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Molecular screening of ADAMTSL2 gene in 33 patients reveals the genetic heterogeneity of geleophysic dysplasia
  1. Slimane Allali1,
  2. Carine Le Goff1,
  3. Isabelle Pressac–Diebold1,
  4. Gwendoline Pfennig1,
  5. Clémentine Mahaut1,
  6. Nathalie Dagoneau1,
  7. Yasemin Alanay2,
  8. Angela F Brady3,
  9. Yanick J Crow4,
  10. Koen Devriendt5,
  11. Valérie Drouin-Garraud6,
  12. Elisabeth Flori7,
  13. David Geneviève8,
  14. Raoul C Hennekam9,
  15. Jane Hurst10,
  16. Deborah Krakow11,
  17. Martine Le Merrer1,
  18. Klaske D Lichtenbelt12,
  19. Sally A Lynch13,
  20. Stanislas Lyonnet1,
  21. Kay MacDermot3,
  22. Sahar Mansour14,
  23. André Megarbané15,
  24. Heloisa G Santos16,
  25. Miranda Splitt17,
  26. Andrea Superti-Furga18,
  27. Sheila Unger18,
  28. Denise Williams19,
  29. Arnold Munnich1,
  30. Valérie Cormier-Daire1
  1. 1Department of Genetics, INSERM U781, Université Paris Descartes, Hôpital Necker, Paris, France
  2. 2Genetics Unit, Department of Pediatrics Hacettepe, University School of Medicine, Ankara, Turkey
  3. 3North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK
  4. 4Genetic Medicine, University of Manchester, Manchester Academic Heath Science Centre, Central Manchester Foundation Trust University Hospitals, Manchester, UK
  5. 5Department of Medical Genetics, Leuven University Hospital, Leuven, Belgium
  6. 6Department of Medical Genetics, Hôpital Charles Nicolle, Rouen, France
  7. 7Department of genetics, Strasbourg hospital, Strasbourg, France
  8. 8Service de Génétique Médicale, Hôpital Arnaud de Villeneuve, Montpellier, France
  9. 9Department of Pediatrics, Academic Medical Center, University of Amsterdam, The Netherlands
  10. 10Department of Clinical Genetics, Oxford Radcliffe Hospitals, UK
  11. 11Cedars Sinai Medical Center, Los Angeles, California, USA
  12. 12Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands
  13. 13National Center for Medical Genetics, Dublin, Ireland
  14. 14SW Thames Regional Genetics Service, St George's University of London, London, UK
  15. 15Unité de génétique médicale, Université Saint Joseph, Beyrouth, Lebanon
  16. 16Department of Medical Genetics, Lisboa, Portugal
  17. 17Institute of Human Genetics, Newcastle, UK
  18. 18Department of Pediatrics, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  19. 19West Midlands Regional Clinical Genetics Service, Birmingham Women's Hospital, Birmingham, UK
  1. Correspondence to Professor Valérie Cormier-Daire, Department of Genetics, INSERM U781, Université Paris Descartes, Hôpital Necker, Paris, France; valerie.cormier-daire{at}


Background Geleophysic dysplasia (GD, OMIM 231050) is an autosomal recessive disorder characterised by short stature, small hands and feet, stiff joints, and thick skin. Patients often present with a progressive cardiac valvular disease which can lead to an early death. In a previous study including six GD families, we have mapped the disease gene on chromosome 9q34.2 and identified mutations in the A Disintegrin And Metalloproteinase with Thrombospondin repeats-like 2 gene (ADAMTSL2).

Methods Following this study, we have collected the samples of 30 additional GD families, including 33 patients and identified ADAMTSL2 mutations in 14/33 patients, comprising 13 novel mutations. The absence of mutation in 19 patients prompted us to compare the two groups of GD patients, namely group 1, patients with ADAMTSL2 mutations (n=20, also including the 6 patients from our previous study), and group 2, patients without ADAMTSL2 mutations (n=19).

Results The main discriminating features were facial dysmorphism and tip-toe walking, which were almost constantly observed in group 1. No differences were found concerning heart involvement, skin thickness, recurrent respiratory and ear infections, bronchopulmonary insufficiency, laryngo-tracheal stenosis, deafness, and radiographic features.

Conclusions It is concluded that GD is a genetically heterogeneous condition. Ongoing studies will hopefully lead to the identification of another disease gene.

  • Geleophysic dysplasia
  • cardiac valvular disease
  • genetics
  • clinical genetics, connective tissue disease

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  • SA and CLG equally contributed to this work.

  • Funding The Medical Research Foundation (FRM, to SA) and by French National Research Agency (ANR) award R09183KS (to VC-D). YJC acknowledges the Manchester NIHR Biomedical Research Centre.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Necker Hospital.

  • Provenance and peer review Not commissioned; externally peer reviewed.