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COLVI related myopathies include phenotypes ranging from severe forms (Ullrich congenital muscular dystrophy) to more moderate forms (Bethlem myopathy). They result from abnormalities in the expression and/or secretion of collagen VI (COLVI), a component of the extracellular matrix which is formed by the assembly of 3 chains alpha 1, alpha 2 and alpha 3 each encoded by the COL6A1-A2-A3 genes. Their diagnosis is based on clinical criteria, muscle MRI and genetic analyses. We present the case of a patient with a typical COLVI related myopathy phenotype but for whom initial NGS panel analyzes were not conclusive. Complementary techniques of protein and transcriptional studies allowed confirming the diagnosis. Blood gDNA of the proband was sequenced on a NGS panel containing coding sequences of genes associated with retractile myopathies including COL6A1, COL6A2 and COL6A3. COLVI expression was carried out by immunostaining on fibroblasts obtained from a skin biopsy. A transcriptomic study by RNA-seq on mRNA from fibroblasts made it possible to analyze aberrant splicing of COL6A1-A2-A3. As no variant of interest was retained on the NGS panel, COLVI immunostaining on fibroblasts was carried out and showed an alteration of its secretion with absence of COLVI network. Subsequently, a transcriptomic approach by RNA-seq showed the skipping of exon 11 in the heterozygous state in COL6A1. Reanalysis of the NGS.bam files allowed characterizing the deletion consisting in a short CNV involving part of both exon 11 and intron 11 of COL6A1. Familial segregation could show this was a de novo event. Given the very evocative clinic and thanks to functional studies, we identified the causal genetic variant allowing us to confirm the diagnosis of Ullrich myopathy. This example illustrates the importance of clinician-biologist dialogue, the limits of analyzes on genomic DNA, and the complementarity of functional tests in order to reduce diagnostic wandering. [ABSTRACT FROM AUTHOR]

COL1 -related overlap disorder is a condition, which is not yet considered as part of the 2017 EDS classification. However, it should be investigated as an alternative diagnosis for any patient with hypermobile EDS. This could allow providing appropriate genetic counseling., Competing Interests: The authors declare that they have no conflict of interests., (© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Background: Dominant and recessive autosomal pathogenic variants in the three major genes (COL6A1-A2-A3) encoding the extracellular matrix protein collagen VI underlie a group of myopathies ranging from early-onset severe conditions (Ullrich congenital muscular dystrophy) to milder forms maintaining independent ambulation (Bethlem myopathy). Diagnosis is based on the combination of clinical presentation, muscle MRI, muscle biopsy, analysis of collagen VI secretion, and COL6A1-A2-A3 genetic analysis, the interpretation of which can be challenging., Objective: To refine the phenotypical spectrum associated with the frequent COL6A3 missense variant c.7447A>G (p.Lys2483Glu)., Methods: We report the clinical and molecular findings in 16 patients: 12 patients carrying this variant in compound heterozygosity with another COL6A3 variant, and four homozygous patients., Results: Patients carrying this variant in compound heterozygosity with a truncating COL6A3 variant exhibit a phenotype consistent with COL6-related myopathies (COL6-RM), with joint contractures, proximal weakness and skin abnormalities. All remain ambulant in adulthood and only three have mild respiratory involvement. Most show typical muscle MRI findings. In five patients, reduced collagen VI secretion was observed in skin fibroblasts cultures. All tested parents were unaffected heterozygous carriers. Conversely, two out of four homozygous patients did not present with the classical COL6-RM clinical and imaging findings. Collagen VI immunolabelling on cultured fibroblasts revealed rather normal secretion in one and reduced secretion in another. Muscle biopsy from one homozygous patient showed myofibrillar disorganization and rimmed vacuoles., Conclusions: In light of our results, we postulate that the COL6A3 variant c.7447A>G may act as a modulator of the clinical phenotype. Thus, in patients with a typical COL6-RM phenotype, a second variant must be thoroughly searched for, while for patients with atypical phenotypes further investigations should be conducted to exclude alternative causes. This works expands the clinical and molecular spectrum of COLVI-related myopathies.