Submission Details

Pathogenic variants in the CYP1B1 gene were first described as a cause of primary congenital glaucoma (PCG) by Stoilov et al. in 1997 (PMID: 9097971), through genetic linkage analysis and mutation screening. PCG pathogenicity in patients is associated with the presence of CYP1B1 variants in the homozygous or compound heterozygous state. The clinical features of the disease include increased intraocular pressure, increased corneal diameter, enlarged globe, Haab striae (breaks in Descemet’s membrane), corneal edema, and optic nerve head cupping. Although most CYP1B1 variants are associated with PCG, variants have been also described causing other disease phenotypes including aniridia (PMID:23767995; PMID:24001018), anterior segment dysgenesis 6 (ASGD6, OMIM #617315), Peter’s anomaly (PA, OMIM #617315), and primary open angle glaucoma with adult or juvenile onset (POAG, JOAG; OMIM# 231300; PMID: 24099281; PMID: 19643970). It is important to note, however, that the same variants can be associated with different disease phenotypes (PMID: 17914928), and that diverse disease phenotypes can occur among members of the same family (PMID: 26164761) or within the same individual (PMID: 20827438). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, these findings as well as the similarities in inheritance pattern were found to point to a single disease spectrum rather than multiple distinct disease entities. For the purposes of this curation, this lumped disease entity has been referred to as CYP1B1-related glaucoma with or without anterior segment dysgenesis.

More than 82 variants have been described in the literature (PMID: 17914928). Ten disease-causing variants were scored as part of this curation, which have been recurrently identified in multiple probands having different phenotypes (e.g. ASD6, PCG, PA, POAG) and have been shown in vivo to impair the proper functioning of the protein. Pathogenicity of the variants follows an autosomal recessive mode of inheritance in probands. The mechanism of pathogenicity includes missense, nonsense, and frameshift variants that disrupt or abolish protein function by reducing enzymatic activity (e.g p.Glu387Lys), decreasing protein stability (e.g. p.Pro437Leu), or triggering truncation of the protein product (e.g p.Ala179fs). The variants are observed at a low frequency that is consistent with the disease penetrance.

Experimental evidence indicates that CYP1B1 encodes a protein that is a member of the P450 family of enzymes which are involved in the metabolism of steroids, fatty acids, and retinoids. CYP1B1 is highly expressed in the iris and ciliary body of the human eye. CYP1B1 is hypothesized to participate in the metabolism of a substrate that is important for the normal development and functioning of the anterior segment of the eye, which is further supported by evidence showing a higher expression of this gene in fetal than in adult eyes. Functional, functional alteration and animal models indicate that variants in CYP1B1 interfere with the normal metabolism of other proteins known to be involved in pathogenesis (e.g. upregulation of MYOC, PMID: 23028769), result in disruption of microfibril fibers in the extracellular matrix in glaucoma patients compared to controls, or alter CYP1B1 expression in cultured cells resulting in lower protein activity and instability. Mice deficient in Cyp1b1 expression show abnormalities during development of the ocular tissue (e.g. increased collagen loss resulting in severe atrophy of the trabecular meshwork in mice, PMID 24879660).

In summary, CYP1B1 is definitively associated with autosomal recessive CYP1B1-related glaucoma with or without anterior segment dysgenesis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on January 19th, 2023 (SOP Version 9).