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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. Damien L Bruno (damien.bruno{at}mcri.edu.au)
  1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
    1. Devika Ganesamoorthy (devika.ganesamoorthy{at}mcri.edu.au)
    1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
      1. Jacqueline Schoumans (jacqueline.schoumans{at}ki.se)
      1. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
        1. Agnes Bankier (agnes.bankier{at}ghsv.org.au)
        1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
          1. David Coman (david.coman{at}cuh.ie)
          1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
            1. Martin Delatycki (martin.delatycki{at}ghsv.org.au)
            1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
              1. Mac RJ Gardner (macgardner{at}gmail.com)
              1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                1. Matthew Hunter (matthew.hunter{at}ghsv.org.au)
                1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                  1. Paul A James (paul.james{at}ghsv.org.au)
                  1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                    1. Peter Kannu (peter.kannu{at}ghsv.org.au)
                    1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                      1. George Mcgillivray (george.mcgillivray{at}ghsv.org.au)
                      1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                        1. Nicholas Pachter (nicholas.pachter{at}ghsv.org.au)
                        1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                          1. Heidi Peters (heidi.peters{at}mcri.edu.au)
                          1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                            1. Claudine Rieubland (claudine.rieubland{at}ghsv.org.au)
                            1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                              1. Ravi Savarirayan (ravi.savarirayan{at}ghsv.org.au)
                              1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                                1. Ingrid E Scheffer (scheffer{at}unimelb.edu.au)
                                1. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Australia
                                  1. Leslie Sheffield (les.sheffield{at}ghsv.org.au)
                                  1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                                    1. Tiong Tan (tiong.tan{at}ghsv.org.au)
                                    1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                                      1. Sue M White (sue.white{at}ghsv.org.au)
                                      1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                                        1. Alison Yeung (alison.yeung{at}ghsv.org.au)
                                        1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                                          1. Zoe Bowman (s3138986{at}student.rmit.edu.au)
                                          1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                                            1. Con Ngo (con_ngo{at}ghsv.org.au)
                                            1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                                              1. KW Choy (richardchoy{at}cuhk.edu.hk)
                                              1. Department of Obstetrics and Gynaecology, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong
                                                1. Valere Cacheux
                                                1. Laboratoire de Génétique Médicale et Chromosomique, Hôpital Arnaud de Villeneuve, Montpellier, France
                                                  1. Lee Wong (lee.wong{at}mcri.edu.au)
                                                  1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                                                    1. David Amor (david.amor{at}mcri.edu.au)
                                                    1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia
                                                      1. Howard R Slater (howard.slater{at}ghsv.org.au)
                                                      1. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Australia

                                                        Abstract

                                                        Background: Microarray genome analysis is realising its promise for improving detection of genetic abnormalities in individuals with mental retardation (MR) 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 etiologies as well as new ones.

                                                        Methods: Genome-wide copy number analysis on 117 patients has been performed 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 500kb, significantly larger than the median size of all CNVs detected. Segmental regions of loss of heterozygosity (LOH) larger than 5Mb 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 MR. 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.

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