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Abstract
Molecular defects in type 1 facioscapulohumeral muscular dystrophy (FSHD) are caused by a heterozygous contraction of the D4Z4 repeat array from 1 to 10 repeat units (RUs) on 4q35. This study compared (1) the phenotype and severity of FSHD1 between patients carrying 6–8 vs. 9–10 RUs, (2) the amount of methylation in different D4Z4 regions between patients with FSHD1 with different clinical severity scores (CSS). This cross-sectional multicenter study was conducted to measure functional scales and for genetic analysis. Patients were classified into two categories according to RUs: Group 1, 6–8; Group 2, 9–10. Methylation analysis was performed in 27 patients. A total of 99 carriers of a contracted D4Z4 array were examined. No significant correlations between RUs and CSS (r = 0.04, p = 0.73) and any of the clinical outcome scales were observed between the two groups. Hypomethylation was significantly more pronounced in patients with high CSS (>3.5) than those with low CSS (<1.5) (in DR1 and 5P), indicating that the extent of hypomethylation might modulate disease severity. In Group 1, the disease severity is not strongly correlated with the allele size and is mostly correlated with the methylation of D4Z4 regions.
Highlights
Facioscapulohumeral muscular dystrophy (FSHD1; OMIM 158900) is a common form of muscular dystrophy, affecting 1 in 20,000 to 1 in 8000 people, characterized by asymmetric and progressive weakness of the facial, shoulder girdle, and upper arm muscles [1,2,3,4], but often with subsequent lower limb involvement
The contraction of D4Z4 repeats at the 4q35 locus has been associated with FSHD1
Given the variability of disease presentation among patients, incomplete penetrance, and familial heterogeneity, genotype–phenotype correlations remain a challenge for genetic counseling or prediction of the clinical disease progression
Summary
Facioscapulohumeral muscular dystrophy (FSHD1; OMIM 158900) is a common form of muscular dystrophy, affecting 1 in 20,000 to 1 in 8000 people, characterized by asymmetric and progressive weakness of the facial, shoulder girdle, and upper arm muscles [1,2,3,4], but often with subsequent lower limb involvement. In FSHD1, the reduced size of the D4Z4 array is associated with hypomethylation of the repetitive element, whereas in FSHD2, decreased DNA methylation is more pronounced and often segregates with SMCHD1 gene mutation on chromosome 18p [15]. Changes in this epigenetic mark have been associated with the clinical expression of FSHD1 [1,16], and in a subset of patients carrying borderline D4Z4 arrays and SMCHD1 mutations [17]
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