Facioscapulohumeral dystrophy (FSHD) is a common muscular dystrophy characterized by initial weakness of the facial, shoulder and upper arm muscles but progressing to affect almost all skeletal muscles. In families with the most frequent genetic cause of the disease (FSHD1), a contraction of the polymorphic D4Z4 macrosatellite repeat array on a specific FSHD-permissive haplotype of chromosome 4q, the disease segregates as a dominant trait. In a small proportion of cases, the disease is caused by mutations in SMCHD1, a member of the condensin/cohesin family of chromatin compaction complexes that binds to the D4Z4 repeat array. In these FSHD2 families, the disease shows a more complex digenic inheritance because the mutation of SMCHD1 on chromosome 18 segregates independently from the FSHD-permissive chromosome 4q haplotype. In both forms of the disease, the mutations are associated with a partial relaxation of the D4Z4 chromatin structure and a failure to repress DUX4, a transcription f...