Genetic Causes of Facioscapulohumeral Muscular Dystrophy
FSHD is caused by genetic abnormalities affecting the D4Z4 repeat array on chromosome 4q35, with two distinct forms: FSHD1 results from contraction/deletion of the D4Z4 repeat array, while FSHD2 results from mutations in the SMCHD1 gene combined with a permissive D4Z4 allele.
FSHD1 (Most Common Form)
FSHD1 accounts for approximately 95% of cases and is caused by partial deletion of the D4Z4 repeat array on chromosome 4q35. 1
Molecular Mechanism
- The disease results from contraction of the 3.3-kb subtelomeric D4Z4 repeat units on chromosome 4q35, leading to chromatin relaxation and inappropriate expression of the DUX4 gene in skeletal muscle 2
- Normal individuals have multiple copies of these repeat units, while affected individuals have deletions resulting in shortened arrays 1
- The deletion involves loss of most copies of the D4Z4 repeat array, and the length of the residual repeat correlates with disease severity 3
Inheritance Pattern
- FSHD1 is inherited in an autosomal dominant manner 3
- De novo mutations are common, occurring in approximately 30-40% of cases 3
- Somatic mosaicism is present in 40% of de novo cases, affecting either the patient or an asymptomatic parent 3
Important Diagnostic Complexity
A critical pitfall is that chromosome 10q26 contains a highly homologous repeat array that can cross-hybridize and complicate genetic diagnosis. 1
- Approximately 10-20% of the normal population has exchanged repeat arrays between chromosomes 4 and 10 4
- Some individuals carry hybrid repeat arrays consisting of both 4-derived and 10-derived repeat units 4
- FSHD is exclusively linked to chromosome 4 deletions, not chromosome 10, despite the homology 5
- Triple DNA analysis using multiple restriction enzymes (EcoRI, EcoRI/BlnI, and XapI) is necessary to definitively characterize all four alleles and distinguish 4-derived from 10-derived arrays 1
Sex-Dependent Phenotype
- Mosaic males are typically affected and symptomatic 3
- Mosaic females more often remain asymptomatic parents of affected offspring, with higher proportions of somatic mosaicism than males 3
- A genotypic-severity score combining residual repeat size and degree of somatic mosaicism correlates consistently with disease severity and age at onset 3
FSHD2 (Less Common Form)
FSHD2 is caused by digenic inheritance requiring both a mutation in the SMCHD1 gene on chromosome 18 AND a normal-sized D4Z4 array on a chromosome 4 haplotype that is permissive for DUX4 expression. 2
Molecular Mechanism
- SMCHD1 mutations reduce SMCHD1 protein levels and cause genome-wide D4Z4 CpG hypomethylation 2
- This hypomethylation leads to chromatin relaxation and DUX4 expression independent of D4Z4 array contraction 2
- SMCHD1 functions as an epigenetic modifier of the D4Z4 metastable epiallele 2
Inheritance Pattern
- FSHD2 requires inheritance of TWO genetic factors: the SMCHD1 mutation AND a permissive D4Z4 allele on chromosome 4 2
- This digenic inheritance pattern explains why FSHD2 has unclear inheritance patterns in families 2
Mechanism of Repeat Instability
The high mutation rate in FSHD appears to result from transchromosomal interactions between chromosomes 4 and 10 during mitosis. 3
- Supernumerary homologous repeat arrays significantly enhance repeat deletion 3
- In mosaic individuals, 4-type repeats on chromosome 10 are nearly five times more frequent than in the general population 3
- Mitotic interchromosomal gene conversion or translocation between fully homologous 4-type repeat arrays may be the major mechanism for FSHD mutations 3
- The predominantly mitotic origin is supported by the high frequency of somatic mosaicism 3
Clinical Implications
The region proximal to the D4Z4 repeat array can be deleted in healthy individuals without causing FSHD, but expansion of this deletion into the repeat array itself causes disease. 4