Submission Details

EFEMP1 has been a candidate gene for glaucoma since its identification as an extracellular matrix gene regulated at the expression level by TGFβ2 in trabecular meshwork cells (PMID: 19450457). It was subsequently identified in a genome-wide association screen as a locus associated with optic disc cup area (PMID: 25631615). Variants in EFEMP1 were first reported in relation to open-angle glaucoma in 2015, with the publication of a family with multiple affected members showing onset after age 35 years (Mackay et al., PMID: 26162006). Subsequent publications have established that affected individuals may be diagnosed with open-angle glaucoma either during childhood (PMID: 34923728, PMID: 39264138) or in adulthood, and present with ocular hypertension, optic nerve abnormalities including increased vertical cup-to-disc ratio, reduced visual acuity, and/or peripheral visual field constriction. Publications have also linked monoallelic EFEMP1 variants to the progressive retinal condition Doyne honeycomb degeneration of retina (also known as malattia leventinese, PMID: 10369267). Biallelic EFEMP1 variants have also been linked to the connective tissue disorder cutis laxa type 1D (PMID: 31792352). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, cases of open-angle glaucoma were found to have a molecular mechanism (monoallelic missense or stop-loss variants with enhanced intracellular or endoplasmic reticulum retention) and mode of inheritance (autosomal dominant) that were distinguishable from the biallelic loss-of-function mechanism of autosomal recessive cutis laxa type 1D. Doyne honeycomb degeneration of retina shares the autosomal dominant mode of inheritance and is also characterized by aberrant intracellular accumulation of EFEMP1 protein in the endoplasmic reticulum (PMID: 34923728), however, it has so far been associated with one particular EFEMP1 variant (encoding p.Arg345Trp) and has a very distinct phenotype. While one study has found open-angle glaucoma in an affected individual who also shows severe retinal abnormalities (PMID: 39264138), the phenotype is not a sufficiently clear match for Doyne honeycomb degeneration of retina to conclude that the two conditions are part of the same spectrum of disease. Therefore, cases of open-angle glaucoma caused by monoallelic EFEMP1 variants have been split for curation under a separate disease entity referred to as EFEMP1-related open-angle glaucoma.

Eight suspected disease-causing variants in EFEMP1 have been scored as part of this curation (five missense and three stop-loss). These variants have been collectively reported in nine probands in six publications (PMID: 26162006, PMID: 34923728, PMID: 32476818, PMID: 35946471, PMID: 38083999, PMID: 39264138). All nine probands were heterozygous for their respective variants. Some of these variants have been shown to accumulate intracellularly and/or in the endoplasmic reticulum, and two have been shown to cause disease in animal intravitreal injection models relative to a wild-type control (PMID: 38083999, PMID: 38467175). The mechanism of pathogenicity appears to be monoallelic disruption of EFEMP1 protein localization, possibly leading to loss of retinal ganglion cells (PMID: 38083999).

This gene-disease association is also supported by expression profiling indicating that EFEMP1 has an expression pattern similar to other genes associated with early onset glaucoma, with high levels in beam cells, trabecular meshwork-related cells, and cribiform juxtacanalicular cells (PMID: 34923728). EFEMP1 encodes a glycoprotein component of the extracellular matrix, and functions to contribute to the integrity of basement membrane zones and to anchor other extracellular matrix structures such as elastic fibers to basement membranes. Animal models relevant to open-angle glaucoma are limited to the aforementioned intravitreal injection studies in mice and rats showing progressive increases in intraocular pressure, ganglion cell loss (PMID: 38083999), and increased staining for the extracellular matrix marker fibronectin (PMID: 38467175).

In summary, EFEMP1 has moderate evidence of association with EFEMP1-related open-angle glaucoma. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Moderate classification. Additional genetic evidence from cases with EFEMP1 variants will be required to reach a more definitive classification. This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on December19th, 2024 (SOP Version 11).