Fig. 1

Schematic representation of the D4Z4 repeat array on chromosome 4q35.2, the genetic locus associated with FSHD. Each D4Z4 unit is 3.3 kb in length. FSHD is caused by contraction of these repeats [1,2,3,4,5,6,7,8,9,10] or mutations in chromatin regulators such as SMCHD1, DNMT3B and LRIF1, leading to hypomethylation of the region and aberrant expression of the DUX4 gene in the most distal repeat. DUX4 expression additionally requires a permissive 4qA allele containing a polyadenylation signal to stabilize its transcript. Cases caused by D4Z4 contraction per se are categorized as FSHD1, while those associated with variants in other genes are categorized as FSHD2. These standard criteria accommodate cases that overlap both categories (such as FSHD1 with modifier effects from SMCHD1 variants). In FSHD1, disease severity roughly correlates inversely with the number of D4Z4 repeats: cases with 1–3 repeats tend to be most severe including more early onset cases, those with 4–7 repeats moderately severe, and those with 8–10 repeats relatively mild. Asymptomatic cases are more frequently observed among individuals with longer repeat arrays