Double trouble: a comprehensive study into unrelated genetic comorbidities in adult patients with Facioscapulohumeral Muscular Dystrophy Type I

Abstract

Facioscapulohumeral dystrophy type 1 (FSHD1) displays prominent intra- and interfamilial variability, which complicates the phenotype-genotype correlation. In this retrospective study, we investigated FSHD1 patients classified as category D according to the Comprehensive Clinical Evaluation Form (CCEF), a category defined by FSHD patients showing uncommon clinical features, to identify genetic causes explaining these uncommon phenotypes. Demographics, clinical data and clinical scales of FSHD1 patients were retrospectively evaluated. Patients were divided into four CCEF categories, and comparisons between groups were performed. In category D, when uncommon features suggested the presence of an unrelated genetic disease, a more extensive collection of data was performed. 157 FSHD1 patients were included in the study (82 males, 75 females) with mean age of 52.1 ± 13.5 years at the time of the study. D4Z4 repeat sizes ranged between 2 and 10 RU. According to the CCEF, 114 patients were classified into category A, 8 into category B and C each, and 27 into category D. In category D, 9 patients presented uncommon features related to commonly acquired comorbidities, whereas in the remaining 18 patients, all but two with upper-sized FSHD1 D4Z4 repeats (7-10 RU), we suspected an unrelated genetic neurological disease based on clinical phenotype. In 14/18 patients, we identified FSHD-unrelated genetic causes, most often unrelated repeat expansion disorders. This emphasizes the need of careful clinical and genetic work-up to avoid confusion between FSHD-intrinsic clinical variability and clinical features unrelated to the disease.

Fig. 1

Breakdown of patients with double trouble.

Fig. 2. Distribution of D4Z4 repeat units, FSHD score, age at onset, and disease duration in patients divided according to CCEF categories and subcategories.

In black, mean and SD values are represented. 1A Significant differences in D4Z4 size among all A subcategories (****p < 0.0001, **p = 0.01, *p = 0.03); 1B Significant differences in D4Z4 size between A and B (****p < 0.0003), C (****p < 0.0003) and D categories (***p = 0.002); 2A Significant differences in FSHD score among all A subcategories (****p < 0.0001, **p = 0.01); 2B Significant differences in FSHD score between A, B and D categories (****p < 0.0001); 3A Significant differences for age at onset between A1 vs A2 (***p = 0.003) and vs A3 subcategories (**p = 0.01); 3B Significant differences for age at onset between C and A (***p = 0.003) and C and D categories (**p = 0.008); 4A Significant differences for disease duration between A1 and A2 (***p = 0.004), and A1 and A3 subcategories (**p = 0.03); 4B Significant differences for disease duration between C (***p = 0.0005) and A (*p = 0.03), B and D categories (**p = 0.003).

Fig. 3

Pedigrees of the eleven families.

Fig. 4. Distribution of FSHD score, age at onset, and disease duration in A, B, C, D1w and D1wo categories and A1, A2, and A3 subcategories with patients carrying 7-10 RU.

In black, mean and SD values are reported.1A Significant difference in FSHD score between A and B (*****p < 0.0001), A and D1w (***p = 0.005), B and D1w (****p = 0.001), and, B and D1wo (****p = 0.001); 1B Significant difference in FSHD score between D1w and A2 (***p = 0.003), and A3 subcategories (*****p < 0.0001) and for D1wo compared to A1 (***p = 0.006), A2 (*p = 0.04) and A3, (*p = 0.04); 2A Significant difference for age at onset between A and D1w (**p = 0.02) and, D1w and C (**p = 0.02); 2B Significant difference for age at onset between D1w and A2 (**p = 0.02) and A3 patients (**p = 0.02); 3A Significant difference for disease duration between A and C (**p = 0.02), D1w and C (*p = 0.04), D1wo and C (**p = 0.02); 3B Significant difference for disease duration between D1w and A1 patients (***p = 0.004).