Novel COL12A1 variant as a cause of mild familial extracellular matrix‐related myopathy

To the Editor: COL12A1 defects cause extracellular matrix-related myopathy with eight different variants reported so far. The disease manifests mainly with congenital hypotonia, muscular weakness and joints contractures, however, the phenotype differs between patients. We present a Polish family with a novel COL12A1 variant associated with remarkably different phenotypes. The female proband aged 16 months presented with severe hypotonia and decreased spontaneous movements noted after birth. She also had hyperextensible joints, relatively large head, narrow shoulder girdle, sunken lower part of the sternum, widely spaced nipples, umbilical hernia, and prominent calcaneus. The family history elicited from parents at first consultation was negative. Whole-exome sequencing (WES) revealed a variant in COL12A1 (chr6:75829080-C>T (Hg19), NM_004370.5 c.7196G>A, (p. (Gly2399Glu)) which was consistent with proband's phenotype, but present also in her father. The variant was predicted as damaging by DANN, MutationTaster, FATHMM, FATHMM-MKL, MetaSVM, MetalR, MutationAssessor, SIFT, Provean; it was absent from gnomAD database and local database of >1000 Polish samples. We hypothesized that p.(Gly2399Glu) was mosaic in father. However, amplicon deep sequencing (ADS) on father's DNA samples from buccal swab, hair follicles and semen tissue showed the variant in approximately 50% of reads. Next, we tested buccal swab DNA from parents of proband's father (grandparents) and monozygotic twin of proband's father. The p.(Gly2399Glu) was found in twin brother in heterozygous state while it was excluded in both grandparents. Thus, p.(Gly2399Glu) occurred de novo in monozygotic twins. p.(Gly2399) lies in the von Willebrand A domain in a putative binding region for tenascin-X close to MIDAS motif (DXSXSX, residues 2329-2334, graphical abstract, E). These aminoacids are also conserved in collagen XII from other species and their primarily role is metal ion coordination (ie, formation of covalent bond between ion and aminoacid side chains) crucial for binding other proteins. For integrins, the residues Leu203, Leu204, Leu205, and Met140 located close to the MIDAS motif form a solvent-exposed hydrophobic ridge likely contributing to a binding site for integrin partners—intercellular adhesion molecules. For collagen XII this patch is only partially present and comprises of conserved, nonpolar amino acids Gly2398, Gly2399 and Trp2332 (graphical abstract, F). Thus, p.(Gly2399Glu) might weaken the interaction between collagen and its protein partners like tenascin-X. Interestingly, the Ile2334Thr variant located close to Gly2399 was associated with an Ehlers-Danlos-like phenotype in a mechanism of weakened binding of other proteins by disrupting the interactions between the metal ion and MIDAS motif. At the age 4 years proband examination showed pes planovalgus, knee valgus, increased thoracic kyphosis, hyperextension in interphalangeal joints, prominent calcanei (Figure 1A-C). Interestingly, clinical reassessment of proband's father and uncle (aged 34 years) revealed finger flexion contractures and laxity of metacarpal joints in both and an area of atrophic skin in the latter (Figure 1D-J). In conclusion, we confirm the association of COL12A with joint hypermobility phenotypes and emphasize their phenotypic variability.