Array-Based Comparative Genomic Hybridization for the Genomewide Detection of Submicroscopic Chromosomal Abnormalities

Vissers, L. E. L. M., de Vries, B. B. A., Osoegawa, K., Janssen, I. M., Feuth, T., Choy, C. O., Straatman, H., van der Vliet, W., Huys, E. H. L. P. G., van Rijk, A., Smeets, D., van Ravenswaaij-Arts, C. M. A., Knoers, N. V., van der Burgt, I., de Jong, P. J., Brunner, H. G., van Kessel, A. G., Schoenmakers, E. F. P. M. & Veltman, J. A., Dec-2003, In : American Journal of Human Genetics. 73, 6, p. 1261-1270 10 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Lisenka E L M Vissers
  • Bert B A de Vries
  • Kazutoyo Osoegawa
  • Irene M Janssen
  • Ton Feuth
  • Chik On Choy
  • Huub Straatman
  • Walter van der Vliet
  • Erik H L P G Huys
  • Anke van Rijk
  • Dominique Smeets
  • Conny M A van Ravenswaaij-Arts
  • Nine V Knoers
  • Ineke van der Burgt
  • Pieter J de Jong
  • Han G Brunner
  • Ad Geurts van Kessel
  • Eric F P M Schoenmakers
  • Joris A Veltman

Microdeletions and microduplications, not visible by routine chromosome analysis, are a major cause of human malformation and mental retardation. Novel high-resolution, whole-genome technologies can improve the diagnostic detection rate of these small chromosomal abnormalities. Array-based comparative genomic hybridization allows such a high-resolution screening by hybridizing differentially labeled test and reference DNAs to arrays consisting of thousands of genomic clones. In this study, we tested the diagnostic capacity of this technology using approximately 3,500 flourescent in situ hybridization-verified clones selected to cover the genome with an average of 1 clone per megabase (Mb). The sensitivity and specificity of the technology were tested in normal-versus-normal control experiments and through the screening of patients with known microdeletion syndromes. Subsequently, a series of 20 cytogenetically normal patients with mental retardation and dysmorphisms suggestive of a chromosomal abnormality were analyzed. In this series, three microdeletions and two microduplications were identified and validated. Two of these genomic changes were identified also in one of the parents, indicating that these are large-scale genomic polymorphisms. Deletions and duplications as small as 1 Mb could be reliably detected by our approach. The percentage of false-positive results was reduced to a minimum by use of a dye-swap-replicate analysis, all but eliminating the need for laborious validation experiments and facilitating implementation in a routine diagnostic setting. This high-resolution assay will facilitate the identification of novel genes involved in human mental retardation and/or malformation syndromes and will provide insight into the flexibility and plasticity of the human genome.

Original languageEnglish
Pages (from-to)1261-1270
Number of pages10
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - Dec-2003
Externally publishedYes


  • Chromosome Aberrations, Genome, Human, Humans, In Situ Hybridization, Fluorescence/methods, Intellectual Disability/genetics, Polymorphism, Genetic, Sensitivity and Specificity

View graph of relations

ID: 92706430