COL5A1 – Ehlers-Danlos syndrome, classic type

Classical Ehlers-Danlos syndrome (cEDS) is an autosomal dominant connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, generalized joint hypermobility, and easy bruising. Consensus diagnostic criteria require major features including marked skin and joint involvement and atrophic “cigarette paper” scars.

Pathogenic variants in COL5A1 underlie ~85% of cEDS cases, primarily through haploinsufficiency mechanisms. In a case report, a novel heterozygous nonsense variant c.379C>T (p.Gln127Ter) segregated with cEDS features in a 4-year-old proband and three affected relatives (mother, uncle, grandfather) (PMID:24001420). Large cohort analyses of 168 probands with molecular confirmation identified COL5A1 defects in 121 individuals, establishing it as the predominant genetic cause (PMID:34265140).

COL5A1 variants span diverse classes: single-nucleotide nonsense and frameshift mutations leading to premature stops, multi-exon deletions and intermediate-sized duplications, canonical splice-site changes, and missense substitutions within collagen helical domains. Recurrent gross deletions and rare duplications further expand the allelic spectrum.

Segregation studies in multiple families demonstrate autosomal dominant inheritance with affected relatives in at least three multigenerational pedigrees (≥5 additional relatives) (PMID:24001420). Functional assays in dermal fibroblasts from 76 individuals revealed decreased expression of one COL5A1 allele, transcript instability, and diminished type V collagen consistent with haploinsufficiency (PMID:19370768).

In vitro splicing analyses of acceptor‐site mutations (e.g., IVS6-2A>G) show exon skipping and aberrant N-propeptide processing, corroborating dominant-negative or null effects. Complementary in vivo and in vitro data align with the human phenotype, supporting the pathogenic mechanism.

Integration of genetic and functional evidence yields a Strong clinical validity classification. Genetic testing for COL5A1 variants enables definitive diagnosis, informs recurrence risk, and guides tailored management and surveillance in cEDS patients.

Key Take-Home: COL5A1 haploinsufficiency is the principal driver of classic Ehlers-Danlos syndrome, with broad allelic heterogeneity and robust functional corroboration underpinning strong clinical utility in diagnostic practice.

References

• Acta dermatovenerologica Croatica • 2013 • Classic Ehlers-Danlos syndrome: case report and brief review of literature. PMID:24001420
• PLoS One • 2011 • A novel splice variant in the N-propeptide of COL5A1 causes an EDS phenotype with severe kyphoscoliosis and eye involvement. PMID:21611149
• Human Mutation • 2009 • Molecular mechanisms of classical Ehlers-Danlos syndrome (EDS). PMID:19370768
• Human Mutation • 2021 • Clinical and molecular characteristics of 168 probands and 65 relatives with a clinical presentation of classical Ehlers-Danlos syndrome. PMID:34265140

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