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.

Figure 1

An illustration of the type III repeat region of COMP and the location of missense mutations and in-frame deletions, insertions or indels that lead to PSACH and/or MED. Each of the eight type III repeats are indicated on the left (T3₁, T3₂ etc.) along with the number of the COMP residue at the start of each repeat. The N- and C-type motifs are shown at the top and the residues that comprise each motif are boxed. The consensus sequence for the N- and C-type motifs are shown below. Residues that have missense mutations which cause MED are coloured GREEN, those that cause PSACH are coloured RED and mutations reported to cause both PSACH and MED are coloured BLUE. In-frame deletions, insertions or indels are double underlined using the same PSACH–MED colour scheme. The number of patients with a missense mutation identified at each codon is indicated above the relevant residue. Missense mutations in blocks of COMP residues that cause MED are highlighted in blue and those that cause PSACH are highlighted in green.