To examine the relationship of clinical and genetic features of patients with facioscapulohumeral muscular dystrophy (FSHD) with 7–10 residual D4Z4 repeats in a large genetically defined FSHD1 cohort.

We performed a prospective cross-sectional observational study of 74 clinically affected patients with FSHD1. Measures of clinical severity were compared between patients with 1–6 D4Z4 repeats and 7–10 repeats, and included D4Z4 CpG methylation, age at diagnosis, age-adjusted clinical severity score, a muscle pathology grade of quadriceps biopsies (0 = normal, 12 = severe dystrophic changes), quantitative myometry of biopsied muscles, global manual muscle testing scores, and frequency of wheelchair use.

Twenty-eight (37.8%) participants had 7–10 D4Z4 repeats, and compared to participants with 1–6 repeats, were diagnosed 6.6 years older (p = 0.17); had lower CpG methylation than would be predicted by D4Z4 repeat size (p = 0.04); had age-adjusted clinical severity 39.8 points lower (p = 0.004); had muscle pathology grades that were 2.4 points less severe (p < 0.0001); had quantitative myometry 28.3% predicted of normal higher (p = 0.002); had global manual muscle testing scores 0.6 higher (p = 0.005); and did not require wheelchairs.

Patients with FSHD with 7–10 D4Z4 repeats have milder disease than other genetically defined patients with FSHD1. The lower than predicted methylation in the 7–10 residual repeat group may suggest that additional epigenetic factors play a role in the severity of disease expression.