Collagen VI and XII related myopathies: clinical variability and novel variants found in Hong Kong patients

Abstract

Objectives: Mutations in the genes encoding collagen VI alpha subunits (COL6A1, COL6A2, COL6A3 and COL12A1) cause severe Ullrich congenital muscular dystrophy (UCMD), mild Bethlem myopathy (BM) and the intermediate (IM) phenotypes. These were not separate entities but represent a continuous clinical spectrum. We analysed the clinical characteristics and the specific neuromuscular investigations findings of the patients with collagen-related myopathy in Hong Kong. Methods: This is a retrospective study. The clinical, histological, radiological and genetic characteristics in 12 patients with collagen-related myopathy confirmed with variants in the COL6A1, COL6A2, COL6A3 and COL12A1 genes were reviewed and illustrated. Results: Among 12 patients with collagen-related myopathies, 4 (33.3%) patients had the phenotype of typical UCMD, 3 (25%) patients showed IM phenotype and 5 (41.7%) patients had the BM phenotype. The mutations in COL6A1 (n=5), COL6A2 (n=4), COL6A3 (n=3) and COL12A1 (n=1) included 7 missense variants, 1 nonsense variant, 1 frameshift variant, 1 in-frame deletion, 1 deep-intronic pseudo-exon inserting variant and 2 variants destroying the splice sites leading to exon skipping. Eleven variants (11/13, 84.6%) are dominant negative, of which 10 are de novo, and 2 variants are autosomal recessive. For the 12 variants identified in collagen VI gene in 11 patients, majority (10/12, 83.3%) are located at THD and 2 are located at C-terminal. Three novel variants have been found in the patients including an in-frame mutation [c.1084_1092del, p.(Ser362_Gly364del)] and a missense mutation [c.811G>C, p.(Gly271Arg)] located at THD of COL6A2, both leading to UCMD phenotypes, and a truncating variant [c.9113dupC, p.(Gly3039argfs*7)] of COL12A1 leading to BM phenotype. Those patients with muscle biopsies had findings showing distinct pathological features. Muscle MRI studies also revealed selective pattern of leg muscle involvement. Conclusions: Collagen-related myopathy with characteristic features are not uncommon in Hong Kong. We found the dominant negative mutations in the THD of the three collagen VI genes in our patients, with a spectrum of mild to severe presentation, are the most common mutations associated with this condition. Genotypic-phenotypic correlation is found in some but not all cases. Muscle MRI and muscle biopsy gives diagnostic clues to guide genetic diagnosis. Diagnosis of deep intronic pseudo-exon inserting variant could be challenging.