Facioscapulohumeral Muscular Dystrophy: Genetics

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscular dystrophy that presents clinically with progressive weakness of the facial, scapular and humeral muscles, with later involvement of the trunk and lower extremities. FSHD is a unique disease with complex genetic and epigenetic aetiology and the underlying biological mechanisms are still not fully deciphered. FSHD1 is more frequent (95%) and is associated with the contraction of the D4Z4 macrosatellite repeat array located on a permissive 4qA chromosome combined with decreased methylation of cytosines at the 4q35‐linked D4Z4 units. D4Z4 contraction allows epigenetic derepression of the D4Z4 array allowing the expression of the toxic DUX4 transcription factor encoded within the terminal D4Z4 repeat in skeletal muscles. FSHD2 associated with approximately 2–3% of the FSHD patients results from haploinsufficiency of the SMCHD1 gene in individuals carrying a permissive 4qA allele and marked hypomethylation of 4q and 10q D4Z4, which leads to the derepression of DUX4 hence DUX4 appears to be a key player in both types of FSHD. Currently, there is no reliable treatment for this condition, therefore for the successful development of new treatments, an integration of clinical and pathogenetic information is vital. Key Concepts FSHD is the third most common inherited muscular dystrophy characterised by a typical phenotype and involvement of specific groups of muscles. FSHD is characterised by a highly variable penetrance and clinical severity. In most cases, FSHD involves shortening of a repetitive macrosatellite array. The D4Z4 macrosatellite linked to FSHD encodes the DUX4 transcription factor. A small proportion of FSHD patients carry mutation in the SMCHD1 gene. Epigenetic changes in FSHD are closely associated with molecular features. FSHD is a unique disease with complex genetic and epigenetic aetiology and the underlying biological mechanisms are still not fully deciphered. There is no reliable treatment for the disease.

Early-Onset Infantile Facioscapulohumeral Muscular Dystrophy: A Timely Review

“…Subsequently, the DUX4 expressed from the permissive chromosomal allele with a polyadenylation signal (PAS) results in transcriptional dysregulation and consequent degeneration of muscle cells [ 2 , 5 ]. FSHD2, representing less than 5% of patients with clinically defined FSHD, is not associated with deletions of D4Z4 copies but mutations of the SMCHD1 (on chromosome 18p11) or DNMT3B gene (on chromosome 20q11) in the presence of a disease-permissive 4qA haplotype [ 6 , 8 , 13 ]. However, the comprehensive molecular genetic testing of FSHD2 is relatively complex and has not been made commercially available so far.…”

“…Interestingly, the inheritance of infantile FSHD is often sporadic, and de novo mutations were more frequent in patients with infantile FSHD than classical FSHD [ 10 , 20 ]. Although positive family history is rare, patients with infantile FSHD obtaining a de novo mutation usually have unaffected carrier parents who carry somatic mosaicism of the mutation [ 12 , 13 ]. FSHD with somatic mosaicism of D4Z4 array lengths is more penetrant in males than in females [ 32 ].…”

“…On the other hand, as many as 30% of FSHD1 cases confirmed by genetic testing may be asymptomatic, especially those with small deletions (8-10 D4Z4 repeats), which delineate the mildest end of the disease severity spectrum [17]. Therefore, it is implied that the fragment size of D4Z4 is roughly negatively correlated with the clinical severity of FSHD [3,8,13,18,19].…”

Joining mainstream research on Facioscapulohumeral Dystophy: disease prevalence in China

“…An early onset of the disease is usually associated with higher disease severity. 3 As life expectancy is considered as normal, disease duration and progression is long, posing societal and socio-economic burden for patients and their families.…”

“…A total of 1802 cases collected were collected; 1744 were tested for FSHD1 by Pulse Field Gel Electrophoresis and Southern blotting 3 at the Fujian Neuromedical Center, the clinical genetic test hospital for FSHD in China. The size of the D4Z4 array was determined together with the presence of A-type haplotype.…”