubMed  Google Scholar 

  • Monni O, Barlund M, Mousses S, Kononen J, Sauter G, Heiskanen M, Paavola P, Avela K, Chen Y, Bittner ML, Kallioniemi A (2001) Comprehensive copy number and gene expression profiling of the 17q23 amplicon in human breast cancer. Proc Natl Acad Sci USA 98:5711–5716

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Takio K, Eto Y, Shibai H, Titani K, Sugino H (1990) Activin-binding protein from rat ovary is follistatin. Science 247:836–838

    CAS  PubMed  Google Scholar 

  • Nilsen H, Stamp G, Andersen S, Hrivnak G, Krokan HE, Lindahl T, Barnes DE (2003) Gene-targeted mice lacking the Ung uracil-DNA glycosylase develop B-cell lymphomas. Oncogene 22:5381–5386

    Article  CAS  PubMed  Google Scholar 

  • Piccolo S, Sasai Y, Lu B, De Robertis EM (1996) Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4. Cell 86:589–598

    Article  CAS  PubMed  Google Scholar 

  • Pinkel D, Landegent J, Collins C, Fuscoe J, Segraves R, Lucas J, Gray J (1988) Fluorescence in situ hybridization with human chromosome-specific libraries: detection of trisomy 21 and translocations of chromosome 4. Proc Natl Acad Sci USA 85:9138–9142

    CAS  PubMed  Google Scholar 

  • Pinkel D, Segraves R, Sudar D, Clark S, Poole I, Kowbel D, Collins C, Kuo WL, Chen C, Zhai Y, Dairkee SH, Ljung BM, Gray JW, Albertson DG (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 20:207–211

    Article  CAS  PubMed  Google Scholar 

  • Pollack JR, Sorlie T, Perou CM, Rees CA, Jeffrey SS, Lonning PE, Tibshirani R, Botstein D, Borresen-Dale AL, Brown PO (2002) Microarray analysis reveals a major direct role of DNA copy number alteration in the transcriptional program of human breast tumors. Proc Natl Acad Sci USA 99:12963–12968

    Article  CAS  PubMed  Google Scholar 

  • Redon R, Hussenet T, Bour G, Caulee K, Jost B, Muller D, Abecassis J, du Manoir S (2002) Amplicon mapping and transcriptional analysis pinpoint cyclin L as a candidate oncogene in head and neck cancer. Cancer Res 62:6211–6217

    CAS  PubMed  Google Scholar 

  • Reiss J, Dorche C, Stallmeyer B, Mendel RR, Cohen N, Zabot MT (1999) Human molybdopterin synthase gene: genomic structure and mutations in molybdenum cofactor deficiency type B. Am J Hum Genet 64:706–711

    Article  CAS  PubMed  Google Scholar 

  • Scambler PJ (2000) The 22q11 deletion syndromes. Hum Mol Genet 9:2421–2426

    Article  CAS  PubMed  Google Scholar 

  • Shaw-Smith C, Redon R, Rickman L, Rio M, Willatt L, Fiegler H, Firth H, Sanlaville D, Winter R, Colleaux L, Bobrow M, Carter NP (2004) 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 41:241–248

    Article  CAS  PubMed  Google Scholar 

  • Shimomura H, Sanke T, Hanabusa T, Tsunoda K, Furuta H, Nanjo K (2000) Nonsense mutation of islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history. Diabetes 49:1597–1600

    CAS  PubMed  Google Scholar 

  • Solinas-Toldo S, Lampel S, Stilgenbauer S, Nickolenko J, Benner A, Dohner H, Cremer T, Lichter P (1997) Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20:399–407

    Article  CAS  PubMed  Google Scholar 

  • Tanaka SS, Toyooka Y, Akasu R, Katoh-Fukui Y, Nakahara Y, Suzuki R, Yokoyama M, Noce T (2000) The mouse homolog of Drosophila Vasa is required for the development of male germ cells. Genes Dev 14:841–853

    CAS  PubMed  Google Scholar 

  • van den Heuvel L, Ruitenbeek W, Smeets R, Gelman-Kohan Z, Elpeleg O, Loeffen J, Trijbels F, Mariman E, de Bruijn D, Smeitink J (1998) Demonstration of a new pathogenic mutation in human complex I deficiency: a 5-bp duplication in the nuclear gene encoding the 18-kD (AQDQ) subunit. Am J Hum Genet 62:262–268

    Article  PubMed  Google Scholar 

  • Veltman JA, Fridlyand J, Pejavar S, Olshen AB, Korkola JE, DeVries S, Carroll P, Kuo WL, Pinkel D, Albertson D, Cordon-Cardo C, Jain AN, Waldman FM (2003) Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Cancer Res 63:2872–2880

    CAS  PubMed  Google Scholar 

  • Veltman JA, Schoenmakers EF, Eussen BH, Janssen I, Merkx G, van Cleef B, van Ravenswaaij CM, Brunner HG, Smeets D, Van Kessel AG (2002) High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization. Am J Hum Genet 70:1269–1276

    Article  CAS  PubMed  Google Scholar 

  • Vissers LE, de Vries BB, Osoegawa K, Janssen IM, Feuth T, Choy CO, Straatman H, van der Vliet W, Huys EH, Van Rijk A, Smeets D, Ravenswaaij-Arts CM, Knoers NV, van der Burgt I, de Jong PJ, Brunner HG, van Kessel AG, Schoenmakers EF, Veltman JA (2003) Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. Am J Hum Genet 73:1261–1270

    Article  CAS  PubMed  Google Scholar 

  • Vitelli F, Taddei I, Morishima M, Meyers EN, Lindsay EA, Baldini A (2002) A genetic link between Tbx1 and fibroblast growth factor signaling. Development 129:4605–4611

    CAS  PubMed  Google Scholar 

  • Wessendorf S, Schwaenen C, Kohlhammer H, Kienle D, Wrobel G, Barth TF, Nessling M, Moller P, Dohner H, Lichter P, Bentz M (2003) Hidden gene amplifications in aggressive B-cell non-Hodgkin lymphomas detected by microarray-based comparative genomic hybridization. Oncogene 22:1425–1429

    Article  CAS  PubMed  Google Scholar 

  • Wilhelm M, Veltman JA, Olshen AB, Jain AN, Moore DH, Presti JC Jr, Kovacs G, Waldman FM (2002) Array-based comparative genomic hybridization for the differential diagnosis of renal cell cancer. Cancer Res 62:957–960

    CAS  PubMed  Google Scholar 

  • Yagi H, Furutani Y, Hamada H, Sasaki T, Asakawa S, Minoshima S, Ichida F, Joo K, Kimura M, Imamura S, Kamatani N, Momma K, Takao A, Nakazawa M, Shimizu N, Matsuoka R (2003) Role of TBX1 in human del22q11.2 syndrome. Lancet 362:1366–1373

    Article  CAS  PubMed  Google Scholar 

  • Yoshida K, Taga T, Saito M, Suematsu S, Kumanogoh A, Tanaka T, Fujiwara H, Hirata M, Yamagami T, Nakahata T, Hirabayashi T, Yoneda Y, Tanaka K, Wang WZ, Mori C, Shiota K, Yoshida N, Kishimoto T (1996) Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc Natl Acad Sci USA 93:407–411

    Article  CAS  PubMed  Google Scholar 

  • Yu W, Ballif BC, Kashork CD, Heilstedt HA, Howard LA, Cai WW, White LD, Liu W, Beaudet AL, Bejjani BA, Shaw CA, Shaffer LG (2003) Development of a comparative genomic hybridization microarray and demonstration of its utility with 25 well-characterized 1p36 deletions. Hum Mol Genet 12:2145–2152

    Article  CAS  PubMed  Google Scholar 

  • Yujiri T, Sather S, Fanger GR, Johnson GL (1998) Role of MEKK1 in cell survival and activation of JNK and ERK pathways defined by targeted gene disruption. Science 282:1911–1914

    Article  CAS  PubMed  Google Scholar 

  • Zemmyo M, Meharra EJ, Kuhn K, Creighton-Achermann L, Lotz M (2003) Accelerated, aging-dependent development of osteoarthritis in alpha1 integrin-deficient mice. Arthritis Rheum 48:2873–2880

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Heike Fiegler and Chiara Bacchelli for technical support and the Wellcome Trust Sanger Institute Microarray Core Facility for printing the microarrays. This work is funded by the Wellcome Trust.

Author information

Authors and Affiliations

  1. Molecular Medicine Unit, Institute of Child Health, University College London, 30, Guilford Street, London, WC1N 1EH, UK

    Katrina Prescott & Peter Scambler

  2. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK

    Kathryn Woodfine & Nigel P. Carter

  3. North East London Regional Cytogenetics Laboratory, Great Ormond Street Hospital, London, UK

    Paula Stubbs & Rodger Palmer

  4. Royal Manchester Children’s Hospital, Hospital Road, Pendlebury, Manhester, UK

    Maurice Super & Bronwyn Kerr

Authors
  1. Katrina Prescott
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kathryn Woodfine
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paula Stubbs
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maurice Super
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bronwyn Kerr
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rodger Palmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nigel P. Carter
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Peter Scambler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Scambler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Prescott, K., Woodfine, K., Stubbs, P. et al. A novel 5q11.2 deletion detected by microarray comparative genomic hybridisation in a child referred as a case of suspected 22q11 deletion syndrome. Hum Genet 116, 83–90 (2005). https://doi.org/10.1007/s00439-004-1195-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-004-1195-6

Keywords

Search

Navigation