SMCHD1 mutations in facioscapulohumeral muscular dystrophy type 2. R. J. L. F. Lemmers1, M. P. Nieuwenhuizen2, P. J. van der Vliet1, M. Vos-Versteeg2, J. Balog1, J. J. Goeman3, D. G. Miller4, S. J. Tapscott5, S. Saconni6, R. Tawil7, B. Bakker2, S. M. van der Maarel1 1) Human Genetics, Leiden University Medical Center, Leiden, Netherlands; 2) Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands; 3) Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, Netherlands; 4) Department of Pediatrics, University of Washington, Seattle, Washington, USA. Seattle Childrens Hospital, Seattle, WA, USA; 5) Divisions of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 6) Neuromuscular Diseases Specialized Center, Nice University Hospital, France; 7) University of Rochester Medical Center, Department of Neurology, Rochester, NY, USA.

   Facioscapulohumeral muscular dystrophy (FSHD) is one of the commonest muscular dystrophies. FSHD is characterized by a high clinical variability in onset, progression and severity. This variability is observed both between families and within families. FSHD is associated with an opening of the chromatin structure in the D4Z4 macrosatellite repeat array localized on chromosome 4 and transcriptional derepression of the D4Z4-encoded DUX4 gene in skeletal muscle. Two variants of chromosome 4 have been described of which only one is permissive to DUX4 expression because of the presence of a polymorphic DUX4 polyadenylation site. In most patients, chromatin relaxation-associated DUX4 expression is caused by contraction of the D4Z4 repeat array (autosomal dominant FSHD1) on a permissive allele. However, in some patients D4Z4 chromatin decondensation occurs independent of D4Z4 repeat array size and is caused by mutations in the chromatin modifier structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) on chromosome 18. The chromatin modifier SMCHD1 binds directly to the D4Z4 repeat where it is involved in establishment and/or maintenance of CpG methylation. In FSHD2 patients there is reduced binding of SMCHD1 to D4Z4, resulting in D4Z4 CpG hypomethylation and causing disease when combined with a permissive allele. In support, knock down of SMCHD1 in normal myoblasts containing a permissive haplotype leads to DUX4 expression. We performed a SMCHD1 mutation screen in 62 independent FSHD2 patients with the objectives to define the mutation spectrum of SMCHD1. In 51 families (82%) we identified SMCHD1 variations that were inferred to be disease causing. The mutation spectrum is unique and strongly suggests a selection bias that predicts a balanced interplay between SMCHD1 activity and D4Z4 repeat size in the somatic repression of DUX4. We anticipate that further genotype-phenotype analyses, combined with functional studies will facilitate our understanding of repeat mediated epigenetic silencing mechanisms in mammalian cells.

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