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A molecular and clinical study of Larsen syndrome caused by mutations in FLNB
  1. Louise S Bicknell1,
  2. Claire Farrington-Rock2,
  3. Yousef Shafeghati3,
  4. Patrick Rump4,
  5. Yasemin Alanay5,
  6. Yves Alembik6,
  7. Navid Al-Madani7,
  8. Helen Firth8,
  9. Mohammad Hassan Karimi-Nejad7,
  10. Chong Ae Kim9,
  11. Kathryn Leask10,
  12. Melissa Maisenbacher11,
  13. Ellen Moran12,
  14. John G Pappas13,
  15. Paolo Prontera14,
  16. Thomy de Ravel15,
  17. Jean-Pierre Fryns15,
  18. Elizabeth Sweeney16,
  19. Alan Fryer16,
  20. Sheila Unger17,
  21. L C Wilson18,
  22. Ralph S Lachman2,
  23. David L Rimoin2,
  24. Daniel H Cohn2,
  25. Deborah Krakow2,
  26. Stephen P Robertson1
  1. 1Department of Paediatrics and Child Health, University of Otago, Dunedin, New Zealand
  2. 2Medical Genetics Institute, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  3. 3Genetics Research Centre, University of Welfare Science & Rehabilitation, Evin, Tehran, Iran
  4. 4Department of Clinical Genetics, University Medical Centre, Groningen, The Netherlands
  5. 5Clinical Genetics Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
  6. 6Department of Clinical Genetics, CHRU de Strasbourg, Strasbourg, France
  7. 7Karimi-Nejad Najmabadi Genetics Centre, Shahrake Gharb, Tehran, Iran
  8. 8Department of Medical Genetics, Addenbrookes Hospital, Cambridge, UK
  9. 9Pediatria-Genética, Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
  10. 10Department of Clinical Genetics, St Mary’s Hospital, Manchester, UK
  11. 11Department of Pediatrics, University of Florida, Florida, USA
  12. 12Department of Genetics, NYU-Hospital for Joint Diseases, New York, New York, USA
  13. 13Human Genetics Program, New York University School of Medicine, New York, New York, USA
  14. 14Universita degli Studi di Ferrara, Genetica Medica, Ferrara, Italy
  15. 15Department of Clinical Genetics, University Medical Center, Leuven, Belgium
  16. 16Alder Hey Children’s Hospital, Liverpool, UK
  17. 17Institute for Human Genetics, University of Freiburg, Freiburg, Germany
  18. 18Clinical Genetics Unit, Great Ormond Street Hospital and Institute of Child Health, London, UK
  1. Correspondence to:
 S P Robertson
 Department of Paediatrics and Child Health, Dunedin School of Medicine, PO Box 913, Dunedin, New Zealand; stephen.robertson{at}stonebow.otago.ac.nz

Abstract

Background: Larsen syndrome is an autosomal dominant osteochondrodysplasia characterised by large-joint dislocations and craniofacial anomalies. Recently, Larsen syndrome was shown to be caused by missense mutations or small inframe deletions in FLNB, encoding the cytoskeletal protein filamin B. To further delineate the molecular causes of Larsen syndrome, 20 probands with Larsen syndrome together with their affected relatives were evaluated for mutations in FLNB and their phenotypes studied.

Methods: Probands were screened for mutations in FLNB using a combination of denaturing high-performance liquid chromatography, direct sequencing and restriction endonuclease digestion. Clinical and radiographical features of the patients were evaluated.

Results and discussion: The clinical signs most frequently associated with a FLNB mutation are the presence of supernumerary carpal and tarsal bones and short, broad, spatulate distal phalanges, particularly of the thumb. All individuals with Larsen syndrome-associated FLNB mutations are heterozygous for either missense or small inframe deletions. Three mutations are recurrent, with one mutation, 5071G→A, observed in 6 of 20 subjects. The distribution of mutations within the FLNB gene is non-random, with clusters of mutations leading to substitutions in the actin-binding domain and filamin repeats 13–17 being the most common cause of Larsen syndrome. These findings collectively define autosomal dominant Larsen syndrome and demonstrate clustering of causative mutations in FLNB.

  • FLNA, filamin A gene
  • FLNA, filamin B gene
  • MCPP, metacarpophalangeal pattern
  • OMIM, on-line mendelian inheritance in man
  • OPD, otopalatodigital syndrome
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Footnotes

  • Published Online First 26 June 2006

  • Funding: SPR is supported by the Child Health Research Foundation of New Zealand and the Health Research Council of New Zealand.

  • Competing interests: None declared.

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