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Autosomal dominant retinitis pigmentosa (adRP) is characterized by progressive photoreceptor degeneration leading to nyctalopia and peripheral visual field loss. ARL3 (ADP-ribosylation factor-like 3) has emerged as a novel adRP gene based on exome sequencing in small pedigrees.
In 2016, Strom et al. identified a de novo ARL3 missense variant c.269A>G (p.Tyr90Cys) in the index of a three-member family (mother and two affected offspring) with adRP ([PMID:26964041]). Follow-up Sanger screening in 94 additional RP pedigrees revealed no further ARL3 variants, indicating extreme rarity of ARL3-related adRP ([PMID:26964041]).
A second unrelated family was reported in 2019, confirming the same c.269A>G (p.Tyr90Cys) variant in a sporadic index and his affected son with non-syndromic adRP and early central vision loss, central retinal thinning and cataract ([PMID:30932721]). This variant occurred de novo in each index case and segregated with disease in five total affected individuals across both families.
Structural analysis of Tyr90 in ARL3 revealed disruption of α/β core packing upon cysteine substitution, predicting impaired folding and stability ([PMID:30932721]). No functional rescue or animal models have yet been reported.
The ARL3 c.269A>G (p.Tyr90Cys) variant is absent from population databases and undetected in large RP cohorts, supporting pathogenicity. Despite limited case numbers, the consistency of de novo occurrence, familial segregation, absence in controls, and concordant structural modelling justify a moderate level of clinical validity.
Key Take-home: Heterozygous ARL3 c.269A>G (p.Tyr90Cys) causes a rare form of autosomal dominant retinitis pigmentosa, meriting inclusion in diagnostic gene panels for early detection of adRP.
Gene–Disease AssociationModerateFive affected individuals across two unrelated families with de novo occurrence and segregation; absent in large control cohorts Genetic EvidenceModerateTwo independent de novo variant occurrences and co-segregation in five affected individuals; variant not observed in 94+431 RP patients Functional EvidenceLimited3D structural modelling demonstrates disrupted α/β core packing and predicted instability |