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Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2


Facioscapulohumeral dystrophy (FSHD) is characterized by chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4 and expression of the D4Z4-encoded DUX4 gene in skeletal muscle. The more common form, autosomal dominant FSHD1, is caused by contraction of the D4Z4 array, whereas the genetic determinants and inheritance of D4Z4 array contraction–independent FSHD2 are unclear. Here, we show that mutations in SMCHD1 (encoding structural maintenance of chromosomes flexible hinge domain containing 1) on chromosome 18 reduce SMCHD1 protein levels and segregate with genome-wide D4Z4 CpG hypomethylation in human kindreds. FSHD2 occurs in individuals who inherited both the SMCHD1 mutation and a normal-sized D4Z4 array on a chromosome 4 haplotype permissive for DUX4 expression. Reducing SMCHD1 levels in skeletal muscle results in D4Z4 contraction–independent DUX4 expression. Our study identifies SMCHD1 as an epigenetic modifier of the D4Z4 metastable epiallele and as a causal genetic determinant of FSHD2 and possibly other human diseases subject to epigenetic regulation.

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Figure 1: D4Z4 methylation test and families with FSHD2.
Figure 2: Families with FSHD2 with SMCHD1 mutations.
Figure 3: SMCHD1 haploinsufficiency results in DUX4 expression in normal human myoblasts.

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The authors thank all subjects and family members for their participation. We thank D. Nickerson and J. Shendure for excellent assistance and B. Trask for helpful discussions and critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (NIH) (National Institute of Neurological Disorders and Stroke (NINDS) P01NS069539, Clinical & Translational Science Award (CTSA) UL1RR024160, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R01AR045203 and National Human Genome Research Institute (NHGRI) HG005608 and HG006493), a Netherlands Genomics Initiative (NGI) Horizon Valorization Project Grant (93515504), The University of Washington Center for Mendelian Genomics, the Muscular Dystrophy Association (MDA; 217596), the Fields Center for FSHD Research, the Geraldi Norton and Eklund family foundation, the FSH Society, The Friends of FSH Research, European Union Framework Programme 7 agreements 223026 (NMD-chip), 223143 (TechGene) and 2012-305121 (NEUROMICS) and the Stichting FSHD. Y.S. is supported by the China Scholarship Council.

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R.J.L.F.L., R.T., M.J.B., S.J.T., D.G.M., R.R.F., B.B., A.M.A.-R. and S.M.v.d.M. conceived of and designed the study. D.G.M., S.J.T. and S.M.v.d.M. directed the study. G.W.E.S., Y.S., Q.H. and D.G.M. performed the bioinformatics data analysis. R.T., B.G.M.v.E., G.W.P., S.S., C.D. and M.d.V. performed assessments of the FSHD2 phenotype. R.J.L.F.L., D.G.M., L.M.P., J.B., G.J.B., A.M.A., P.J.v.d.V., R.A., K.R.S., Y.D.K., R.K. and J.C.d.G. performed experiments. R.T., J.T.d.D., C.M.D.-S., G.W.P., B.G.M.v.E., G.N.F., M.d.V., C.D. and S.S. contributed samples, reagents, data and comments on the manuscript. R.J.L.F.L., S.J.T., D.G.M. and S.M.v.d.M. analyzed and interpreted data, and wrote the manuscript with the assistance and final approval of all authors.

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Correspondence to Stephen J Tapscott or Daniel G Miller or Silvère M van der Maarel.

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The authors declare no competing financial interests.

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Lemmers, R., Tawil, R., Petek, L. et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet 44, 1370–1374 (2012).

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