title: PAR1 deletions downstream of SHOX are the most frequent defect in a Spanish cohort of Léri-Weill dyschondrosteosis (LWD) probands.
abstract: Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and Madelung deformity. Mutations or deletions of the SHOX gene have been previously identified as the main cause of LWD. We recently identified the existence of a second class of pseudoautosomal region 1 (PAR1) deletions which do not include SHOX, implicated in the etiopathogenesis of LWD. The deletions map at least 30-250 kb downstream of SHOX, are variable in size and clearly cosegregate with the LWD phenotype. In order to determine the frequency of this new type of deletions in the Spanish population we analyzed the distribution of PAR1 defects, including the screening of SHOX deletions, mutations, and PAR1 deletions downstream of SHOX, in a total of 26 LWD probands by a combination of MLPA, microsatellite analysis, SNP genotyping, dHPLC, and DNA sequencing. A molecular defect was identified in 16/26 LWD patients (61.5%): 10 PAR1 deletions downstream of SHOX, four SHOX encompassing deletions, and two SHOX mutations. No apparent phenotypic differences were observed between patients with SHOX defects and those with PAR1 deletions downstream of SHOX. In the examined cohort of Spanish LWD probands, PAR1 deletions downstream of SHOX represent the highest proportion of identified mutations (38%) compared to SHOX deletions (15%) and mutations (8%). As a consequence of our findings, the screening of this region should be included in the routine genetic testing of LWD. Also, LWD patients who tested negative for SHOX defects should be re-evaluated for PAR1 deletions downstream of SHOX.
authors.affiliation: Dept. of Endocrinology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Benito-Sanz
authors.forename: Darya Gorbenko
authors.initials: DG
authors.lastname: del Blanco
authors.forename: Miriam
authors.initials: M
authors.lastname: Aza-Carmona
authors.forename: Luis F
authors.initials: LF
authors.lastname: Magano
authors.forename: Pablo
authors.initials: P
authors.lastname: Lapunzina
authors.forename: Jesús
authors.initials: J
authors.lastname: Argente
authors.forename: Angel
authors.initials: A
authors.lastname: Campos-Barros
authors.forename: Karen E
authors.initials: KE
authors.lastname: Heath
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D002872:Chromosome Deletion; D015331:Cohort Studies; D004252:DNA Mutational Analysis / Q000379:methods; D017353:Gene Deletion; D018740:Genetic Heterogeneity; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D010009:Osteochondrodysplasias / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D000074122:Short Stature Homeobox Protein; D013030:Spain; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; D014157:Transcription Factors