CHST14 and Musculocontractural Ehlers-Danlos Syndrome

This report reviews the association between CHST14 and musculocontractural Ehlers-Danlos syndrome, a connective tissue disorder characterized by multiple congenital malformations and progressive fragility of skin and joints. The evidence spans multiple case reports and multi‐patient studies that consistently identify pathogenic variants in CHST14, supporting its critical role in the correct biosynthesis of dermatan sulfate. The clinical presentations include joint hypermobility, skin fragility, abnormal facial features, and congenital contractures, underscoring a broad phenotypic spectrum (PMID:22581468).

Genetic studies have reported numerous distinct variants in CHST14, with several independent families demonstrating segregation of these alleles with the disease phenotype. For example, the variant c.821G>C (p.Arg274Pro) is representative of the spectrum that includes missense, nonsense, and frameshift mutations. In multi‐patient studies, more than 60 patients from diverse ethnic backgrounds were evaluated, and the consistent identification of pathogenic variants in CHST14 provides robust support for a strong gene–disease association (PMID:34815299).

The genetic evidence is further bolstered by segregation data, with affected relatives in extended pedigrees demonstrating co‐segregation of CHST14 variants. Multiple case series have described familial occurrences where both consanguineous and non‑consanguineous unions yielded affected probands with demonstrable biallelic mutations in CHST14. This convergence of case reports, variant classification, and consistent segregation patterns reinforces a strong level of genetic evidence (PMID:35464846).

Functional studies substantially support the pathogenic mechanism underlying this condition. Experimental models, including Chst14 knockout and CRISPR/Cas9-edited mouse models, have shown that loss-of-function leads to depletion of dermatan sulfate, disorganized collagen network formation, and skin fragility. In vitro fibroblast analyses demonstrate that altered extracellular matrix assembly is central to the disease phenotype. These findings are concordant with the clinical observations and confirm that impaired dermatan sulfate biosynthesis is the fundamental mechanism of pathogenicity (PMID:32601684; PMID:34850861).

There are minor reports of phenotypic variability, and in some instances, additional genes such as DSE have been implicated in overlapping connective tissue disorders. However, the vast majority of evidence attributes the core musculocontractural phenotype to biallelic loss-of-function mutations in CHST14. No studies have convincingly refuted the association, and any discrepancies are outweighed by the combined genetic and functional data.

In summary, the integration of robust case-level genetic data with compelling functional evidence firmly supports a strong gene–disease association for CHST14 in musculocontractural Ehlers-Danlos syndrome. The well-characterized mutation spectrum alongside mechanistic insights into impaired dermatan sulfate formation provides essential information for diagnostic decision-making, commercial assay development, and further research. Key take‑home: CHST14 mutation screening is critical for accurate diagnosis, prognosis, and management of musculocontractural Ehlers-Danlos syndrome.

References

• American journal of medical genetics. Part A • 2012 • Extracellular matrix and platelet function in patients with musculocontractural Ehlers-Danlos syndrome caused by mutations in the CHST14 gene PMID:22581468
• Frontiers in genetics • 2022 • Case Report: A Novel Mutation Identified in CHST14 Gene in a Fetus With Structural Abnormalities PMID:35464846
• Journal of medical genetics • 2022 • Clinical and molecular features of 66 patients with musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14) PMID:34815299
• Glycobiology • 2021 • Systematic investigation of the skin in Chst14-/- mice: A model for skin fragility in musculocontractural Ehlers-Danlos syndrome caused by CHST14 variants (mcEDS-CHST14) PMID:32601684
• Disease models & mechanisms • 2021 • A new mouse model of Ehlers-Danlos syndrome generated using CRISPR/Cas9-mediated genomic editing PMID:34850861
• Human mutation • 2010 • Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome PMID:20533528

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