title: Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy.
abstract: Facioscapulohumeral muscular dystrophy 1 (FSHD1) is caused by a contraction in the number of D4Z4 repeats on chromosome 4, resulting in relaxation of D4Z4 chromatin causing inappropriate expression of DUX4 in skeletal muscle. Clinical severity is inversely related to the number of repeats. In contrast, FSHD2 patients also have inappropriate expression of DUX4 in skeletal muscle, but due to constitutional mutations in SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1), which cause global hypomethylation and hence general relaxation of chromatin. Thirty patients originally referred for FSHD testing were screened for SMCHD1 mutations. Twenty-nine had >11 D4Z4 repeats. SMCHD1 c.1040+1G>A, a pathogenic splice-site variant, was identified in a FSHD1 family with a borderline number of D4Z4 repeats (10) and a variable phenotype (in which a LMNA1 sequence variant was previously described), and SMCHD1 c.2606 G>T, a putative missense variant (p.Gly869Val) with strong in vitro indications of pathogenicity, was identified in a family with an unusual muscular dystrophy with some FSHD-like features. The two families described here emphasise the genetic complexity of muscular dystrophies. As SMCHD1 has a wider role in global genomic methylation, the possibility exists that it could be involved in other complex undiagnosed muscle disorders. Thus far, only 15 constitutional mutations have been identified in SMCHD1, and these two sequence variants add to the molecular and phenotypic spectrum associated with FSHD.
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Jincy
authors.initials: J
authors.lastname: Winston
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Duerden
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mort
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Frayling
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Rogers
authors.affiliation: Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Meena
authors.initials: M
authors.lastname: Upadhyaya
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D019066:Facies; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016415:Sequence Alignment; D055815:Young Adult
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C578241:SMCHD1 protein, human
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