Submission Details

Knobloch syndrome (KS) was initially described in 1972 by Knobloch and Layer (PMID:4629232) in a non consanguineous family with 5 affected members presenting with high myopia, vitreoretinal degeneration with detachment, occipital encephalocele, pendular nystagmus, reduced central vision and hypoplasia of the macula. First genotype-phenotype association was obtained in 2000 by Sertié et al. (PMID:10942434) when one homozygous splice site pathogenic variant of COL18A1 gene was detected in 12 affected individuals from a consanguineous family. One single report (PMID: 30007336) for autosomal dominant acute angle closure associated with COL18A1 variants in a family with multiple affected members was not included for the purposes of this curation. Recent data report a de novo missense variant in PAK2 gene (Antonarakis et al., 2021, PMID:33693784) in two affected siblings associated with Knobloch type 2 syndrome.

COL18A1 is a heparan sulfate proteoglycan with crucial role in cell-matrix interactions that produces endostatin via proteolytic cleavage. Structurally contains 10 collagenous domains interrupted by 9 non-collagenous domains and N-terminal and C-terminal non collagenous domains. This gene has 2 promoters and produces 3 protein isoforms that differ in their N-terminal non collagenous domain.

Phenotypic variability has been reported in patients carrying pathogenic variants in COL18A1 gene with most patients exhibiting ocular defects, brain malformations, developmental delay and some seizures. The mechanism of pathogenicity is biallelic inherited loss-of-function variants. Twenty five frameshift variants were reported in 48 patients across thirteen publications (PMIDs: 14695535, 35693012, 19160445, 25456301, 32178553, 27259167, 33238767, 29178892, 32700429, 33710595, 34751625, 34680907, 33449584), 1 non frameshift duplication in 1 proband (PMID:35253627), 4 splice site in 18 probands (PMIDs: 10942434, 35693012, 17546652, 27259167), 1 nonsense variant in 1 proband (PMID:34680907) and 5 missense in 8 probands (PMID: 14695535, 12707952, 35253627, 34751625, 34680907). Not all variants from the aforementioned PMIDs were scored because maximum genetic evidence points were reached.

The gene-disease relationship is also supported by the phenotypic similarities of Col18a1-/- mice (PMID: 15254016), the positively co-expression of COL18A1 with other genes known to be implicated in cortical malformation syndromes (PMID: 25456301), as well as the detection of COL18A1 mRNA in in pyramidal neurons of all layers of the cortical plate (PMID: 25456301).

In summary, COL18A1 is definitively associated with autosomal recessive Knobloch syndrome type 1. This has been repeatedly demonstrated and has been upheld over time. This was approved by the ClinGen Brain Malformation GCEP on 28/2/2023.