Facioscapulohumeral muscular dystrophy (FSHD) is a relatively common autosomal dominant disorder with an estimated incidence of 1: 20 000 births. 1 It is clinically characterised by progressive weakness of facial, shoulder girdle, and upper arm muscles; less frequently, the lower limbs are also affected. Some intriguing phenotypic observations are still not understood at the molecular level, such as the existence of clinical anticipation in some multigenerational families, which was observed in several population studies. 2–5 In addition, a remarkable inter-and intra-familial clinical variability, ranging from severe infantile forms to asymptomatic or non-penetrant gene carrying, may occur in individuals with an FSHD deleted fragment of the same size. It has been reported that a greater proportion of females than males remain asymptomatic, 1 6 and more recently we have observed that these non-penetrant individuals seem to be concentrated in some families. 7 The FSHD1 locus has been mapped to chromosome 4q35, and in most patients the probe p13E-11 detects a polymorphic EcoRI fragment smaller than 35 kb. The size of this fragment ranges from 35 to 300 kb in normal individuals and consists of multiple copies of a tandem repeated 3.3 kb KpnI unit (D4Z4). 8 As the 4q35 region is highly homologous to 10q26, the confirmation of molecular diagnosis is performed using BlnI, which cleaves the 10q26 units only into the 3.3 kb fragments, which are undetectable. 9 It has been shown that deletions of an integral number of the chromosome 4 units lead to FSHD and that this contraction might affect nearby genes by altering the chromosomal structure, inducing position effect variegation. 10 A polymorphic segment distal to D4Z4 with alleles 4qA and 4qB was described by Van Geel et al. 11 In a survey in the Dutch population, Lemmers et al12 found that while in control individuals both alleles are equally present, FSHD is uniquely associated with the 4qA allele. Moreover only type A alleles were observed on chromosome 10. Gabellini et al13 described a repressor complex that binds to the D4Z4 repeats. Partial deletion of this repeat would result in transcriptional derepression and consequently upregulation of the genes proximal to 4q35. According to these authors, the overexpression is inversely related to the number of D4Z4 repeats, which would explain why patients with a severe course have on average the smallest EcoRI fragments. Yip et al14 examined the effect on reporter gene activity and myoblast differentiation in vitro of increasing the D4Z4 repeat number, and observed that increasing D4Z4 repeats have a significant trans effect on myoblast differentiation with only a minor cis effect on reporter gene activity. Although FSHD is an autosomal dominant condition, asymptomatic or mildly affected individuals may not be diagnosed, and consequently offspring from two FSHD parents may carry two deleted alleles. Although individuals homozygous for other autosomal dominant diseases have been reported, this condition has never been described for FSHD.

In Huntington’s Disease (HD), an autosomal dominant late onset disorder, homozygous individuals were described in the pre-molecular era16 and confirmed at a later stage through molecular analysis. 16 Surprisingly, not only was the age at onset not earlier in homozygous compared with heterozygous patients, but in fact, heterozygous individuals seemed to have a more rapid progression of disease than homozygotes. 17 On the other hand, there are some diseases where homozygotes seem to be more severely affected than heterozygotes. One