ARHGEF18

Inheritance Pattern: AR

Disease ID:MONDO:0044314

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0044314

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0044314

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: ClinGen

*ARHGEF18* was first described as a retinitis pigmentosa-associated gene in 2017 (Arno et al. 2017, PMID: 28132693). The specific disease entity, retinitis pigmentosa 78 (MIM#: 617433), is one of at least 90 reported forms of retinopathy referred to as retinitis pigmentosa. Some of the most common patient phenotypes include; reduced visual acuity, nyctalopia, optic disc pallor, cystoid macular edema, and photopsia, often with diagnosis in adulthood. For the purposes of this gene curation, cases were lumped under the more inclusive disease term "ARHGEF18-related retinopathy", to acknowledge the potential for a broader spectrum of disease to emerge in association with variants in this gene. This curation includes five variants: (1 missense, 2 nonsense, 1 In-frame multiple-codon deletion, and 1 disrupting splicing) that have collectively been reported in 3 probands in 1 publication (PMID: 28132693). An additional proband harboring two variants in *ARHGEF18* has been considered for inclusion but not scored (PMID: 37217489). Overall, the mechanism of pathogenicity appears to be biallelic loss of function, as shown in the variant types found in the probands. This gene-disease relationship is also supported by multiple forms of experimental evidence including animal models and rescue experiments in medaka fish (PMID: 23698346) and studies characterizing the biochemical function of ARHGEF18. Expression of ARHGEF18 activates RhoA and Rac1 but not cdc42, while ARHGEF18 deletion stops the activation of RhoA and Rac1, indicating a role as a specific guanine nucleotide exchange factor in the pathway establishing apicobasal polarity (PMID: 23698346). Two medaka fish models were generated by chemical mutagenesis screening for defects of retinal epithelial polarity, and were identified with loss-of-function mutations in the *ArhGEF18* gene (PMID: 23698346). The models exhibited aberrant retinal morphologies and retinal pigmentation as well as profound disruption of retinal lamination and retinal polarity. This was recapitulated by morpholino-based silencing of the *ArhGEF18* gene, and could be rescued by injection of mRNA encoding either medaka or human *ARHGEF18* (PMID: 23698346). The concurrence of both rescue models suggests that ARHGEF18 function is conserved throughout vertebrates. These experiments show that ARHGEF18 controls retinal layer organization, which could be related to its role in contributing to cell polarity. In conclusion, ARHGEF18 has moderate evidence of association with ARHGEF18-related retinopathy. This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time without the emergence of contradictory evidence. The publication of additional case reports will be critical for this gene-disease relationship to reach a more definitive classification. This classification was approved by the Retina GCEP on November 7th, 2024 (SOP Version 10).