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Hints for Advanced Genotype–Phenotype Correlation in a Cohort of Suspected Facioscapulohumeral Muscular Dystrophy Patients From Serbia

Year: 2026

Type: article

Abstract: BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary myopathy characterized by marked clinical variability and diagnostic complexity. It comprises two forms: FSHD1, associated with contraction of D4Z4 repeats on chromosome 4q35, and FSHD2, linked to variants in chromatin remodeling genes. The presence of FSHD-associated molecular signatures in healthy individuals further complicates diagnosis. METHODS: We evaluated 39 unrelated Serbian probands with suspected FSHD. Family investigations were conducted in 30 probands (76.9%), involving 54 relatives (total n = 93). Clinical assessment was performed using the Comprehensive Clinical Evaluation Form (CCEF), and molecular testing followed the standard workflow for FSHD1. RESULTS: A D4Z4 reduced allele (DRA, 1-10 repeats) was identified in 31 probands (79.5%). Of these, 24 (77.4%) showed a classical phenotype, while 7 (22.6%) had facial-sparing presentations. Among 39 relatives from 23 DRA-positive families, 13 (33.3%) carried a DRA; among them, 5 had classical FSHD and 8 were asymptomatic or mildly affected. Eight probands (20.5%) were DRA-negative. Among 15 relatives from these families who were all DRA-negative, one showed a classical phenotype, and six were asymptomatic or mildly affected. CONCLUSION: These findings confirm the marked phenotypic heterogeneity of suspected FSHD and highlight the importance of standardized clinical assessment and family investigations to improve diagnosis, genetic counseling, and patient selection for clinical trials.

Source: European Journal of Neurology

DOI: 10.1111/ene.70764