title: Genotype to phenotype correlations in cartilage oligomeric matrix protein associated chondrodysplasias.
abstract: Pseudoachondroplasia (PSACH) and autosomal dominant multiple epiphyseal dysplasia (MED) are chondrodysplasias resulting in short-limbed dwarfism, joint pain and stiffness and early onset osteoarthritis. All PSACH, and the largest proportion of MED, result from mutations in cartilage oligomeric matrix protein (COMP). The first mutations in COMP were identified in 1995 in patients with both PSACH and MED and subsequently there has been over 30 publications describing COMP mutations in at least 250 PSACH-MED patients. However, despite these discoveries, a methodical analysis of the relationship between COMP mutations and phenotypes has not been undertaken. In particular, there has, to date, been little correlation between the type and location of a COMP mutation and the resulting phenotype of PSACH or MED. To determine if genotype to phenotype correlations could be derived for COMP, we collated 300 COMP mutations, including 25 recently identified novel mutations. The results of this analysis demonstrate that mutations in specific residues and/or regions of the type III repeats of COMP are significantly associated with either PSACH or MED. This newly derived genotype to phenotype correlation may aid in determining the prognosis of PSACH and MED, including the prediction of disease severity, and in the long term guide genetic counselling and contribute to the clinical management of patients with these diseases.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Briggs
authors.affiliation: National Genetics Reference Laboratory (Manchester), Saint Mary's Hospital, Manchester, UK.
authors.forename: Joanne
authors.initials: J
authors.lastname: Brock
authors.affiliation: National Genetics Reference Laboratory (Manchester), Saint Mary's Hospital, Manchester, UK.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Ramsden
authors.affiliation: Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Bell
mesh_terms: D000130:Achondroplasia / Q000175:diagnosis / Q000235:genetics*; D000595:Amino Acid Sequence; D064236:Cartilage Oligomeric Matrix Protein / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis
chemical_list: D064236:Cartilage Oligomeric Matrix Protein; C577553:TSP5 protein, human