Facioscapulohumeral muscular dystrophy has been genetically linked to reduced 
numbers (≤ 8) of D4Z4 repeats at 4q35 combined with 4A(159/161/168) DUX4 
polyadenylation signal haplotype. However, we have recently reported that 1.3% 
of healthy individuals carry this molecular signature and 19% of subjects 
affected by facioscapulohumeral muscular dystrophy do not carry alleles with 
eight or fewer D4Z4 repeats. Therefore, prognosis for subjects carrying or at 
risk of carrying D4Z4 reduced alleles has become more complicated. To test for 
additional prognostic factors, we measured the degree of motor impairment in a 
large group of patients affected by facioscapulohumeral muscular dystrophy and 
their relatives who are carrying D4Z4 reduced alleles. The clinical expression 
of motor impairment was assessed in 530 subjects, 163 probands and 367 
relatives, from 176 unrelated families according to a standardized clinical 
score. The associations between clinical severity and size of D4Z4 allele, 
degree of kinship, gender, age and 4q haplotype were evaluated. Overall, 32.2% 
of relatives did not display any muscle functional impairment. This phenotype 
was influenced by the degree of relation with proband, because 47.1% of second- 
through fifth-degree relatives were unaffected, whereas only 27.5% of 
first-degree family members did not show motor impairment. The estimated risk of 
developing motor impairment by age 50 for relatives carrying a D4Z4 reduced 
allele with 1-3 repeats or 4-8 repeats was 88.7% and 55%, respectively. Male 
relatives had a mean score significantly higher than females (5.4 versus 4.0, P 
= 0.003). No 4q haplotype was exclusively associated with the presence of 
disease. In 13% of families in which D4Z4 alleles with 4-8 repeats segregate, 
the diagnosis of facioscapulohumeral muscular dystrophy was reported only in one 
generation. In conclusion, this large-scale analysis provides further 
information that should be taken into account when counselling families in which 
a reduced allele with 4-8 D4Z4 repeats segregates. In addition, the reduced 
expression of disease observed in distant relatives suggests that a family's 
genetic background plays a role in the occurrence of facioscapulohumeral 
muscular dystrophy. These results indicate that the identification of new 
susceptibility factors for this disease will require an accurate classification 
of families.