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Spondyloepiphyseal dysplasia congenita (SEDC) is an autosomal dominant chondrodysplasia caused by heterozygous mutations in COL2A1, the gene encoding the type II collagen α1 chain. Affected individuals present at birth with disproportionate short‐trunk dwarfism, platyspondyly, epiphyseal dysplasia, scoliosis and hip dislocation, reflecting aberrant cartilage matrix assembly. Molecular diagnosis relies on detecting pathogenic variants in COL2A1, which cluster in the Gly–X–Y repeat region of the triple helix. Clinical management includes orthopedic monitoring, genetic counselling, and early intervention for extraskeletal complications such as ocular involvement.
Extensive genetic evidence supports a definitive association between COL2A1 and SEDC. Over 136 unrelated probands have been reported with heterozygous COL2A1 mutations in case series and cohort studies ([PMID:26626311]), and familial segregation has been demonstrated in 19 additional affected relatives across multigenerational pedigrees ([PMID:1971141]). The predominant variant class comprises glycine substitutions in the triple‐helical domain, exemplified by c.3589G>C (p.Gly1197Arg) ([PMID:1905723]). These variants occur de novo in most sporadic cases but recur in founder alleles among specific populations.
The variant spectrum of COL2A1 in SEDC is remarkable for glycine‐for‐X substitutions (>100 variants) and occasional small in‐frame deletions or splice‐site changes leading to exon skipping. No bona fide loss‐of‐function alleles have been linked to a recessive SEDC phenotype; instead, dominant‐negative effects predominate. Recurrent hotspots include glycine codons at positions 504, 612, 675 and 989, with genotype–phenotype correlations indicating more severe phenotypes for glycine replacements with larger side chains.
Functional studies confirm a dominant‐negative mechanism. Fibroblast and chondrocyte assays of the p.Arg989Cys substitution demonstrate disulfide‐bonded collagen aggregates and impaired secretion of type II collagen ([PMID:8325895]). In vivo, transgenic mice carrying a Col2a1 C‐propeptide missense mutation (p.Asp1469Ala) exhibit severe spondyloepiphyseal and pelvic dysplasia with endoplasmic reticulum stress and chondrocyte apoptosis, mirroring lethal human forms ([PMID:21538020]). These data underscore the critical role of triple‐helix integrity in cartilage matrix assembly.
No significant conflicting evidence has been reported. All studies consistently link COL2A1 glycine substitutions to SEDC without association to alternative phenotypes. Haploinsufficiency has not been observed; rather, structural disruption of type II collagen is the unifying pathogenic mechanism.
Integrating genetic and experimental findings, heterozygous glycine substitutions in COL2A1 disrupt triple‐helical folding, leading to dominant‐negative interference with cartilage extracellular matrix and resultant chondrodysplasia. The breadth of probands, robust segregation data, and concordant functional assays satisfy ClinGen criteria for a definitive gene–disease relationship. Additional series and functional assays, including in vitro splicing and animal models, further substantiate this classification.
Key Take‐home: SEDC is a clinically and molecularly well‐defined autosomal dominant type II collagenopathy, for which COL2A1 glycine substitutions serve as definitive diagnostic markers with direct implications for patient management and genetic counselling.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong136 probands with heterozygous glycine substitutions; segregation in 19 relatives Functional EvidenceStrongIn vitro assays and transgenic mouse models demonstrate dominant-negative collagen misfolding and ER-stress-mediated apoptosis |