Identification of 15 novel partial SHOX deletions and 13 partial duplications, and a review of the literature reveals intron 3 to be a hotspot region.
Short stature homeobox gene (SHOX) is located in the pseudoautosomal region 1 of the sex chromosomes. It encodes a transcription factor implicated in the skeletal growth. Point mutations, deletions or duplications of SHOX or its transcriptional regulatory elements are associated with two skeletal dysplasias, Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), as well as in a small proportion of idiopathic short stature (ISS) individuals. We have identified a total of 15 partial SHOX deletions and 13 partial SHOX duplications in LWD, LMD and ISS patients referred for routine SHOX diagnostics during a 10 year period (2004-2014). Subsequently, we characterized these alterations using MLPA (multiplex ligation-dependent probe amplification assay), fine-tiling array CGH (comparative genomic hybridation) and breakpoint PCR. Nearly half of the alterations have a distal or proximal breakpoint in intron 3. Evaluation of our data and that in the literature reveals that although partial deletions and duplications only account for a small fraction of SHOX alterations, intron 3 appears to be a breakpoint hotspot, with alterations arising by non-allelic homologous recombination, non-homologous end joining or other complex mechanisms.
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.|Unidad Multidisciplinar de Displasias Esqueléticas (UMDE), Hospital Universitario La Paz, Madrid, Spain.
Sara
S
Benito-Sanz
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.|Unidad Multidisciplinar de Displasias Esqueléticas (UMDE), Hospital Universitario La Paz, Madrid, Spain.
Alberta
A
Belinchon-Martínez
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.|Unidad Multidisciplinar de Displasias Esqueléticas (UMDE), Hospital Universitario La Paz, Madrid, Spain.
Miriam
M
Aza-Carmona
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain.
Carolina
C
de la Torre
Department of Genetics, Université Paris Descartes-Sorbonne Paris Cité, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
Celine
C
Huber
Unidad Multidisciplinar de Displasias Esqueléticas (UMDE), Hospital Universitario La Paz, Madrid, Spain.|Department of Pediatric Endocrinology, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain.
Isabel
I
González-Casado
Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA.
Judith L
JL
Ross
Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK.
N Simon
NS
Thomas
Dermott Center for Human Growth and Development and Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX, USA.
Andrew R
AR
Zinn
Department of Genetics, Université Paris Descartes-Sorbonne Paris Cité, Institut IMAGINE, Hôpital Necker-Enfants Malades, Paris, France.
Valerie
V
Cormier-Daire
Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.|Unidad Multidisciplinar de Displasias Esqueléticas (UMDE), Hospital Universitario La Paz, Madrid, Spain.
Karen E
KE
Heath
D001483:Base Sequence; D055028:Comparative Genomic Hybridization; D020440:Gene Duplication / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D060885:Multiplex Polymerase Chain Reaction; D021141:Nucleic Acid Amplification Techniques; D010009:Osteochondrodysplasias / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*; D000074122:Short Stature Homeobox Protein
D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein