COL18A1 – Knobloch syndrome

Knobloch syndrome is a rare autosomal recessive disorder caused by biallelic pathogenic variants in COL18A1, encoding collagen XVIII and its proteolytic fragment endostatin. First mapped to 21q22.3, pathogenic truncating variants lead to deficiency of collagen XVIII isoforms and endostatin, disrupting fetal vascular regression and ocular development ([PMID:12415512]).

Autosomal recessive inheritance is supported by over 100 reported cases and more than 20 distinct COL18A1 mutations across multiple populations (PMID:32700429). Segregation has been documented in at least 19 additional affected relatives within 7 families, confirming co-segregation of biallelic loss-of-function alleles with disease. Case series include 12 patients from 7 families exhibiting consistent genotype–phenotype correlation ([PMID:27259167]).

Loss-of-function variants predominate the spectrum, with frameshift and nonsense mutations dispersed throughout COL18A1. The recurrent 2-bp deletion c.3523_3524del (p.Leu1175fs) in exon 41 is found in multiple unrelated alleles ([PMID:12415512]). Other reported variants include splice-site, deep-intronic, and large deletions leading to absent endostatin.

Clinically, patients present in infancy or early childhood with high myopia (HP:0011003), vitreoretinal degeneration, and retinal detachment (HP:0000541). Occipital encephalocele (HP:0002085) is variably present. Electrophysiology reveals cone-rod dysfunction and progressive ERG attenuation mirroring findings in Col18a1 knockout mice.

Functional studies demonstrate absence of type XVIII collagen in skin and vascular basement membranes by immunofluorescence, and reduced endostatin binding to extracellular matrix (PMID:19390655). A human iPSC model derived from a Knobloch patient recapitulates collagen XVIII deficiency, offering an in vitro platform for mechanistic and therapeutic research (PMID:37269665).

Taken together, the abundant genetic and experimental evidence over >20 years supports a definitive gene–disease relationship. COL18A1 mutational analysis informs diagnosis, genetic counseling, and management of ocular complications in Knobloch syndrome.

References

• American Journal of Human Genetics • 2002 • Molecular analysis of collagen XVIII reveals novel mutations, presence of a third isoform, and possible genetic heterogeneity in Knobloch syndrome PMID:12415512
• American Journal of Medical Genetics Part A • 2010 • Collagen XVIII mutation in Knobloch syndrome with acute lymphoblastic leukemia PMID:20799329
• JAMA Ophthalmology • 2016 • Molecular and Clinical Findings in Patients With Knobloch Syndrome PMID:27259167
• Molecular Vision • 2009 • Novel pathogenic mutations and skin biopsy analysis in Knobloch syndrome PMID:19390655
• Stem Cell Research • 2023 • Generation of an induced pluripotent stem cell line (ZSZOCi001-A) from a patient with Knobloch syndrome caused by biallelic mutations in the gene COL18A1 PMID:37269665
• American Journal of Medical Genetics Part A • 2020 • Knobloch syndrome in a patient from Chile PMID:32700429

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