Fascioscapulohumeral dystrophy (FSHD) has 2 main phenotypes, types 1 and 2 , with the latter comprising only 5% of all cases. We report a case of FSHD type II associated with a novel missense mutation in SMCHD1 gene.

A 55-year-old woman presented with childhood onset facial and limb muscle weakness, which worsened over the last 10 years, resulting in an unsteady gait and a fall off her bike prompting medical attention. Examination showed mild weakness of the facial muscles, and MRC 4/5 strength in the shoulder abductors, hip extensors/flexors and knee flexors/extensors.

N/A

Electromyography showed myopathic motor unit action potentials in proximal limb girdle muscles. Quadriceps muscle biopsy showed atrophic myofibers, nuclear clumping and rare necrosis. Genetic testing revealed the 4q35A allele with hypomethylation (7% methylation) in the D4Z4 region and a heterozygous missense mutation by replacement of glycine with arginine (p.Gly285Arg) in the SMCHD1 on chromosome 18.

FSHD2 is caused by a digenic abnormality in which there is hypomethylation of the D4Z4 region of 4q35A and a mutation in the SMCHD1. The missense mutation in our patient has not been previously described in the literature. This mutation affects a highly conserved residue where the electrically neutral glycine is substituted by a positively charged arginine.

Thus, it is reasonable to expect that this mutation would affect protein structure and its adjacent ATPase domain function, thereby leading to DNA hypomethylation. Indeed, less than 11±5% D4Z4 methylation is required to cause FSHD2 phenotype, while hypomethylation in our patient was <7%. Together, these findings suggest that Gly285Arg is likely pathogenic.