Retrospective clinical and genetic analysis of COL6-RD patients with a long-term follow-up at a single French center

Abstract

Collagen type VI-related dystrophies (COL6-RD) are rare diseases with a wide phenotypic spectrum ranging from severe Ullrich's congenital muscular dystrophy Ullrich congenital muscular dystrophy to much milder Bethlem myopathy Both dominant and recessive forms of COL6-RD are caused by pathogenic variants in three collagen VI genes (COL6A1, COL6A2 and COL6A3). The prognosis of these diseases is variable and difficult to predict during early disease stages, especially since the genotype-phenotype correlation is not always clear. For this reason, studies with long-term follow-up of patients with genetically confirmed COL6-RD are still needed. In this study, we present phenotypic and genetic data from 25 patients (22 families) diagnosed with COL6-RD and followed at a single French center, in both adult and pediatric neurology departments. We describe three novel pathogenic variants and identify COL6A2:c.1970-9G>A as the most frequent variant in our series (29%). We also observe an accelerated progression of the disease in a subgroup of patients. This large series of rare disease patients provides essential information on phenotypic variability of COL6-RD patients as well as on frequency of pathogenic COL6A gene variants in Southern France, thus contributing to the phenotypic and genetic description of Collagen type VI-related dystrophies.

Keywords: Bethlem myopathy; COL6 genes; COL6-RD; COL6A1; COL6A2; COL6A3; collagen type VI-related myopathies; ullrich’s congenital muscular dystrophy.

FIGURE 1

Variants identified in patients with COL6-RDs. Pathogenic and likely pathogenic variants identified in patients with genetically confirmed COL6-RD are shown. The triple helical domains in each collagen molecule are shown in pink. The exon-intron boundaries are marked by dashed lines. The missense variants are shown in grey, truncating variants are shown in red, while in-frame exon skips and deletions as well as in-frame pseudoexon insertions are shown in lavender. The bi-allelic (recessive) variants are shown above the protein bar, while the mono-allelic (dominant) variants are shown below the protein bar. The following transcripts were used for variant nomenclature: COL6A1 NM_001848.3, COL6A2 NM_001849.4, COL6A3 NM_004369.4.