ELP4

Inheritance Pattern: AD

Disease ID:MONDO:0700246

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0014937

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0014937

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0024507

Submitter: Labcorp Genetics (formerly Invitae)