High proportion of new mutations and possible anticipation in Brazilian facioscapulohumeral muscular dystrophy families

Abstract

A gene responsible for facioscapulohumeral muscular dystrophy (FSHD) has been localized at 4q35. Subsequently, it was found that probe p13E-11 detects a polymorphic EcoRI fragment, usually > 28 kb, in normal individuals, whereas in sporadic and familial FSHD cases, an EcoRI fragment, usually < 28 kb, was found. Although these findings have been amply confirmed, several aspects are as yet either controversial or unsolved. In the present investigation, 34 Brazilian FSHD families were studied at the clinical and the molecular level for the following purposes: to assess the frequency of new mutations and their effect on estimates of biological fitness, to characterize FSHD-associated EcoRI fragments detected with probe p13E-11 in familial--as compared with isolated--FSHD cases, and to assess whether anticipation occurs in multigenerational families. Results from our study suggest that new mutations are apparently frequent for FSHD and may account for at least one-third of the cases, that somatic mosaicism may not be rare, and that biological fitness appeared to be reduced in FSHD, ranging from 0.6 to 0.82 by different estimates, with no difference in sexes. Interestingly, the size of the new EcoRI fragment is apparently smaller in more severely affected isolated patients. Moreover, the age at onset of clinical signs, as well as the age at ascertainment, in patients from multigenerational families suggests that anticipation occurs for FSHD in the majority of the families.