Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction 
of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. The residual 
number of D4Z4 units inversely correlates with clinical severity, but 
significant clinical variability exists. Each unit contains a copy of the DUX4 
retrogene. Repeat contractions are associated with changes in D4Z4 chromatin 
structure that increase the likelihood of DUX4 expression in skeletal muscle, 
but only when the repeat resides in a genetic background that contains a DUX4 
polyadenylation signal. Mutations in the structural maintenance of chromosomes 
flexible hinge domain containing 1 (SMCHD1) gene, encoding a chromatin modifier 
of D4Z4, also result in the increased likelihood of DUX4 expression in 
individuals with a rare form of FSHD (FSHD2). Because SMCHD1 directly binds to 
D4Z4 and suppresses somatic expression of DUX4, we hypothesized that SMCHD1 may 
act as a genetic modifier in FSHD1. We describe three unrelated individuals with 
FSHD1 presenting an unusual high clinical severity based on their upper-sized 
FSHD1 repeat array of nine units. Each of these individuals also carries a 
mutation in the SMCHD1 gene. Familial carriers of the FSHD1 allele without the 
SMCHD1 mutation were only mildly affected, suggesting a modifier effect of the 
SMCHD1 mutation. Knocking down SMCHD1 in FSHD1 myotubes increased DUX4 
expression, lending molecular support to a modifier role for SMCHD1 in FSHD1. We 
conclude that FSHD1 and FSHD2 share a common pathophysiological pathway in which 
the FSHD2 gene can act as modifier for disease severity in families affected by 
FSHD1.