Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual 
pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 
macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies 
provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, 
DUX4, is expressed in the human germline and then epigenetically silenced in 
somatic tissues. In FSHD, the combination of inefficient chromatin silencing of 
the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize 
the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein 
expression in muscle cells. FSHD is thereby the first example of a human disease 
caused by the inefficient repression of a retrogene in a macrosatellite repeat 
array.