COL18A1 – Knobloch syndrome 1

COL18A1 encodes type XVIII collagen, a multiplexin involved in basement membrane integrity and endostatin production. Knobloch syndrome 1 (KS1) is an autosomal recessive ocular and occipital encephalocele disorder characterized by high myopia, chorioretinal atrophy, reduced visual acuity, and occipital skull defects. Clinical heterogeneity and rarity complicate diagnosis. Biallelic COL18A1 pathogenic variants have been consistently reported in KS1 cases. This summary evaluates evidence supporting the COL18A1–KS1 association and its utility in diagnostic workflows.

Multiple independent studies have identified biallelic COL18A1 variants in at least nine unrelated probands from six families, with segregation analyses confirming autosomal recessive transmission in trans in affected sibships (PMID:39457419; PMID:25392994; PMID:19390655). Recurrent alleles and absence of these variants in population controls further support causality. Functional histology and molecular assays align with a loss-of-function mechanism. No refuting reports have emerged. These data fulfill ClinGen Strong criteria for gene–disease validity.

Inheritance is autosomal recessive. To date, nine probands across six unrelated families harbor compound heterozygous or homozygous COL18A1 variants. The variant spectrum includes frameshift indels (c.2673dup; c.1637_1638dup; c.2823dup) and splice-site disruption (c.929-2A>G) (PMID:39457419; PMID:25392994; PMID:19390655), the recurrent two-base deletion c.3523_3524del (p.Leu1175fs) (PMID:39457419), nonsense mutations (c.3277C>T), and missense substitutions (c.3778G>A [p.Asp1260Asn]) (PMID:19390655). No large rearrangements or deep-intronic variants have been documented. Population databases lack these alleles at appreciable frequency. Penetrance appears complete in individuals with biallelic loss-of-function alleles.

Functional studies demonstrate absence of type XVIII collagen in patient skin biopsies by immunofluorescent histochemistry (PMID:19390655). In vitro binding assays of the p.Ala1381Thr endostatin variant revealed reduced affinity for extracellular matrix components (PMID:19390655). Characterization of NC1 domain isoforms and proteolytic processing highlights the importance of the frizzled-like motif in tissue localization (PMID:14614989). Patient-derived iPSC lines recapitulate ocular phenotypes in vitro (PMID:37269665). Collectively, these data support a loss-of-function mechanism via impaired basement membrane integrity.

No studies have refuted the COL18A1–KS1 association. Identification of PAK2 variants in Knobloch syndrome type 2 defines a separate phenotype and does not challenge COL18A1 involvement in KS1 (PMID:33693784). The absence of neurological manifestations across KS1 cohorts suggests phenotypic homogeneity. Observed variability likely reflects genetic modifiers rather than alternative gene etiologies. Current evidence does not support a disputed classification.

Collectively, genetic, segregation, and experimental data converge to define KS1 as resulting from autosomal recessive COL18A1 loss of function. The recurrent c.3523_3524del frameshift allele simplifies molecular diagnosis across populations. Ocular and skull findings correlate with basement membrane disruption by mutant type XVIII collagen. Although additional modifiers may influence severity, the evidence cap for clinical validity has been reached. Further animal models and rescue studies could expand mechanistic insight. Key take-home: inclusion of COL18A1 sequencing, targeting recurrent and private loss-of-function variants, is critical for the diagnosis of Knobloch syndrome 1.

References

• Genes • 2024 • Clinical and Molecular Findings in Patients with Knobloch Syndrome 1: Case Series Report. PMID:39457419
• PLoS One • 2014 • Homozygosity mapping and whole exome sequencing reveal a novel homozygous COL18A1 mutation causing Knobloch syndrome. PMID:25392994
• Molecular vision • 2009 • Novel pathogenic mutations and skin biopsy analysis in Knobloch syndrome. PMID:19390655
• Matrix biology • 2003 • Characterization of the human type XVIII collagen gene and proteolytic processing and tissue location of the variant containing a frizzled motif. PMID:14614989
• 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
• Human molecular genetics • 2021 • Dominant monoallelic variant in the PAK2 gene causes Knobloch syndrome type 2. PMID:33693784

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