Type 1 FSHD with 6–10 Repeated Units: Factors Underlying Severity in Index Cases and Disease Penetrance in Their Relatives Attention

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.

Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7

“…Macrosatellite length generally inversely correlates to disease onset and severity. D4Z4 unit reduction leads to epigenetic derepression at the locus, including DNA hypomethylation and chromatin relaxation, although the extent is not strictly dictated by repeat length (van Overveld et al , 2003 ; Lemmers et al , 2015 ; Himeda & Jones, 2019 ; Salort‐Campana et al , 2020 ).…”

Muscle Fiber Conduction Velocity Correlates With the Age at Onset in Mild FSHD Cases

“…Moreover, several genotype-phenotype correlation studies reported a rough inverse correlation between the number of D4Z4 repeats and the severity of FSHD (Lunt et al, 1995;Tawil et al, 1996;Ricci et al, 1999). However, more recent publications did not find satisfactory correlations, even using a large number of patients (Ruggiero et al, 2020;Salort-Campana et al, 2020;Vercelli et al, 2021).…”