Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy is an autosomal dominant muscle disorder, mapped to 4q35. It is characterized by remarkable inter- and intrafamilial clinical variability ranging from severe phenotype to asymptomatic carriers. The aim of the present study was to assess the size of the Eco RI fragment in a large sample of asymptomatic or minimally affected carriers as well as symptomatic patients, comparing both sexes, in order to verify if asymptomatic carriers are randomly distributed or concentrated in some particular families and if there is preferential parental transmission (maternal or paternal) resulting in non-penetrant carriers. We have analysed a total of 506 individuals from 106 unrelated families with at least one affected facioscapulohumeral muscular dystrophy proband. In all patients the molecular diagnosis was confirmed following double digestion (Eco RI/Bln I fragment <35 kb). About 20% among probands' relatives who were found to carry the small fragment were asymptomatic or minimally affected, without preferential parental transmission, but with a significantly higher proportion of females (n=37) than males (n=14). Although asymptomatic carriers were found in about 30% of the families, some genealogies seem to concentrate more non-penetrant cases. A significant correlation between the size of the Eco RI fragment and severity of the phenotype was observed in the total sample but surprisingly this correlation is significant only among affected females. The gender difference in clinical manifestation as well as the observation that asymptomatic carriers are not rare should be taken into consideration in genetic counseling of affected patients or 'at-risk' relatives.