This work provides further evidence about the pathogenicity of the COL6A2 G733R mutation.

Mutations in COL6A2 are associated with Bethlem myopathy and Ullrich congenital muscular dystrophy, with an autosomal dominant or recessive pattern of inheritance. Here we present an Argentine patient, with family history of autosomal dominant Bethlem myopathy, who started at 8-years-old with muscular weakness and developed respiratory insufficiency during adulthood.

The patient underwent clinical and neurophysiological evaluation as well as muscle MRI and biopsy. Whole exome sequencing and Sanger validation were performed on the proband’s genomic DNA obtained from a blood sample. Co-segregation study was performed in one available family member affected with the disease.

Clinical assessment revealed mild weakness affecting axial, upper and lower limbs muscles, finger flexor contractures, distal articular hypermotility and skin anomalies. Muscle biopsy showed moderate fibrosis with perimysial lipomatosis and focal endomysial fibrosis; and muscle MRI presented periphery affection of quadriceps and a “tigroid” pattern of muscles. Exome sequencing revealed a heterozygous missense Glycine-to-Arginine mutation at codon 733 of COL6A2 (NM_001849.3, c.2197G>A, Exon 26). This variant is classified as likely pathogenic according to ACMG guidelines and predicted to be damaging by CADD score and Polyphen-2, and has been described in one patient with Bethlem myopathy (Inoue et al., 2021). Co-segregation test in proband’s aunt –who present similar phenotype– revealed that she’s also a mutation carrier. Taken together, these results and proband’s family medical history support the role of the variant in the disease pathogenesis.

We report a heterozygous COL6A2 G733R mutation in a patient with familiar Bethlem myopathy, with early childhood onset. Taken together with previous reports of other mutations in this gene, our data strongly suggest that this variant is likely pathogenic, with autosomal dominant inheritance.