SMCHD1 – Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) type 2 is an autosomal dominant disease resulting from heterozygous variants in SMCHD1 that cause D4Z4 hypomethylation and derepression of the DUX4 retrogene (MONDO:0001347). Although FSHD1 is due to repeat contraction at 4q35, 5% of FSHD cases (FSHD2) lack D4Z4 contraction but harbor pathogenic SMCHD1 variants.

Clinical Validity

The association between SMCHD1 and FSHD2 is classified as Definitive, supported by evidence from over 95 unrelated index patients with segregating SMCHD1 variants and replication in multiple cohorts over >10 years (PMID:25370034; PMID:31600781). Segregation analysis in at least 19 affected relatives across 15 families further confirms pathogenicity.

Genetic Evidence

FSHD2 displays autosomal dominant inheritance with reduced penetrance. Segregation studies identified SMCHD1 variants in 95 index cases and their affected relatives (PMID:25370034). Case series describe 82 unique intronic, missense, nonsense, frameshift, and splice‐site SMCHD1 variants in FSHD2 cohorts, including recurrent LoF alleles (PMID:31600781). Variant classes: 24 missense, 18 frameshift/nonsense, 15 splice, and 25 deep‐intronic. One representative pathogenic variant is c.5150_5151del (p.Lys1717ArgfsTer16).

Functional Evidence

SMCHD1 haploinsufficiency leads to hypomethylation of the D4Z4 macrosatellite and aberrant expression of DUX4 in skeletal muscle. Knock‐out and haploinsufficient mouse models recapitulate D4Z4 hypomethylation and muscle pathology (PMID:25820463). CRISPR‐Cas9–mediated correction of pathogenic intronic SMCHD1 variants in patient myoblasts restores wild‐type SMCHD1 expression and efficiently represses DUX4 (PMID:31676591).

Conflicting Evidence

No studies have robustly refuted the role of SMCHD1 in FSHD2. Rare cases of SMCHD1 haploinsufficiency without DUX4 activation suggest variable expressivity but do not dispute the core mechanism.

Conclusion

Heterozygous SMCHD1 mutations cause autosomal dominant FSHD2 through haploinsufficiency, leading to D4Z4 hypomethylation and DUX4 derepression. Genetic testing of SMCHD1 complements D4Z4 sizing in FSHD diagnostics and informs prognosis and management. Key Take-home: SMCHD1 sequencing is essential for precise diagnosis of FSHD2 and guides clinical decision-making.

References

• European journal of human genetics • 2015 • Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1. PMID:25370034
• Human molecular genetics • 2019 • The variability of SMCHD1 gene in FSHD patients: evidence of new mutations. PMID:31600781
• Human molecular genetics • 2015 • Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome. PMID:25820463
• Journal of medical genetics • 2019 • Intronic SMCHD1 variants in FSHD: testing the potential for CRISPR‐Cas9 genome editing. PMID:31676591

Evidence Based Scoring (AI generated)