Genetic and epigenetic contributors to FSHD

Curr Opin Genet Dev. 2015 Aug;33:56-61. doi: 10.1016/j.gde.2015.08.007. Epub 2015 Sep 7.


Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscle disorder characterized by distinct chromatin changes including DNA hypomethylation of the D4Z4 macrosatellite repeat array on a disease-permissive 4qA allele and aberrant expression of the D4Z4-embedded DUX4 retrogene in skeletal muscle. Insufficient epigenetic repression of the D4Z4 repeat is the result of at least two different genetic mechanisms leading to two forms of disease, FSHD1 and FSHD2. In the case of FSHD1, a contraction of the D4Z4 repeat array is disease causing whereas FSHD2 is most often caused by mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene. Recent studies indicate that a combination of genetic and epigenetic factors that act on the D4Z4 repeat array determine the probability of DUX4 expression in skeletal muscle and disease penetrance and progression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alleles
  • Chromatin / genetics
  • Chromosomal Proteins, Non-Histone / biosynthesis*
  • Chromosomal Proteins, Non-Histone / genetics
  • DNA Methylation / genetics*
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Homeodomain Proteins / biosynthesis
  • Homeodomain Proteins / genetics*
  • Humans
  • Microsatellite Repeats / genetics
  • Muscle, Skeletal / pathology
  • Muscular Dystrophy, Facioscapulohumeral / genetics*
  • Muscular Dystrophy, Facioscapulohumeral / pathology


  • Chromatin
  • Chromosomal Proteins, Non-Histone
  • DUX4L1 protein, human
  • Homeodomain Proteins
  • SMCHD1 protein, human

Supplementary concepts

  • Facioscapulohumeral muscular dystrophy 1a