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Epithelial recurrent erosion dystrophy (ERED) is an autosomal dominant corneal dystrophy characterized by recurrent corneal epithelial erosions, subepithelial opacities, and progressive visual impairment. COL17A1 encodes type XVII collagen, a hemidesmosomal transmembrane protein essential for adhesion between the corneal epithelium and basement membrane. A heterozygous synonymous variant, c.3156C>T (p.Gly1052=), was first reported in a Thai pedigree with two affected siblings, shown to introduce a cryptic splice donor and aberrant transcript (PMID:29708937).
Subsequent studies confirmed autosomal dominant segregation of the same c.3156C>T variant in four white families comprising 28 affected and 17 unaffected members, with in vitro assays validating splice‐alteration and keratectomy specimens revealing basement membrane fragmentation (PMID:26786512). A cohort of 15 affected individuals from four Finnish-Swedish families demonstrated age-dependent subepithelial scarring and response to phototherapeutic keratectomy, supporting recurrent founder effect of c.3156C>T across Northern European populations (PMID:37289141). A separate northern Swedish kindred exhibited segregation of a novel missense variant, c.2816C>T (p.Thr939Ile), in a pedigree spanning >200 years (PMID:25676728).
In total, 45 affected individuals across three ancestries harbor the c.3156C>T founder variant, which co‐segregates fully with disease status and is absent in unaffected relatives, underscoring high penetrance. Phenotypic variability in severity and age at onset suggests additional genetic modifiers.
Functional evidence is moderate: in vitro splicing assays demonstrated that c.3156C>T activates a cryptic donor site causing aberrant COL17A1 transcripts, and histopathology of patient keratectomy specimens showed epithelial irregularities, basement membrane breaks, and fibroblast–myofibroblast activation consistent with defective type XVII collagen function (PMID:29708937; PMID:37289141). No studies have refuted the COL17A1–ERED association.
Key Take-home: Heterozygous COL17A1 variants, especially the recurrent founder c.3156C>T splice‐altering allele, are strongly and definitively associated with autosomal dominant ERED. Genetic testing for COL17A1 should be integrated into diagnostic workflows for recurrent corneal erosions to enable precise diagnosis, familial counseling, and targeted interventions such as phototherapeutic keratectomy.
Gene–Disease AssociationStrongEvidence from 45 affected individuals (2 in Thai family (PMID:29708937), 15 in Finnish-Swedish families (PMID:37289141), 28 in four white families (PMID:26786512)); autosomal dominant segregation in multiple pedigrees; recurrent c.3156C>T founder variant Genetic EvidenceStrongAutosomal dominant inheritance with c.3156C>T variant segregating in 45 affected across diverse populations; recurrence in unrelated families Functional EvidenceModerateIn vitro splicing assays demonstrate that c.3156C>T creates a cryptic splice donor leading to aberrant transcripts; patient corneal specimens show basement membrane disruption consistent with COL17A1 dysfunction |