By employing a clinical and radiographic review protocol, in which all referred MED cases were evaluated by a panel of skeletal dysplasia experts, we were able to increase the mutation detection rate to 81%. These findings indicate that mutations in the six known MED-disease genes are responsible for the vast majority of MED cases, and lower detection rates in previous studies are probably the result of misdiagnosis. Itoh et al
recently reported a high mutation detection rate of 54% when screening patients with MED for mutations in the six known MED genes.10
These patients were recruited through specialized skeletal dysplasia clinics, which might have contributed to the high mutation detection rate. In our study, rigorous clinical–radiological preselection through a panel of experts resulted in an even higher mutation detection rate.
The lack of an identifiable mutation in 19% of cases with the typical clinical–radiological features of MED suggests that a small, but significant, proportion of MED cases are caused by mutation in an as yet unknown gene. It should be noted that our mutation screening strategy does not allow us to detect single exon deletions, more complex deletions or mutations in intronic splicing elements outside of the immediate splice donor and acceptor sequences. There remains therefore the remote possibility that mutations of this type could account for the phenotype in these cases.
Most mutations identified in this study were located in the COMP gene verifying that it is the major genetic locus for MED and suggesting that mutations in matrilin-3 and type IX collagen are responsible for only a small proportion of autosomal dominant MED cases. To date, all recessive forms of MED (rMED: EDM4) can be ascribed to mutations in SLC26A2, but this does not exclude the possibility that mutations in other genes can also account for rMED.
The relaxation of diagnostic criteria to allow for the existence of possible MED variants significantly decreased the mutation detection rate. In only one of five cases with an atypical presentation was a mutation identified (20%). These findings indicate that the MED phenotype is relatively well defined and that while the identification of rare MED variants is important from an academic point of view, strict diagnostic criteria should be applied in a routine diagnostic setting to allow for an efficient screening protocol.
In addition to improving the mutation detection rate and thus making genetic testing for MED more efficient, expert clinical–radiographic review allowed the revision of the diagnosis in two cases. One case was diagnosed with a type II collagenopathy, and a mutation in COL2A1 was subsequently identified. No molecular testing is available to confirm the revised diagnosis of SEMD (type Hall or leptodactylic type) in the second case, but the consensus of several experts makes this diagnosis very likely. Both cases would have remained undiagnosed without expert clinical–radiological review before genetic testing.
In summary, we conclude that expert clinical and radiological review can improve diagnostic accuracy and significantly enhance mutation detection rates. Review and preselection should be part of any diagnostic mutation screening protocol for patients with skeletal dysplasias or any other rare genetic disease that requires expert knowledge for diagnosis. Furthermore, our data confirm that COMP is the major genetic locus for autosomal dominant forms of MED.