AIPL1 was first reported in relation to autosomal recessive Leber congenital amaurosis in 2000 (Sohochi et al., PMID: 10615133). AIPL1 has been associated with autosomal recessive cone-rod dystrophy, juvenile retinitis pigmentosa, and Leber congenital amaurosis [OMIM#604393]. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, the aforementioned disease entities have been lumped into one disease entity, AIPL1-related retinopathy.
11 variants (of variant types including missense, deletion, nonsense, and frameshift) that have been reported in nine probands in four publications (PMIDs: 10615133, 25596619) are included in this curation. Notably, the c.834G>A (p.Trp278Ter) nonsense variant (ClinVar variation ID: 5565) has been reported to be a common variant in this gene (Aboshiha et al., PMID: 25596619). Functional studies have demonstrated that this p.Trp278Ter nonsense variant alters cellular function, affecting the modulation of NUB1, a downstream target of AIPL1 (van der Spuy et al., PMID: 15347646). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Additional functional studies have demonstrated that missense variants (such as c.784G>A (p.Gly262Ser)) can lead to abnormal splicing of transcript (Bellingham et al., PMID: 26650897).
This gene-disease association is also supported by mouse models, in which AIPL1-deficient mice have displayed retinal degeneration (Dyer et al., PMIDs: 15582159).
In summary, AIPL1 is definitively associated with AIPL1-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on February 2nd, 2023 (SOP Version 9).
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