DNA rearrangements in Japanese facioscapulohumeral muscular dystrophy patients: clinical correlations

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disorder in which the disease locus has been mapped to chromosome 4q35-qter. In most patients, the DNA rearrangements associated with FSHD have been found in the EcoRI fragment detected by the p13E-11 probe, and deletions of the 3.2 kb repeat units within the fragment are thought to cause the disease. To examine FSHD-associated DNA rearrangements in the Japanese population, we performed Southern blot analysis of the genomic DNA, using the p13E-11 and pFR-1 probes, in 158 Japanese individuals, including 38 FSHD patients from 19 families. We found that all but one (a possible affected recombinant) of the Japanese FSHD patients (97.4%) had specific smaller (<28 kb) EcoRl fragments which cosegregated with the disease; this included four patients who had severe inflammatory changes in the muscle and eight patients with de novo DNA rearrangements. We found no FSHD patient who had a fragment larger than 28 kb. By contrast, only two of 35 Japanese controls (5.7%) had EcoRI fragments smaller than 28 kb. Our patients showed anticipation, i.e. decreased size of the EcoRI fragment in parallel with earlier onset of the disease ( r=0.531, P=0.003, with younger age at onset in children (17.8±7.0) than their affected parents (31.5±14.8) ( P=0.019). However, since each family had a specific small EcoRI fragment associated with the disease, the differing clinical severity within a family cannot be explained by the size of the fragment alone. We found two severely affected patients (new mutations) who had the shortest EcoRI fragment ever reported (10 kb) that contained no more than one 3.2 kb repeat unit. None of the patients with neurogenic scapuloperoneal muscular atrophy had smaller EcoRI fragments detected by the probes. We conclude that the p13E-11 and pFR-1 probes are tightly linked markers of FSHD and can detect most DNA rearrangements associated with the disease in the Japanese population.