Facio-scapulo-humeral dystrophy (FSHD) results from deletions in the 
subtelomeric macrosatellite D4Z4 array on the 4q35 region. Upregulation of the 
DUX4 retrogene from the last D4Z4 repeated unit is thought to underlie FSHD 
pathophysiology. However, no one knows what triggers muscle defect and when 
alteration arises. To gain further insights into the molecular mechanisms of the 
disease, we evaluated at the molecular level, the perturbation linked to the 
FSHD genotype with no a priori on disease onset, severity or penetrance and 
prior to any infiltration by fibrotic or adipose tissue in biopsies from fetuses 
carrying a short pathogenic D4Z4 array (n = 6) compared with fetuses with a 
non-pathogenic D4Z4 array (n = 21). By measuring expression of several 
muscle-specific markers and 4q35 genes including the DUX4 retrogene by an RT-PCR 
and western blotting, we observed a global dysregulation of genes involved in 
myogenesis including MYOD1 in samples with <11 D4Z4. The DUX4-fl pathogenic 
transcript was detected in FSHD biopsies but also in controls. Importantly, in 
FSHD fetuses, we mainly detected the non-spliced DUX4-fl isoform. In addition, 
several other genes clustered at the 4q35 locus are upregulated in FSHD fetuses. 
Our study is the first to examine fetuses carrying an FSHD-linked genotype and 
reveals an extensive dysregulation of several muscle-specific and 4q35 genes at 
early development stage at a distance from any muscle defect. Overall, our work 
suggests that even if FSHD is an adult-onset muscular dystrophy, the disease 
might also involve early molecular defects arising during myogenesis or early 
differentiation.