In most cases facioscapulohumeral muscular dystrophy (FSHD) is caused by 
contraction of the D4Z4 repeat in the 4q subtelomere. This contraction is 
associated with local chromatin decondensation and derepression of the DUX4 
retrogene. Its complex genetic and epigenetic cause and high clinical 
variability in disease severity complicate investigations on the pathogenic 
mechanism underlying FSHD. A validated cellular model bypassing the considerable 
heterogeneity would facilitate mechanistic and therapeutic studies of FSHD. 
Taking advantage of the high incidence of somatic mosaicism for D4Z4 repeat 
contraction in de novo FSHD, we have established a clonal myogenic cell model 
from a mosaic patient. Individual clones are genetically identical except for 
the size of the D4Z4 repeat array, being either normal or FSHD sized. These 
clones retain their myogenic characteristics, and D4Z4 contracted clones differ 
from the noncontracted clones by the bursts of expression of DUX4 in sporadic 
nuclei, showing that this burst-like phenomenon is a locus-intrinsic feature. 
Consequently, downstream effects of DUX4 expression can be observed in D4Z4 
contracted clones, like differential expression of DUX4 target genes. We also 
show their participation to in vivo regeneration with immunodeficient mice, 
further expanding the potential of these clones for mechanistic and therapeutic 
studies. These cell lines will facilitate pairwise comparisons to identify 
FSHD-specific differences and are expected to create new opportunities for 
high-throughput drug screens.