Submission Details

ARL2BP was first described as a Retinitis Pigmentosa (RP)-causing gene in 2013 (Davidson et al. 2013, PMID: 23849777). Since that time, the range of common patient phenotypes has expanded to include reduced visual acuity, macular atrophy, nyctalopia, photopsia, constriction of peripheral visual field, photophobia, and chorioretinal atrophy. Additional extraocular phenotypes such as situs inversus totalis, asthenozoospermia, or reduced sperm motility have been reported as well. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic ARL2BP loss of function) have been found to be consistent among patients diagnosed with retinitis pigmentosa 82 with or without situs inversus, while the phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic ARL2BP variants have been lumped into a single disease entity, referred to as "ARL2BP-related ciliopathy".

This curation includes 7 variants ( 2 frameshift, 1 missense, and 4 disrupting canonical splice sites) that have collectively been reported in 7 probands in 5 publications (PMID: 23849777, 27790702, 31425546, 36507858, 38649918). All of the included probands were born into consanguineous families, and all were diagnosed during adulthood after experiencing a variety of ocular symptoms during childhood. Overall, the mechanism of pathogenicity appears to be biallelic loss of function, as indicated by the variant types found in the probands.

This gene-disease relationship is also supported by experimental evidence that ARL2BP protein localizes to the base of the cilia in mouse fibroblast cells and human retinal pigment epithelial cells (PMID: 23849777). This matches the localizations of the retinopathy-related gene products RPGR, RP1 and MAK to the ciliary basal body and rootlet (PMID: 29718757). In the absence of ARL2BP, the length and formation of cilia are affected, and photoreceptor outer segment does not develop normally or have correct doublet microtubule formation, axoneme extension, or disk alignment (PMID: 23849777). Multiple mouse knockout models, including a global knockout generated by CRISPR-Cas9, showed loss of photoreceptor nuclei in the outer nuclear layer, consistent with retinal layer atrophy in affected human patients (PMID: 29718757, PMID: 31425546). The mouse model also exhibited situs inversus and immotile sperm (PMID: 31425546).

In conclusion, ARL2BP has a definitive association with ARL2BP-related ciliopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on January 2nd, 2025 (SOP Version 10).