title: Duplications upstream and downstream of SHOX identified as novel causes of Leri-Weill dyschondrosteosis or idiopathic short stature.
abstract: Leri-Weill dyschondrosteosis is a pseudoautosomal dominantly-inherited skeletal dysplasia ascribed to haploinsufficiency of the SHOX gene caused by deletions, point mutations, or partial duplications of the gene, or to heterozygous deletions upstream or downstream of the intact SHOX gene involving conserved non-coding cis-regulatory DNA elements that show enhancer activity. Recently, two SHOX conserved non-coding element duplications, one upstream and one downstream, were reported in patients referred with idiopathic short stature. To further evaluate the role of these duplications in SHOX-related disorders, we describe seven patients (five with Leri-Weill dyschondrosteosis and two with short stature) all of whom have duplications of part of the upstream or downstream conserved non-coding element regions, identified by multiplex ligation-dependent probe amplification. In addition, we show data from 32 patients with an apparently identical downstream duplication that includes a proposed putative regulatory element (identified by multiplex ligation-dependent probe amplification or array comparative genome hybridization), which results in a variable phenotype from normal to mild Leri-Weill dyschondrosteosis. These additional data provide further evidence that duplications of upstream and downstream long range cis-regulatory DNA elements can result in a SHOX-related phenotype.
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wiltshire, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bunyan
authors.affiliation: Laboratory of Human Genetics, E.O. Ospedali Galliera, Genoa, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Baffico
authors.affiliation: Genomic Research Center, Cante di Montevecchio, Fano PU, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Capone
authors.affiliation: Auxologic Unit, University of Turin, Turin, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Vannelli
authors.affiliation: Department of Medical and Surgical Sciences of Mothers, Children, and Adults, University of Modena and Reggio Emilia, Modena MO, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Iughetti
authors.affiliation: Laboratory of Molecular Genetics, Institute of Biology, CHU de Nantes, Nantes, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Schmitt
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wiltshire, United Kingdom.
authors.forename: Emma-Jane
authors.initials: EJ
authors.lastname: Taylor
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wiltshire, United Kingdom.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Herridge
authors.affiliation: Clinical Genetics, Churchill Hospital, Oxford, Oxfordshire, United Kingdom.
authors.forename: Deborah
authors.initials: D
authors.lastname: Shears
authors.affiliation: Genomic Research Center, Cante di Montevecchio, Fano PU, Italy.
authors.forename: Antonino
authors.initials: A
authors.lastname: Forabosco
authors.affiliation: Laboratory of Human Genetics, E.O. Ospedali Galliera, Genoa, Italy.
authors.forename: Domenico A
authors.initials: DA
authors.lastname: Coviello
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D058674:Chromosome Duplication; D015331:Cohort Studies; D055028:Comparative Genomic Hybridization; D004392:Dwarfism / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D006130:Growth Disorders / Q000175:diagnosis* / Q000235:genetics*; D006239:Haplotypes; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D010009:Osteochondrodysplasias / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D000074122:Short Stature Homeobox Protein; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein
keywords: Duplication; Regulatory element; SHOX