title: Pseudoachondroplasia and multiple epiphyseal dysplasia: a 7-year comprehensive analysis of the known disease genes identify novel and recurrent mutations and provides an accurate assessment of their relative contribution.
abstract: Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are relatively common skeletal dysplasias resulting in short-limbed dwarfism, joint pain, and stiffness. PSACH and the largest proportion of autosomal dominant MED (AD-MED) results from mutations in cartilage oligomeric matrix protein (COMP); however, AD-MED is genetically heterogenous and can also result from mutations in matrilin-3 (MATN3) and type IX collagen (COL9A1, COL9A2, and COL9A3). In contrast, autosomal recessive MED (rMED) appears to result exclusively from mutations in sulphate transporter solute carrier family 26 (SLC26A2). The diagnosis of PSACH and MED can be difficult for the nonexpert due to various complications and similarities with other related diseases and often mutation analysis is requested to either confirm or exclude the diagnosis. Since 2003, the European Skeletal Dysplasia Network (ESDN) has used an on-line review system to efficiently diagnose cases referred to the network prior to mutation analysis. In this study, we present the molecular findings in 130 patients referred to ESDN, which includes the identification of novel and recurrent mutations in over 100 patients. Furthermore, this study provides the first indication of the relative contribution of each gene and confirms that they account for the majority of PSACH and MED.
authors.affiliation: Wellcome Trust Centre for Cell Matrix Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Gail C
authors.initials: GC
authors.lastname: Jackson
authors.forename: Laureane
authors.initials: L
authors.lastname: Mittaz-Crettol
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Taylor
authors.forename: Geert R
authors.initials: GR
authors.lastname: Mortier
authors.forename: Juergen
authors.initials: J
authors.lastname: Spranger
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zabel
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Valerie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hall
authors.forename: Amaka
authors.initials: A
authors.lastname: Offiah
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wright
authors.forename: Ravi
authors.initials: R
authors.lastname: Savarirayan
authors.forename: Gen
authors.initials: G
authors.lastname: Nishimura
authors.forename: Simon C
authors.initials: SC
authors.lastname: Ramsden
authors.forename: Rob
authors.initials: R
authors.lastname: Elles
authors.forename: Luisa
authors.initials: L
authors.lastname: Bonafe
authors.forename: Andrea
authors.initials: A
authors.lastname: Superti-Furga
authors.forename: Sheila
authors.initials: S
authors.lastname: Unger
authors.forename: Andreas
authors.initials: A
authors.lastname: Zankl
authors.forename: Michael D
authors.initials: MD
authors.lastname: Briggs
mesh_terms: D000130:Achondroplasia / Q000235:genetics*; D000595:Amino Acid Sequence; D027321:Anion Transport Proteins / Q000235:genetics*; D064236:Cartilage Oligomeric Matrix Protein; D002648:Child; D002675:Child, Preschool; D024081:Collagen Type IX / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D064235:Matrilin Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D010009:Osteochondrodysplasias / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017410:Practice Guidelines as Topic; D000076988:Sulfate Transporters
chemical_list: D027321:Anion Transport Proteins; D064236:Cartilage Oligomeric Matrix Protein; D024081:Collagen Type IX; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D064235:Matrilin Proteins; C089651:SLC26A2 protein, human; D000076988:Sulfate Transporters; C577553:TSP5 protein, human