Abstract
Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms to Bethlem muscular dystrophy, with milder symptoms typically recognized later, and intermediate COL6-RD falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of COL6-RD, some patients remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterized an international cohort of forty-four patients with this COL6A1 intron 11 variant, one of the most common recurrent causative variants in the collagen 6 genes. Patients manifest a consistently severe phenotype characterized by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD. One patient was found to have somatic mosaicism for this COL6A1 intron 11 variant and notably manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant. Our detailed characterization of this cohort contributes to the clinical trial readiness of this COL6A1 c.930+189C>T patient population.