De Novo Facioscapulohumeral Muscular Dystrophy: A Severe Subtype Driven by D4Z4 Repeat Contractions

Facioscapulohumeral muscular dystrophy (FSHD) includes approximately 10%-30% sporadic cases, where de novo pathogenic variants are hypothesized to be associated with more severe phenotypes. However, the systematic clinical characteristics and natural history of these cases remain poorly defined.

This retrospective observational cohort study was conducted at the Fujian Neuromedical Center, enrolling patients with genetically confirmed FSHD who were classified as de novo (dnFSHD) when no pathogenic D4Z4 contraction was detected in blood samples from either available parent. Clinical and genetic parameters at baseline and during subsequent evaluations were compared between dnFSHD and familial FSHD (fFSHD). The fFSHD cohort was matched for sex and disease duration. Mediation analysis was applied to explore the relationships among de novo pathogenic variants, the number of D4Z4 repeats, and disease progression.

A total of 92 patients with genetically confirmed FSHD who were classified as de novo cases were included, representing 17.8% of all FSHD type 1 cases. Compared with fFSHD, patients with dnFSHD exhibited an earlier age at onset (median: 10 years vs 16 years, p < 0.0001), higher clinical score (median: 8 vs 6, p = 0.0001), and smaller number of D4Z4 repeat units (RUs) (median: 3 vs 5, p < 0.0001). Survival analysis revealed significantly increased risks in patients with dnFSHD for lower extremity involvement (hazard ratio 1.55, p = 0.021). Mediation analysis indicated that D4Z4 RUs mediated 72% of the correlation between dnFSHD and lower extremity involvement and 48% of the association with age-corrected clinical severity scale.

This study establishes dnFSHD as a distinct, high-risk FSHD subtype characterized by unique clinical features, with its severe phenotype primarily mediated by a shorter D4Z4 repeat array.