COL5A2 – Classical Ehlers-Danlos Syndrome

Classical Ehlers-Danlos syndrome (cEDS) is a dominantly inherited connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (HP:0000974; HP:0001075; HP:0001382). COL5A2 encodes the α2(V) chain of type V collagen, a minor fibrillar collagen essential for heterotypic fibril formation in skin and other tissues. Pathogenic variants in COL5A2 account for a subset of cEDS cases, with biochemical and histopathological abnormalities reflecting defective collagen V assembly.

Genetic evidence supporting COL5A2 in cEDS includes a cohort of 168 probands and 65 relatives, in which 145 probands harbored type V collagen defects and 24 (16.5%) carried heterozygous COL5A2 variants (PMID:34265140). Identified variant classes comprise missense substitutions, synonymous changes affecting splicing, and in-frame exon deletions. A de novo synonymous variant c.1977G>A (p.Pro659=) was shown by RT-PCR to induce exon 29 skipping, leading to abnormal α2(V) chains and the cEDS phenotype (PMID:33834621). In a human case report, a heterozygous c.1997G>A (p.P659P) variant was associated with classic cutaneous signs in a 30-year-old female (PMID:31517854), while a private missense change c.2366G>T (p.Gly789Val) segregated in a Holstein calf and dam with cEDS-like features, establishing a large-animal model (PMID:33143196).

Segregation analysis across multiple families demonstrates concordant transmission of COL5A2 variants with affected status, totaling 65 additional relatives (PMID:34265140). Penetrance appears high for skin and joint manifestations, though expressivity is variable. No pathogenic loss-of-function variants were reported in homozygosity, consistent with a dominant-negative or haploinsufficiency mechanism.

Functional studies reveal that splice-altering synonymous variants in COL5A2 impair normal mRNA processing, reducing or altering α2(V) secretion and disrupting collagen I/V fibrillogenesis in patient fibroblasts. Histopathology of affected skin shows thin, wavy collagen bundles with abnormal fibril diameters, and animal models recapitulate the skin fragility and hyperextensibility.

No studies refute the association, and no conflicting phenotypes have been assigned to COL5A2 variants in cEDS. While other collagen genes (COL5A1, COL1A1) also contribute to cEDS, COL5A2 is firmly established as a causative gene for ~16% of molecularly confirmed cases.

Integration of genetic and experimental data supports a definitive role for COL5A2 in cEDS. Diagnostic testing should include analysis of COL5A2 for missense, splice, and synonymous variants with in silico and functional validation. Key take-home: COL5A2 sequencing enhances molecular diagnosis and informs surveillance in cEDS patients.

References

• Human Mutation • 2021 • Clinical and molecular characteristics of 168 probands and 65 relatives with a clinical presentation of classical Ehlers-Danlos syndrome. PMID:34265140
• Molecular Genetics & Genomic Medicine • 2021 • Clinical and genetic analysis of classical Ehlers-Danlos syndrome patient caused by synonymous mutation in COL5A2. PMID:33834621
• Animals • 2020 • A Heterozygous Missense Variant in the COL5A2 in Holstein Cattle Resembling the Classical Ehlers-Danlos Syndrome. PMID:33143196
• Medicine • 2019 • A case of Ehlers-Danlos syndrome presenting with widened atrophic scars of forehead, elbow, knee, and pretibial area: A case report. PMID:31517854

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