Article Text

Download PDFPDF
Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice
  1. D L Bruno1,
  2. D Ganesamoorthy1,
  3. J Schoumans3,
  4. A Bankier1,
  5. D Coman1,
  6. M Delatycki1,
  7. R J M Gardner1,
  8. M Hunter1,
  9. P A James1,
  10. P Kannu1,
  11. G McGillivray1,
  12. N Pachter1,
  13. H Peters1,
  14. C Rieubland1,
  15. R Savarirayan1,
  16. I E Scheffer4,
  17. L Sheffield1,
  18. T Tan1,
  19. S M White1,2,
  20. A Yeung1,
  21. Z Bowman1,
  22. C Ngo1,
  23. K W Choy5,
  24. V Cacheux6,
  25. L Wong1,
  26. D J Amor1,2,
  27. H R Slater1,2
  1. 1
    Victorian Clinical Genetics Services, Murdoch Children’s Research Institute
  2. 2
    Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Parkville, Victoria, Australia
  3. 3
    Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  4. 4
    Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia
  5. 5
    Department of Obstetrics and Gynaecology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong, SAR
  6. 6
    Laboratoire de Génétique Médicale et Chromosomique, Hôpital Arnaud de Villeneuve, Montpellier, France
  1. Dr H R Slater, Cytogenetics Laboratory, VCGS Pathology, MCRI, Royal Children’s Hospital, Parkville, VIC 3052, Australia; howard.slater{at}


Background: Microarray genome analysis is realising its promise for improving detection of genetic abnormalities in individuals with mental retardation and congenital abnormality. Copy number variations (CNVs) are now readily detectable using a variety of platforms and a major challenge is the distinction of pathogenic from ubiquitous, benign polymorphic CNVs. The aim of this study was to investigate replacement of time consuming, locus specific testing for specific microdeletion and microduplication syndromes with microarray analysis, which theoretically should detect all known syndromes with CNV aetiologies as well as new ones.

Methods: Genome wide copy number analysis was performed on 117 patients using Affymetrix 250K microarrays.

Results: 434 CNVs (195 losses and 239 gains) were found, including 18 pathogenic CNVs and 9 identified as “potentially pathogenic”. Almost all pathogenic CNVs were larger than 500 kb, significantly larger than the median size of all CNVs detected. Segmental regions of loss of heterozygosity larger than 5 Mb were found in 5 patients.

Conclusions: Genome microarray analysis has improved diagnostic success in this group of patients. Several examples of recently discovered “new syndromes” were found suggesting they are more common than previously suspected and collectively are likely to be a major cause of mental retardation. The findings have several implications for clinical practice. The study revealed the potential to make genetic diagnoses that were not evident in the clinical presentation, with implications for pretest counselling and the consent process. The importance of contributing novel CNVs to high quality databases for genotype–phenotype analysis and review of guidelines for selection of individuals for microarray analysis is emphasised.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.