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Zoom-in CGH arrays for the characterization of variable breakpoint contiguous gene syndromes
  1. Jennifer J. Johnston (jjohnsto{at}
  1. NIH, United States
    1. Robert L Walker
    1. NIH, United States
      1. Sean Davis
      1. NIH, United States
        1. Flavia Facio
        1. NIH, United States
          1. Joyce T Turner
          1. NIH, United States
            1. David P Bick
            1. Medical College of Wisconsin, United States
              1. Donna L Daentl
              1. Shriners Hospital of Northern California, United States
                1. Jay W Ellison
                1. Mayo Clinic, United States
                  1. Paul S Meltzer
                  1. NIH, United States
                    1. Leslie G Biesecker
                    1. NIH, United States


                      Contiguous gene syndromes cause pathology via haploinsufficiency for adjacent genes. Some contiguous gene syndromes have stereotypical breakpoints, but others have variable breakpoints. In the latter, the extent of the deletions may be correlated with severity. The Greig cephalopolysyndactyly contiguous gene syndrome (GCPS-CGS) is a multiple malformation syndrome caused by haploinsufficiency of GLI3 and adjacent genes. As well, non-CGS GCPS can be caused by deletions or duplications within GLI3. Although FISH can identify large deletion mutations in patients with GCPS or GCPS-CGS, it is not practical for identification of small intragenic deletions or insertions and it is difficult to accurately characterize the extent of the large deletions using this technique. We have designed a custom CGH array that allows identification of deletions and duplications at kilobase resolution in the vicinity of GLI3. The array averages one probe every 730 basepairs for a total of ~14,000 probes over 10 Mb. We have analyzed 16 individuals with known or suspected deletions/duplications. In 15/16 individuals (14 deletions and one duplication) the array confirmed the prior results. In the remaining patient, the normal array CGH result was correct and the prior assessment was a false positive qPCR. We conclude that high-density CGH array analysis is more sensitive than FISH analysis for deletion detection and provides clinically useful results on the extent of the deletion. We suggest that high-density array CGH analysis should replace FISH analysis for assessment of deletions and duplications in patients with contiguous gene syndromes caused by variable deletions.

                      • GLI3
                      • comparative genomic hybridization
                      • oligonucleotide array

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