Telomeres may regulate human disease by at least two independent mechanisms. 
First, replicative senescence occurs once short telomeres generate DNA-damage 
signals that produce a barrier to tumor progression. Second, telomere position 
effects (TPE) could change gene expression at intermediate telomere lengths in 
cultured human cells. Here we report that telomere length may contribute to the 
pathogenesis of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a 
late-onset disease genetically residing only 25-60 kilobases from the end of 
chromosome 4q. We used a floxable telomerase to generate isogenic clones with 
different telomere lengths from affected patients and their unaffected siblings. 
DUX4, the primary candidate for FSHD pathogenesis, is upregulated over ten-fold 
in FSHD myoblasts and myotubes with short telomeres, and its expression is 
inversely proportional to telomere length. FSHD may be the first known human 
disease in which TPE contributes to age-related phenotype.