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Screening of the 1 Mb SOX9 5′ control region by array CGH identifies a large deletion in a case of campomelic dysplasia with XY sex reversal
  1. R Pop1,2,
  2. C Conz3,
  3. K S Lindenberg1,2,*,
  4. S Blesson4,
  5. B Schmalenberger5,
  6. S Briault4,
  7. D Pfeifer3,
  8. G Scherer1
  1. 1Institute of Human Genetics and Anthropology, University of Freiburg, Freiburg, Germany
  2. 2Faculty for Biology, University of Freiburg, Freiburg, Germany
  3. 3BioChip Technologies GmbH, Freiburg, Germany
  4. 4Service de Génétique, Hôpital Bretonneau, Tours, France
  5. 5Medizinische Genetik, Neuburg, Germany
  1. Correspondence to:
 Dr G Scherer
 Institute of Human Genetics und Anthropology, Breisacherstr. 33, D-79106 Freiburg, Germany;

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Campomelic dysplasia (CD; OMIM #114290) is a semi-lethal, autosomal dominant osteochondrodysplasia, characterised by congenital shortening and bowing of the long bones (campomelia) in combination with other skeletal anomalies such as hypoplasia of the scapular and pelvic bones, lack of mineralisation of thoracic pedicles, a missing pair of ribs, and clubbed feet. Severe respiratory distress resulting from Robin sequence, hypoplastic lungs with narrow airways, and a bell shaped narrow thorax are the major cause of death, which mostly occurs during the neonatal period. About two thirds of karyotypic male CD patients show XY sex reversal. As is the case for any of the symptoms, campomelia is not an obligatory feature and is absent in about 10% of the cases, referred to as the acampomelic form of CD (ACD).1,2

Most CD cases have heterozygous de novo mutations in the coding region of the transcription factor gene SOX9 on 17q.3,4 The mutations cause loss of DNA binding or of the transactivation function of SOX9, implying that CD results from haploinsufficiency for SOX9. In accordance with the human phenotype caused by SOX9 mutations, studies in the mouse have shown that Sox9 functions as an essential developmental regulator at various steps of chondrogenesis5,6 and during the initial phase of testis determination and differentiation.7–9 Furthermore, heterozygous Sox9 knockout mice recapitulate essentially all the symptoms seen in CD patients but for the sex reversal.5,10

Some CD cases have two intact copies of the SOX9 structural gene but a chromosomal rearrangement in the vicinity of one SOX9 allele. These rearrangements, which include translocations and inversions, occur de novo, and their breakpoints are always 5′ to SOX9. In 11 of these cases, the breakpoints have been mapped from 50 kb up to 950 kb upstream of SOX9. …

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  • * Present address: Department of Neurology, University of Ulm, Ulm, Germany

  • The first two authors contributed equally to this work