The Value of Clinical and Radiological Expertise in Mutation Screening

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As with many types of genetic disease, it is becoming common for clinical diagnosis of skeletal dysplasias to be confirmed at the DNA level. An issue that often arises is whether or not cases submitted for DNA diagnosis should be evaluated by experts before performing DNA testing. A small study involving multiple epiphyseal dysplasia (MED) reported by Zankl et al suggests that preselection of cases through such evaluation significantly increases the rate of mutation detection. The investigation was carried out under the auspices of the European Skeletal Dysplasia Network (ESDN).

MED is characterized by delayed and irregular ossification of epiphyses and precocious osteoarthritis. It is inherited as a dominant trait in most cases, and mutations have been identified in genes encoding 5 cartilage extracellular matrix proteins including cartilage oligomeric matrix protein (COMP), the 3 chains of type IX collagen (COL9A1 , COL9A2 , COL9A3), and matrilin 3 (MATN3). Mutations of COMP are most common. MED is occasionally inherited in a recessive fashion with mutations identified in the gene coding for the diastrophic dysplasia sulfate transporter (DTDST, SLC26A2).

The authors first noted that in a recent study COMP mutations were detected in only 36% of 58 families with MED in whom the diagnosis was made by the referring physician, usually a clinical geneticist. Since they expected the rate to be higher they suspected that some of the referral diagnoses were incorrect and that the mutation detection rate could be improved by adding an expert evaluation step between referral and DNA diagnosis.

Between September 2003 and February 2005 a panel of experts in the clinical and radiographical aspects of skeletal dysplasias evaluated, before testing, 35 patients with a diagnosis of MED. Of the 35 patients, 24 were considered to have “classical” MED by the experts, 5 possible MED variants, 2 most likely had type II collagenopathy, and 4 patients were considered “unknowns.” Genomic DNA was analyzed from 21 of the 29 patients with classical or possible variant MED. Mutations were detected in 13 of the 16 patients with classical MED and one with a possible MED variant. Of the 14 mutations identified, 13 were COMP mutations and one involved MATN3 . A COL2A1 mutation was subsequently identified in the patient with clinical features of type II collagenopathy. No mutation was detected in 3 patients considered to have classical MED.

When the numbers were tallied, the mutation detection rate was 81% for patients with classical MED and 67% if patients with possible MED variant were included, both substantially higher than the 36% reported previously. The authors concluded that review of clinical and radiographical features by experts prior to DNA testing substantially improves the rate of mutation detection since cases misdiagnosed by non-experts are excluded. The results also confirm that mutations of COMP are responsible for most cases of MED.

Zankl A, Jackson GC, Crettol LM, et al. Preselection of cases through expert clinical and radiological review significantly increases mutation detection rate in multiple epiphyseal dysplasia. Eur J Hum Genet. 2007;15:150-4.

Editor’s Comment

From time to time the skeletal dysplasia community debates the value of clinical and especially radiographical expertise in the diagnosis of skeletal dysplasias. The argument is sometimes made that with DNA diagnosis becoming easily accessible through academic and commercial laboratories and government-sponsored networks such as the ESDN, there is no longer a need for special expertise in this field. The issue has received special attention in recent years as prominent radiologists with such expertise, ie, the pioneers of this field, have retired faster than young experts have been trained to fill their niche. Accordingly, this paper is very timely since it documents the value of this expertise. Although not discussed in the paper, another issue is the potential cost savings that could be realized from preselection by experts prior to DNA testing.

William A. Horton, MD

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Last Updated: 04/30/2008