title: Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ricarda
authors.initials: R
authors.lastname: Flöttmann
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Wagner
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kobus
authors.affiliation: Institute for Clinical Genetics, UCFS Fresno, California, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Curry
authors.affiliation: Victorian Clinical Genetics Service, Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.affiliation: Department of Pediatric Imaging, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.affiliation: Tokushima University Hospital, Tokushima, Japan.
authors.forename: Natsuo
authors.initials: N
authors.lastname: Yasui
authors.affiliation: Children's Hospital, University of Mainz, Mainz, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Spranger
authors.affiliation: Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lyons
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina, USA.
authors.forename: Barbara R
authors.initials: BR
authors.lastname: DuPont
authors.affiliation: Greenwood Genetic Center, Greenwood, South Carolina, USA.
authors.forename: Alka
authors.initials: A
authors.lastname: Dwivedi
authors.affiliation: Institute for Human Genetics, Biozentrum, Universität Würzburg, Würzburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Klopocki
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Horn
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany Max Planck Institute for Molecular Genetics, Berlin, Germany Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany Max Planck Institute for Molecular Genetics, Berlin, Germany Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Spielmann
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D001483:Base Sequence; D002869:Chromosome Aberrations; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics; D050699:E2F3 Transcription Factor / Q000235:genetics; D005360:Fibula / Q000002:abnormalities* / Q000473:pathology; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism*; D007866:Leg / Q000002:abnormalities*; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D010009:Osteochondrodysplasias / Q000235:genetics* / Q000473:pathology*; D011884:Radius / Q000002:abnormalities* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D055751:SOXC Transcription Factors; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*; D013977:Tibia / Q000002:abnormalities* / Q000473:pathology; D014457:Ulna / Q000002:abnormalities* / Q000473:pathology; D012359:tRNA Methyltransferases
chemical_list: D050699:E2F3 Transcription Factor; C098319:E2F3 protein, human; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D008565:Membrane Proteins; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D012359:tRNA Methyltransferases; D000123:Acetyltransferases; C521271:MBOAT1 protein, human; D051360:Cyclin-Dependent Kinase 5; C525110:CDKAL1 protein, human