Facioscapulohumeral Muscular Dystrophy 2 via the SMCHD1 Gene

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscle disorder with a prevalence between 1 and 5 in 100,000. Most patients with FSHD present by age 20 years, although marked variability in age of onset and severity is known to occur with some patients remaining asymptomatic. The disease course is progressive with approximately 20% of patients eventually requiring a wheelchair. Affected muscles include facial, scapular, upper arm, lower leg, and hip girdle. Patients exhibit forward sloping shoulders, however, the cardinal clinical feature is scapular winging (Tawil et al. Ann Neurol 43:279–282, 1998). Additional muscle groups involved include lower abdominal muscles, biceps, and triceps. Weak abdominal muscles result in protuberance of the abdomen and lumbar lordosis. Retinal vasculopathy occurs in 40%-60% of patients and high-tone sensorineural hearing loss occurs in approximately 60% of patients (Lemmers et al. GeneReviews, 2012). Serum CK levels are normal to mildly elevated. Muscle biopsies reveal necrotic fibers and fiber size variation. FSHD1 (OMIM 158900) and FSHD2 (OMIM 158901) have different underling genetic causes (see Genetics section), however, their clinical features are quite similar. One differentiating feature may be age of onset. In a series of 33 FSHD2 patients average age at onset was reported to be 26 years, which is nearly 10 years later than in FSHD1 (de Greef et al. Neurology 75:1548-1554, 2010).

FSHD1 (OMIM 158900), the more common form of facioscapulohumeral muscular dystrophy, is inherited as an autosomal dominant disorder secondary to contraction of the 3.3 kb D4Z4 microsatellite repeat at the subtelomeric region of chromosome 4q (Wijmenga et al. Nature Genet 2:26-30, 1992). Contraction of the D4Z4 array to DUX4 gene (OMIM 606009) in skeletal muscle. However, in addition to D4Z4 contraction, expression of the FSHD1 phenotype also requires that the contracted D4Z4 allele be on the same 4q allele as a polymorphism that creates a polyA signal for the most distal DUX4 gene (van Geel et al. Genomics 79: 210-217, 2002). 4qA is the term used to describe the 4q allele that bears this polymorphism. Abnormally close proximity of this polyA signal to the DUX4 gene permits stable expression of the normally silent DUX4 gene (Lemmers et al. Science 329: 1650-1653, 2010). FSHD2 (OMIM 158901) is inherited as a digenic disorder, requiring inheritance of two unlinked genetic factors: 1) a permissive 4qA allele and 2) a loss of function mutation of the SMCHD1 gene (OMIM 614982) which is found on chromosome 18p11 (Lemmers et al. Nature Genet 44:1370-1374, 2012). Notably, contraction of the D4Z4 array on chromosome 4q is not necessary for expression of FSHD2. Co-occurrence of the 4qA allele and a SMCHD1 gene mutation in FSHD2 has the same effect on DUX4 expression as does the 4qA/contracted D4Z4 haplotype in FSHD1, ie, both mechanisms permit stable expression of the normally silent DUX4 gene. The SMCHD1 gene encodes a protein involved with X chromosome inactivation (Blewitt et al. Nature Genet 40: 663-669, 2008) and genome-wide D4Z4 hypomethylation (Lemmers et al. Nature Genet 44:1370-1374, 2012). Currently, only loss of function mutations of the SMCHD1 gene have been reported.

Heterozygous SMCHD1 mutations were found in affected members of 15 of 19 families with FSHD in which FSHD1 was ruled out by molecular methods (Lemmers et al. Nature Genet 44:1370-1374, 2012). In each case with a SCHMD1 mutation, at least one copy of the permissive 4qA allele was also found.

Testing for D4Z4 array contractions, 4qA/4qB status, and methylation status are not currently offered by PreventionGenetics.

This test provides full coverage of all coding exons of the SMCHD1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).