EM.P.4.02 Comprehensive clinical, cellular and molecular assessment of 64 French families with COL6-related muscle disorders: Clues for genotype/phenotype correlations

Collagen VI-related muscle disorders are heterogeneous neuromuscular diseases caused by mutations in the COL6A1, COL6A2 and COL6A3 genes encoding the extracellular matrix protein collagen VI (COL6). Two entities delineate this clinical spectrum: Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM). COL6 expression was studied in fibroblasts from 150 patients with a compatible phenotype, followed by sequencing of cDNA. A total of 74 disease-causing mutations (53 novels) were identified in 64 patients classified in three clinical groups: 39 classical UCMD (neonatal onset, severe and progressive course), 10 classical BM (late onset, slowly progressive) and 15 “overlapping” forms (slowly progressive UCMD or markedly progressive BM). Among the UCMD patients, 17 were mutated in COL6A1, 12 in COL6A2 and 10 in COL6A3. Interestingly, 74% of them harboured dominant de novo mutations, mostly in COL6A1, while only 15% of them had recessive mutations. In the others, only one heterozygous mutation was found to date. Among the BM patients, five had a mutation in COL6A1, two in COL6A2 and three in COL6A3 and 70% of them had familial forms. Within the “overlapping” form, 13 patients harboured dominant de novo and recessive mutations (50% each) in COL6A1 and COL6A2 and 2 had mutations in COL6A3. All types of mutations were identified with mainly missense mutations in the triple helical domains and in frame exon skipping (66%). Deletions of COL6A2 exon 5 and COL6A1 exon 14 were detected in the “overlapping” and Bethlem forms. Finally, 50% of patients without mutations were excluded as COL6-related disorders after clinical reassessment and muscle imaging, while the others with compatible presentation warrant further analysis of the COL6 genes. In conclusion, this study on a large cohort reinforces the complexity in the diagnosis of COL6-related disorders. Importantly, genotype/phenotype relationships are emerging, and have a major impact in the prognosis and genetic counseling.