Very low penetrance in 85 Japanese families with facioscapulohumeral muscular dystrophy 1A.

F acioscapulohumeral muscular dystrophy (FSHD) is the third most common form of muscular disorder with an autosomal dominant trait, and its frequency is about one in 20 000. It is characterised by weakness and atrophy of the facial, shoulder girdle, and upper limb muscles. The pelvic girdle and lower limbs subsequently also become involved, and, eventually, 20% of patients have to use wheelchairs by the age of 40 years. Most patients develop clinical symptoms in late childhood or adolescence, although the onset of the disease and its clinical severity are heterogeneous. The FSHD locus was mapped to the subtelomeric region of the long arm of chromosome 4 by genetic linkage analysis. More than 95% of patients with FSHD had a small (,35 kb) EcoRI fragment on chromosome 4q35 on southern blotting analysis with the probe p13E-11 (FSHD1A; MIM 158900). This EcoRI fragment contains tandem repeats of the 3.3 kb KpnI unit (D4Z4). The number of D4Z4 repeats varies from 11 to 150 in healthy people, although the number is fewer than 11 in patients with FSHD1A. 8 Although no responsible gene has been isolated within the FSHD region, the number of D4Z4 repeats is a critical determinant of the age of onset and clinical severity of the disease. In general, 1–3 D4Z4 repeats are associated with a severe form of the disease that presents in childhood, 4–7 repeats with the most common form of FSHD, and 8–10 repeats with a milder disease and reduced penetrance. Probe p13E-11 crosshybridises with chromosome 10q26, which contains highly homologous 3.3 kb KpnI repeated units. As the BlnI restriction enzyme site exists exclusively within each unit derived from 10q26, but not in D4Z4 (a unit from 4q35), double enzyme digestion with EcoRI and BlnI can discriminate between the 4q35 (BlnI resistant) fragments and 10q26 (BlnI sensitive) fragments. The highly homologous structure means that the subtelomeric interchromosomal translocation between chromosomes 4 and 10 occurs often (in about 20–30% of people) and has been suggested to contribute to deletion of KpnI repeats on chromosome 4q35. The frequency of translocation, however, was not significantly different between healthy people and those with FSHD. More complicatedly, some people have five EcoRI fragments in total, including one additional BlnI resistant fragment. These people were suggested to have somatic mosaicism of the 4q35 region and two cell populations with different fragment sizes. 18–21 To clarify the frequency of the de novo mutation, the penetrance, and influence of the shortened repeats on clinical symptoms, we performed clinical and genetic analyses on patients with FSHD1A and both parents of each patient.