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Identification of novel candidate genes associated with cleft lip and palate using array comparative genomic hybridization
  1. Kazutoyo Osoegawa (kosoegawa{at}chori.org)
  1. Children's Hospital Oakland Research Center Oakland, United States
    1. Gery M. Vessere (gvessere{at}chori.org)
    1. Children's Hospital Oakland Research Center Oakland, United States
      1. Kagistia Hana Utami (kutami{at}chori.org)
      1. Children's Hospital Oakland Research Center Oakland, United States
        1. Maria Adela Mansilla (adela-mansilla{at}uiowa.edu)
        1. University of Iowa, United States
          1. Marla K. Johnson (marla-johnson{at}uiowa.edu)
          1. University of Iowa, United States
            1. Bridget M. Riley (bridget-riley{at}uiowa.edu)
            1. Iniversity of Iowa, United States
              1. Jamie L'Heureux (jamie-lheureux{at}uiowa.edu)
              1. University of Iowa, United States
                1. Rolph Pfundt (r.pfundt{at}antrg.umcn.nl)
                1. Radboud University Nijmegen Medical Centre, Netherlands
                  1. Johan Staaf (johan.staaf{at}onk.lu.se)
                  1. Lund University, Sweden
                    1. Walter A. van der Vliet (w.vandervliet{at}antrg.umcn.nl)
                    1. Radboud University Nijmegen Medical Centre, Netherlands
                      1. Andrew C. Lidral (andrew-lidral{at}uiowa.edu)
                      1. University of Iowa, United States
                        1. Eric F.P.M. Schoenmakers (e.schoenmakers{at}antrg.umcn.nl)
                        1. Radboud University Nijmegen Medical Centre, Netherlands
                          1. Ake Borg (ake.borg{at}onk.lu.se)
                          1. Lund University, Sweden
                            1. Brian C. Schutte (brian-schutte{at}uiowa.edu)
                            1. University of Iowa, United States
                              1. Edward J. Lammer (elammer{at}chori.org)
                              1. Children's Hospital Oakland Research Center Oakland, United States
                                1. Jeffrey C. Murray (jeff-murray{at}uiowa.edu)
                                1. University of Iowa, United States
                                  1. Pieter J. De Jong (pdejong{at}chori.org)
                                  1. Children's Hospital Oakland Research Center Oakland, United States

                                    Abstract

                                    Introduction and methods: We analyzed DNA samples isolated from individuals born with cleft lip and cleft palate to identify deletions and duplications of candidate gene loci using array comparative genomic hybridization (array-CGH). Results: Of 83 syndromic cases analyzed we identified one subject with a previously unknown 2.7 Mb deletion at 22q11.21 coinciding with the DiGeorge syndrome region. Eighteen of the syndromic cases had clinical features of Van der Woude syndrome and deletions were identified in 5 of these, all of which encompassed the interferon regulatory factor 6 (IRF6) gene. In a series of 104 nonsyndromic cases we found one subject with a 3.2 Mb deletion at chromosome 6q25.1-25.2 and another with a 2.2 Mb deletion at 10q26.11-26.13. Analyses of parental DNA demonstrated that the two deletion cases at 22q11.21 and 6q25.1-25.2 were de novo, while the deletion of 10q26.11-26.13 was inherited from the mother, who also has cleft lip. These deletions appear likely to be causally associated with the phenotypes of the subjects. Estrogen receptor 1 (ESR1) and fibroblast growth factor receptor 2 (FGFR2) genes from the 6q25.1-25.2 and 10q26.11-26.13, respectively, were identified as likely causative genes using a gene prioritization software. Discussion: We have shown that array-CGH analysis of DNA samples derived from cleft lip and palate subjects is an efficient and productive method for identifying candidate chromosomal loci and genes, complementing traditional genetic mapping strategies.

                                    • array-CGH
                                    • candidate gene
                                    • cleft lip
                                    • cleft palate

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