All these findings supported the hypothesis that significant alteration of the 4q35 epigenetic landscape is central to FSHD, and that this occurs in FSHD1 by removal of a significant number of D4Z4 heterochromatic elements, and in FSHD2, via SMCHD1 or DNMT3B haploinsufficiency in presence of a specific telomeric polymorphism, 4qA, which allows the expression of the most distal copy of the DUX4 gene. This evidence concerns the gene SMCHD1 and facioscapulohumeral muscular dystrophy.