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 411 D4Z4 repeats. SMCHD1 c.1040 þ 1G4A, 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 G4T, 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.

Recurrent major depression and right hippocampal volume: A bivariate linkage and association study

“…It is likely that SMCHD1 also has epigenetic functions beyond X inactivation [Mould et al, ]. For example, SMCHD1 acts upon the gene FSHD2 in such a way that leads to mutations in chromatin regulatory proteins, which in turn reduces epigenetic repression and increases expression of the deleterious gene DUX4 , which causes facioscapulohumeral muscular dystrophy [Jones et al, ; Lemmers et al, ; Sacconi et al, ; Winston et al, ]. This illness may be unrelated to rMDD, but there is limited evidence to suggest that depression may present as a feature of muscular dystrophy [Sabharwal, ].…”

Identifying diagnostic DNA methylation profiles for facioscapulohumeral muscular dystrophy in blood and saliva using bisulfite sequencing

“…The ~5% of clinical FSHD patients that do not have an FSHD1-sized pathogenic 4qA allele are candidates for FSHD2, but neither assay can identify these individuals as FSHD2 as opposed to another myopathy with similar clinical symptoms. Sequencing the SMCHD1 gene for known FSHD2 mutations in candidates with permissive 4A-type subtelomeres will identify many, but not all, FSHD2 subjects [ 21 , 27 , 28 ].…”

miRNA Expression in Control and FSHD Fetal Human Muscle Biopsies

“…The first one concerns 95% of the patients and is located in the sub-telomeric region of chromosome 4 [ 5 – 7 ]: control individuals carry 11 to 100 repeats of a 3.3 kb tandemly repeated sequence named D4Z4, whereas FSHD1 patients carry only 1 to 10 repeats [ 8 ]. The second locus is located on chromosome 18 and is mutated in 80% of patients, referred to as FSHD2, in whom mutations in the SMCHD1 gene have been found [ 9 – 11 ]. In both FSHD1 and FSHD2 patients, a chromatin relaxation has been noted, associated with the de-repression of the DUX4 transcription factor DUX4 (reviewed by [ 12 , 13 ]).…”