Causative variant profile of collagen VI-related dystrophy in Japan

Abstract

Background Collagen VI-related dystrophy spans a clinical continuum from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy. This disease is caused by causative variants in COL6A1, COL6A2, or COL6A3. Most reported causative variants are de novo; therefore, to identify possible associated causative variants, comprehensive large cohort studies are required for different ethnicities. Methods We retrospectively reviewed clinical information, muscle histology, and genetic analyses from 147 Japanese patients representing 130 families, whose samples were sent for diagnosis to the National Center of Neurology and Psychiatry between July 1979 and January 2020. Genetic analyses were conducted by gene-based resequencing, targeted panel resequencing, and whole exome sequencing, in combination with cDNA analysis. Results Of a total of 130 families with 1–5 members with collagen VI-related dystrophy, 120 had mono-allelic and 10 had bi-allelic variants in COL6A1, COL6A2, or COL6A3. Among them, 60 variants were in COL6A1, 57 in COL6A2, and 23 in COL6A3, including 37 novel variants. Mono-allelic variants were classified into four groups: missense (69, 58%), splicing (40, 33%), small in-frame deletion (7, 6%), and large genomic deletion (4, 3%). Variants in the triple helical domains accounted for 88% (105/120) of all mono-allelic variants. Conclusions We report the causative variant profile of a large set of Japanese cases of collagen VI-related dystrophy. This dataset can be used as a reference to support genetic diagnosis and variant-specific treatment.

A 7‐year‐old female with hypotonia and scoliosis

“…Collagen VI‐related myopathies are known to encompass a clinical continuum with UCMD and Bethlem myopathy (BM) at each end of the spectrum. Collagen VI‐related myopathies are caused by mutations in the triple helical domain (THD) ( 2 ). Collagen VI is an extracellular matrix protein composed of α1, α2, and α3 chains encoded by the COL6A1, COL6A2 , and COL6A3 genes, respectively.…”

“…Collagen VI is an extracellular matrix protein composed of α1, α2, and α3 chains encoded by the COL6A1, COL6A2 , and COL6A3 genes, respectively. Each of the three collagen VI chains has a THD, consisting of 335–336 amino acids with repeating Gly‐Xaa‐Yaa amino acids in the central region ( 1 , 2 ), which is flanked by amino‐ and carboxyl‐globular domains. The three chains are folded, through the interaction at the THD, into collagen VI monomers that are further assembled into dimers and tetramers prior to secretion from cells.…”

“…In the extracellular space, tetramers are associated in an end‐to‐end manner into the characteristic double‐beaded collagen VI microfibrils. Therefore, mutations affecting multiple assembly steps can have strong dominant negative effects, resulting in the absence of collagen VI microfibrils ( 2 ).…”

“…The MRI findings of collagen VI‐related myopathy seem to be highly specific to the disease ( 1 , 2 ). On axial images through the thigh, the periphery of the vastus lateralis was markedly infiltrated by fat, while the central region was spared.…”

“…Furthermore, the central part of the rectus femoris was markedly infiltrated by fat while the periphery was spared. These findings are called “tigroid” and “target” signs ( 1 , 2 ), respectively, with sensitivities of 63.6% and 90.9% and specificities of 97.3% and 96.9% for the diagnosis of collagen VI‐related myopathies ( 1 ). Similarly, at the mid‐calf, the periphery of the soleus and gastrocnemius muscles are also markedly infiltrated by fat ( 2 ).…”