G.O.4

Fascioscapulohumeral muscular dystrophy (FSHD) is associated with partial chromatin relaxation of the D4Z4 macrosatellite repeat array localized on chromosome 4 and transcriptional derepression of the D4Z4-encoded DUX4 retrogene in skeletal muscle. In most patients, D4Z4 chromatin relaxation and DUX4 expression results from a contraction of D4Z4 repeat array on a FSHD-permissive allele defined by the presence of a DUX4 polyadenylation signal (autosomal dominant FSHD1). In the rare form of FSHD (FSHD2), D4Z4 chromatin relaxation occurs in the absence of D4Z4 contraction on a FSHD-permissive allele. Recently we reported that mutations in the structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) gene on chromosome 18 can underlie FSHD2. The chromatin modifier SMCHD1 binds to the D4Z4 repeat to maintain a repressed D4Z4 chromatin structure in somatic cells. FSHD2 patients show a reduced binding of SMCHD1 to D4Z4, causing relaxation of the D4Z4 chromatin structure marked by a partial loss of CpG methylation and an increased likelihood of DUX4 expression. SMCHD1 mutations can also be a modifier of disease severity in FSHD1. We performed a SMCHD1 mutation screen in 60 unrelated FSHD2 families and identified heterozygous SMCHD1 mutations in 51 families (85%). Mutations are found throughout the entire SMCHD1 locus but the mutation spectrum is biased and the damaging potential of the mutation strongly depends on other genetic factors such as the size of the FSHD-permissive D4Z4 repeat array. We also identified a family with autosomal recessive FSHD2 highlighting the variability in SMCHD1 mutations underlying FSHD2. Collectively, our study identifies novel aspects of repeat-mediated epigenetic repression and provides a molecular basis for the striking clinical variability in disease onset and progression.