Homozygous splice variant (c.1741-6G > A) of the COL6A1 gene in three patients with Ullrich congenital muscular dystrophy

The three major collagen VI genes: COL6A1, COL6A2 , and COL6A3 encode microfibrillar components of extracellular matrices in multiple tissues including muscles and tendons. Pathogenic variants in the collagen VI genes cause collagen VI-related dystrophies representing a continuum of conditions from Bethlem myopathy at the milder end to Ullrich congenital muscular dystrophy at the more severe end. Here we describe a pathogenic variant in the COL6A1 gene (NM_001848.3; c.1741-6G > A) found in homozygosity in three patients with Ullrich congenital muscular dystrophy. The patients suffered from severe muscle impairment characterised by proximal weakness, distal hyperlaxity, joint contractures, wheelchair-dependency, and use of nocturnal non-invasive ventilation. The pathogenicity was verified by RNA analyses showing that the variant induced aberrant splicing leading to a frameshift and loss of function. The analyses were in line with immunocytochemistry studies of patient-derived skin fibroblasts and muscle tissue demonstrating impaired secretion of collagen VI into the extracellular matrix. Thereby, we add the variant c.1741-6G > A to the list of pathogenic, recessive, splice variants in COL6A1 causing Ullrich congenital muscular dystrophy. The variant is listed in ClinVar as of uncertain significance and likely benign and may presumably have been overlooked in other patients.& COPY; 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Automated summary

The three major collagen VI genes (COL6A1, COL6A2, and COL6A3) encode microfibrillar components of the extracellular matrix in various tissues. A pathogenic variant (c.1741-6G > A) in the COL6A1 gene was identified in three patients with severe Ullrich congenital muscular dystrophy. The variant induces aberrant splicing, leading to loss of collagen VI function and impaired secretion. This finding expands our understanding of pathogenic variants causing Ullrich congenital muscular dystrophy.