Novel founder variant in the S-antigen visual arrestin gene SAG is the most prevalent cause of autosomal dominant retinitis pigmentosa in Singaporean Chinese.

Abstract

Purpose: To characterise a novel founder variant in the SAG gene causing autosomal dominant retinitis pigmentosa (AD-RP) in Singaporean Chinese individuals.

Design: Single-centre prospective observational cohort study.

Methods: Unrelated probands with AD-RP and their affected relatives were recruited from a tertiary eye hospital in Singapore. Genetic analysis was performed using whole exome sequencing and targeted gene panel testing. Clinical phenotyping included best-corrected visual acuity (BCVA), multimodal imaging and visual field assessments. In silico analyses were conducted to assess variant pathogenicity and conservation.

Results: We identified a novel heterozygous SAG variant, NM_000541.5:c.442G>A (p.Gly148Arg), in five unrelated families of Southern Chinese descent. A shared haplotype of 3.2 Mb among four families suggested a founder effect. Affected individuals presented with mid-life onset nyctalopia (median age 44 years), progressive BCVA loss after age 40 and severe visual field constriction by the fifth decade. Fundus imaging revealed diffuse retinal pigment epithelium atrophy and perivascular pigmentation. In silico predictions suggest that p.Gly148Arg disrupts conformational changes that are required for rhodopsin modulation.

Conclusion: The SAG c.442G>A (p.Gly148Arg) variant represents the first reported SAG-related AD-RP founder variant in ethnic Chinese individuals. Its phenotypic resemblance to the previously described SAG c.440G>T (p.Cys147Phe) variant underscores a common disease mechanism. These findings expand the genetic landscape of AD-RP and highlight SAG as a potential therapeutic target.