International Journal of Molecular Sciences · 16 authors, 6 centres
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This retrospective cohort study analyzed 15 Italian patients with COL6-related myopathy using NGS, histological, immunofluorescence, and ultrastructural techniques, identifying 14 pathogenic variants (3 novel) and documenting extracellular matrix disorganization and sarcolemmal alterations that support variant pathogenicity.
Fifteen Italian patients with COL6-related myopathy—7 classified as Ullrich congenital muscular dystrophy and 8 as Bethlem myopathy—were retrospectively analyzed. Next-generation sequencing detected 14 pathogenic variants, 3 previously unreported. Two variants in the triple-helical domain of COL6A1 were associated with a more severe phenotype. In silico pathogenicity predictions were variable and sometimes contradictory with ACMG classification, making morphological and ultrastructural validation essential. Ultrastructural analysis of muscle biopsies most frequently revealed microvilli-like projections from sarcolemmal membranes, basal lamina splitting, thickening or replication, and subsarcolemmal vacuoles. The authors hypothesize that incorporation of mutated collagen VI into the extracellular matrix alters binding to macromolecules such as decorin and biglycan, weakening mechanical support to the muscle membrane. The study demonstrates that combined genetic and morphological approaches are pivotal for accurate diagnosis.
