Genetic and clinical findings in a Chinese cohort of patients with collagen VI‐related myopathies

Abstract

Collagen VI-related myopathy, caused by pathogenic variants in the genes encoding collagen VI, represents a clinical continuum from Ullrich congenital muscular dystrophy (UCMD) to Bethlem myopathy (BM). Clinical data of 60 probands and their family members were collected and muscle biopsies of 26 patients were analyzed. COL6A1, COL6A2 and COL6A3 exons were analyzed by direct sequencing or next generation sequencing (NGS). Sixty patients were characterized by delayed motor milestones, muscle weakness, skin and joint changes with 40 UCMD and 20 BM. Muscle with biopsies revealed dystrophic changes and showed completely deficiency of collagen VI or sarcolemma specific collagen VI deficiency. We identified 62 different pathogenic variants in these 60 patients, with 34 were first reported while 28 were previously known; 72 allelic pathogenic variants in COL6A1 (25/72, 34.7%), COL6A2 (33/72, 45.8%) and COL6A3 (14/72, 19.4%). We also found somatic mosaic variant in the parent of 1 proband by personal genome machine amplicon deep sequencing for mosaicism. Here we provide clinical, histological and genetic evidence of collagen VI-related myopathy in 60 Chinese patients. NGS is a valuable approach for diagnosis and accurate diagnosis provides useful information for genetic counseling of related families.

Congenital muscular dystrophies in China

“…Inclusion criteria . (a) Evidence of muscle weakness and hypotonia, with diminished or no tendon reflexes at birth or in the first 2 years; however, as in some CMD subtypes (eg, COL6‐related CMD), the onset can be delayed. (b) Clinical features consistent with congenital muscular dystrophy, such as delayed gross motor milestones, congenital/early contractures or scoliosis.…”

“…Candidate gene testings including Sanger sequencing to amplify the open reading frame and intron/exon boundaries, long‐range polymerase chain reaction (PCR) to detect the highly recurrent intronic mutation in COL6A1 , a three PCR‐primer method to detect the retrotransposition element insertion in FKTN and multiplex ligation‐dependent probe amplification or array‐based comparative genomic hybridization to detect copy number variations were performed on the basis of clinical phenotype. The methods have been reported for LAMA2 , the three collagen VI genes, POMT1 , FKRP , POMT2 , FKTN , POMGNT1 , and LMNA …”

“…Immunohistochemical staining of the biopsied muscle for laminin α2, glycosylated α‐dystroglycan, and collagen VI was performed using previously reported methods. Probands were classified as having laminin α2 deficiency, α‐dystroglycanopathy, or collagen VI‐related myopathy if their biopsy showed moderate to severely reduce or no staining.…”

“…Candidate gene testings including Sanger sequencing to amplify the open reading frame and intron/exon boundaries, long-range polymerase chain reaction (PCR) to detect the highly recurrent intronic mutation in COL6A1, a three PCR-primer method to detect the retrotransposition element insertion in FKTN and multiplex ligationdependent probe amplification or array-based comparative genomic hybridization to detect copy number variations were performed on the basis of clinical phenotype. The methods have been reported for LAMA2 13 , the three collagen VI genes 12 For the myopathy-related next-generation sequencing (NGS) custom-designed panels, the NGS approach used was based on the evolving availability of different NGS approaches over the course of the study (supporting information, Figure S1). Between 2013 and 2018, the panel was constantly updated, and four different versions of the panel were used.…”

Mutation Profile of Collagen VI-Related Myopathy in Japan

“…UCMD is the second-most common CMD in Japan [3]. In a study of the population in northern England, prevalence of UCMD was 0.13 cases per 100,000, whilst the prevalence of BM was 0.77 cases per 100,000 [4].Collagen VI-related myopathy shows characteristic clinical phenotypes, which include proximal muscle weakness, skin and joint changes, scoliosis, and respiratory failure [1,5,6]. Muscle pathology encompasses variable histological changes including ber size variation, an increased number of internal nuclei, and disproportionately prominent endomysial connective tissue considering the relative scarceness of necrotic and regenerating bers [2,7].…”