title: Clinical and molecular characterization of duplications encompassing the human SHOX gene reveal a variable effect on stature.
abstract: Deletions of the SHOX gene are well documented and cause disproportionate short stature and variable skeletal abnormalities. In contrast interstitial SHOX duplications limited to PAR1 appear to be very rare and the clinical significance of the only case report in the literature is unclear. Mapping of this duplication has now shown that it includes the entire SHOX gene but little flanking sequence and so will not encompass any of the long-range enhancers required for SHOX transcription. We now describe the clinical and molecular characterization of three additional cases. The duplications all included the SHOX coding sequence but varied in the amount of flanking sequence involved. The probands were ascertained for a variety of reasons: hypotonia and features of Asperger syndrome, Leri-Weill dyschondrosteosis (LWD), and a family history of cleft palate. However, the presence of a duplication did not correlate with any of these features or with evidence of skeletal abnormality. Remarkably, the proband with LWD had inherited both a SHOX deletion and a duplication. The effect of the duplications on stature was variable: height appeared to be elevated in some carriers, particularly in those with the largest duplications, but was still within the normal range. SHOX duplications are likely to be under ascertained and more cases need to be identified and characterized in detail in order to accurately determine their phenotypic consequences.
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, UK. simon.thomas@salisbury.nhs.uk
authors.forename: N Simon
authors.initials: NS
authors.lastname: Thomas
authors.forename: John F
authors.initials: JF
authors.lastname: Harvey
authors.forename: David J
authors.initials: DJ
authors.lastname: Bunyan
authors.forename: Julia
authors.initials: J
authors.lastname: Rankin
authors.forename: Giedre
authors.initials: G
authors.lastname: Grigelioniene
authors.forename: Damien L
authors.initials: DL
authors.lastname: Bruno
authors.forename: Tiong Y
authors.initials: TY
authors.lastname: Tan
authors.forename: Susan
authors.initials: S
authors.lastname: Tomkins
authors.forename: Robert
authors.initials: R
authors.lastname: Hastings
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000293:Adolescent; D001827:Body Height / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D020440:Gene Duplication; D018740:Genetic Heterogeneity; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D010375:Pedigree; D010641:Phenotype; D000074122:Short Stature Homeobox Protein
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein