Submission Details

The ELP4 gene was first reported in relation to aniridia in 2013, with the publication of an affected individual harboring a de novo variant within a highly conserved region of intron 9 (PMID: 24290376). Subsequent publications have established that affected individuals may be diagnosed between early childhood and adulthood, and present with bilateral aniridia and in some cases with cataracts (PMID: 17679951, PMID: 22991255, PMID: 26010655). Patients may exhibit foveal hypoplasia, nystagmus, and/or glaucoma as well. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the molecular mechanism (monoallelic disruption of intronic cis elements that are known to regulate expression of the adjacent PAX6 gene) was found to be consistent among the published cases. In addition, the phenotypes appeared to match those of patients with dominant variants in the PAX6 locus itself resulting in aniridia and other forms of eye disease. Therefore, cases of eye disease caused by inherited variants disrupting cis elements located in the ELP4 locus have been curated under a single disease entity referred to as ocular dysgenesis caused by defects in PAX6 regulation.

Five suspected disease-causing variants have been scored as part of this curation (one single nucleotide substitution in intron 9 and four larger deletion variants encompassing the 3’ intronic regions as well as other coding regions of ELP4. These variants have been collectively reported in five probands in four publications (PMID: 24290376, PMID: 17679951, PMID: 22991255, PMID: 26010655). All five probands were heterozygous for their respective variants. While the literature also includes similar cases harboring additional deletion variants encompassing not only intronic elements from ELP4 but also regions of adjacent loci such as PAX6 (PMID: 11087823, ), this curation has focused only on the monogenic cases limited to the ELP4 locus alone. The mechanism of pathogenicity appears to be monoallelic disruption of enhancer elements located in the introns of ELP4 but required for efficient PAX6 transactivation during ocular development through a feed forward mechanism mediated by binding of the PAX6 transcription factor itself (PMID: 24290376). Although co-segregation of the phenotype with the presence of the variant has been observed in at least 2 published families, the family sizes were not sufficient to contribute to the scoring of the gene-disease relationship (PMID: 17679951). Please note that loss-of-function variants within the coding regions of ELP4 are not expected to contribute to eye disease, but may contribute to a separate condition with neurodevelopmental phenotypes and an autosomal recessive mode of inheritance (PMID: 35698786).

This gene-disease association is also supported by biochemical evidence indicating that cis-regulatory elements within the ELP4 introns 7, 8, and 9 function as long-range enhancer elements, essential for normal expression of PAX6 during ocular development (PMID: 17014839, PMID: 24290376). Chromatin immunoprecipitation studies confirm that the PAX6 protein binds to a conserved 800-bp cis element known as SIMO in intron 9 of ELP4 (PMID: 31700164), identifying this sequence as an autoregulatory PAX6 binding site mediating a positive feedback loop. Studies from mice and zebrafish have shown that the SIMO element from ELP4 drives transgenic reporter expression within lens tissue (PMID: 24290376). Mice with a heterozygous deletion encompassing Pax6, Elp4, and other nearby genes have small eyes as well as other phenotypes such as a white belly. Interestingly, the introduction of a transgene containing Pax6 and part of Elp4 including the SIMO region is sufficient to rescue the aniridia, indicating that the rest of Elp4 is dispensable for the ocular phenotype (PMID: 11889558).

In summary, ELP4 has moderate evidence of association with ocular dysgenesis caused by defects in PAX6 regulation. 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 variants limited to the ELP4 locus and confirmed disruption of PAX6 expression 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 November 16th, 2023 (SOP Version 10).