A Novel Class of Pseudoautosomal Region 1 Deletions Downstream of SHOX Is Associated with Léri-Weill Dyschondrosteosis

• Published in: American journal of human genetics Vol. 77; no. 4; pp. 533 - 544
• Main Authors: Benito-Sanz, Sara, Thomas, N. Simon, Huber, Céline, del Blanco, Darya Gorbenko, Aza-Carmona, Miriam, Crolla, John A., Maloney, Vivienne, Argente, Jesús, Campos-Barros, Ángel, Cormier-Daire, Valérie, Heath, Karen E.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.10.2005; University of Chicago Press; Cell Press; The American Society of Human Genetics
• Subjects: Base Sequence; Biological and medical sciences; Chromosome aberrations; Chromosome Mapping; Cohort Studies; Diseases of the osteoarticular system; DNA Primers; Female; Gene Deletion; General aspects. Genetic counseling; Genetic Heterogeneity; Genetics; Growth disorders; Homeodomain Proteins - genetics; Humans; In Situ Hybridization, Fluorescence; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical genetics; Medical sciences; Mutation; Osteochondrodysplasias - genetics; Pedigree; Radius - abnormalities; Short Stature Homeobox Protein; Skeletal system; Transcription Factors - genetics; Human; Association; Diseases of the osteoarticular system; Dyschondrosteosis; Deletion; Genetics; Osteochondrodysplasia; Genetic disease
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/449313

Léri-Weill dyschondrosteosis (LWD) is a pseudoautosomal dominant disorder characterized by disproportionate short stature and a characteristic curving of the radius, known as the “Madelung deformity.” SHOX mutations resulting in SHOX haploinsufficiency have been found in LWD and in a variable proportion of patients with idiopathic short stature (ISS), whereas homozygous loss of SHOX results in the more severe Langer mesomelic dysplasia (LMD). Defects in SHOX have been identified in ∼60% of LWD cases, whereas, in the remaining ∼40%, the molecular basis is unknown. This suggests either genetic heterogeneity or the presence of mutations in unanalyzed regions of SHOX, such as the upstream, intragenic, or downstream regulatory sequences. Therefore, the pseudoautosomal region 1 (PAR1) of 80 patients with LWD, in whom SHOX deletions and mutations had been excluded, was screened for deletions by use of a new panel of microsatellite markers. We identified 12 patients with LWD who presented with a novel class of PAR1 deletions that did not include SHOX. The deletions were of variable size and mapped at least ∼30–530 kb downstream of SHOX. In our cohort, this type of deletion accounted for 15% of cases. In all cases, the deletions cosegregated with the phenotype. No apparent phenotypic differences were observed between patients with SHOX deletions and those with this new class of PAR1 deletions. Thus, we present here the identification of a second PAR1 region implicated in the etiopathogenesis of LWD. Our findings suggest the presence of distal regulatory elements of SHOX transcription in PAR1 or, alternatively, the existence of an additional locus apparently involved in the control of skeletal development. Deletion analysis of this newly identified region should be included in the mutation screening of patients with LWD, LMD, and ISS.