Pushing the genetic frontier with facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is an enigmatic genetic disorder with consistent major effects on skeletal muscle and less consistent effects on other tissues. Although the location of a causative genetic disturbance has been identified at one end of chromosome 4, the full nature of the disturbance and how this produces the disease is unclear. The study of the relationship between the genetic abnormalities present and the production of disease in FSHD promises not only to benefit the care of patients with FSHD and further our understanding of skeletal muscle biology, but also to shed fundamental light on basic mechanisms of gene regulation and human genetics.

The genetic disturbance present in almost all people with FSHD is of a peculiar nature. It consists of an uncommon deletion of a region at the distal end of chromosome 4q combined with the presence of one of two common sequence variants distal to this deleted region. Both are necessary. Furthermore, unlike the majority of other genetic disorders, the mutant FSHD deleted region does not include any known transcribed sequences. In this issue of Neurology, two articles advance our understanding of FSHD.^1,2 One provides compelling data pertaining to a new hypothesis for the disease mechanism and insight into the relationship between gene expression and nonmuscle systemic disease in FSHD, and the other adds to defining the minimal genetic requirement for the disease.

The article by Osborne …