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Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type
  1. Ricarda Flöttmann1,
  2. Johannes Wagner1,
  3. Karolina Kobus2,
  4. Cynthia J Curry3,
  5. Ravi Savarirayan4,
  6. Gen Nishimura5,
  7. Natsuo Yasui6,
  8. Jürgen Spranger7,
  9. Hilde Van Esch8,
  10. Michael J Lyons9,
  11. Barbara R DuPont9,
  12. Alka Dwivedi9,
  13. Eva Klopocki10,
  14. Denise Horn1,
  15. Stefan Mundlos1,2,11,
  16. Malte Spielmann1,2,11
  1. 1Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany
  2. 2Max Planck Institute for Molecular Genetics, Berlin, Germany
  3. 3Institute for Clinical Genetics, UCFS Fresno, California, USA
  4. 4Victorian Clinical Genetics Service, Royal Children's Hospital, Melbourne, Victoria, Australia
  5. 5Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
  6. 6Tokushima University Hospital, Tokushima, Japan
  7. 7Children's Hospital, University of Mainz, Mainz, Germany
  8. 8Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium
  9. 9Greenwood Genetic Center, Greenwood, South Carolina, USA
  10. 10Institute for Human Genetics, Biozentrum, Universität Würzburg, Würzburg, Germany
  11. 11Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
  1. Correspondence to Dr Malte Spielmann, Institute for Medical Genetics and Human Genetics, Charité—Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; malte.spielmann{at}


Introduction Mesomelic dysplasias are a group of skeletal disorders characterised by shortness of the middle limb segments (mesomelia). They are divided into 11 different categories. Among those without known molecular basis is mesomelic dysplasia Savarirayan type, characterised by severe shortness of the middle segment of the lower limb.

Objective To identify the molecular cause of mesomelic dysplasia Savarirayan type.

Methods and results We performed array comparative genomic hybridisation in three unrelated patients with mesomelic dysplasia Savarirayan type and identified 2 Mb overlapping de novo microdeletions on chromosome 6p22.3. The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4. All patients showed mesomelia of the lower limbs with hypoplastic tibiae and fibulae. We identified a fourth patient with intellectual disability and an overlapping slightly larger do novo deletion also encompassing the flanking gene ID4. Given the fact that the fourth patient had no skeletal abnormalities and none of the genes in the deleted interval are known to be associated with abnormalities in skeletal development, other mutational mechanisms than loss of function of the deleted genes have to be considered. Analysis of the genomic region showed that the deletion removes two regulatory boundaries and brings several potential limb enhancers into close proximity of ID4. Thus, the deletion could result in the aberrant activation and misexpression of ID4 in the limb bud, thereby causing the mesomelic dysplasia.

Conclusions Our data indicate that the distinct deletion 6p22.3 is associated with mesomelic dysplasia Savarirayan type featuring hypoplastic, triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae.

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