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Novel defects in collagen XII and VI expand the mixed myopathy/Ehlers–Danlos syndrome spectrum and lead to variant-specific alterations in the extracellular matrix

Author
Organization
Abstract
Purpose To date, heterozygous or homozygous COL12A1 variants have been reported in 13 patients presenting with a clinical phenotype overlapping with collagen VI–related myopathies and Ehlers–Danlos syndrome (EDS). The small number of reported patients limits thorough investigation of this newly identified syndrome, currently coined as myopathic EDS. Methods DNA from 78 genetically unresolved patients fulfilling the clinical criteria for myopathic EDS was sequenced using a next-generation panel of COL12A1, COL6A1, COL6A2, and COL6A3. Results Among this cohort, we identified four pathogenic heterozygous in-frame exon skipping (∆) defects in COL12A1, clustering to the thrombospondin N-terminal region and the adjacent collagenous domain (Δ52, Δ53, Δ54, and Δ56 respectively), one heterozygous COL12A1 arginine-to-cysteine substitution of unclear significance (p.(Arg1863Cys)), and compound heterozygous pathogenic COL6A1 variants (c.[98–6G>A];[301C>T]) in one proband. Variant-specific intracellular accumulation of collagen XII chains, extracellular overmodification of the long isoform and near-absence of the short isoform of collagen XII, and extracellular decrease of decorin and tenascin-X were observed for the COL12A1 variants. In contrast, the COL6A1 variants abolished collagen VI and V deposition and increased tenascin-X levels. Conclusion Our data further support the significant clinical overlap between myopathic EDS and collagen VI–related myopathies, and emphasize the variant-specific consequences of collagen XII defects.
Keywords
myopathic Ehlers–Danlos syndrome, collagen VI, collagen XII, myopathy, connective tissue

Citation

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Chicago
Delbaere, Sarah, Tibbe Dhooge, Delfien Syx, Florence Petit, Nathalie Goemans, Anne Destrée, Olivier Vanakker, Riet De Rycke, Sofie Symoens, and Fransiska Malfait. 2019. “Novel Defects in Collagen XII and VI Expand the Mixed myopathy/Ehlers–Danlos Syndrome Spectrum and Lead to Variant-specific Alterations in the Extracellular Matrix.” Genetics in Medicine.
APA
Delbaere, S., Dhooge, T., Syx, D., Petit, F., Goemans, N., Destrée, A., Vanakker, O., et al. (2019). Novel defects in collagen XII and VI expand the mixed myopathy/Ehlers–Danlos syndrome spectrum and lead to variant-specific alterations in the extracellular matrix. Genetics in Medicine.
Vancouver
1.
Delbaere S, Dhooge T, Syx D, Petit F, Goemans N, Destrée A, et al. Novel defects in collagen XII and VI expand the mixed myopathy/Ehlers–Danlos syndrome spectrum and lead to variant-specific alterations in the extracellular matrix. Genetics in Medicine. 2019;
MLA
Delbaere, Sarah et al. “Novel Defects in Collagen XII and VI Expand the Mixed myopathy/Ehlers–Danlos Syndrome Spectrum and Lead to Variant-specific Alterations in the Extracellular Matrix.” Genetics in Medicine (2019): n. pag. Print.
@article{8623773,
  abstract     = {Purpose
To date, heterozygous or homozygous COL12A1 variants have been reported in 13 patients presenting with a clinical phenotype overlapping with collagen VI–related myopathies and Ehlers–Danlos syndrome (EDS). The small number of reported patients limits thorough investigation of this newly identified syndrome, currently coined as myopathic EDS.

Methods
DNA from 78 genetically unresolved patients fulfilling the clinical criteria for myopathic EDS was sequenced using a next-generation panel of COL12A1, COL6A1, COL6A2, and COL6A3.

Results
Among this cohort, we identified four pathogenic heterozygous in-frame exon skipping (∆) defects in COL12A1, clustering to the thrombospondin N-terminal region and the adjacent collagenous domain (Δ52, Δ53, Δ54, and Δ56 respectively), one heterozygous COL12A1 arginine-to-cysteine substitution of unclear significance (p.(Arg1863Cys)), and compound heterozygous pathogenic COL6A1 variants (c.[98–6G>A];[301C>T]) in one proband. Variant-specific intracellular accumulation of collagen XII chains, extracellular overmodification of the long isoform and near-absence of the short isoform of collagen XII, and extracellular decrease of decorin and tenascin-X were observed for the COL12A1 variants. In contrast, the COL6A1 variants abolished collagen VI and V deposition and increased tenascin-X levels.

Conclusion
Our data further support the significant clinical overlap between myopathic EDS and collagen VI–related myopathies, and emphasize the variant-specific consequences of collagen XII defects.},
  author       = {Delbaere, Sarah and Dhooge, Tibbe and Syx, Delfien and Petit, Florence and Goemans, Nathalie and Destrée, Anne and Vanakker, Olivier and De Rycke, Riet and Symoens, Sofie and Malfait, Fransiska},
  issn         = {1098-3600},
  journal      = {Genetics in Medicine},
  keywords     = {myopathic Ehlers–Danlos syndrome,collagen VI,collagen XII,myopathy,connective tissue},
  language     = {eng},
  title        = {Novel defects in collagen XII and VI expand the mixed myopathy/Ehlers–Danlos syndrome spectrum and lead to variant-specific alterations in the extracellular matrix},
  url          = {http://dx.doi.org/10.1038/s41436-019-0599-6},
  year         = {2019},
}

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