Allelic Architecture and Clinical Spectrum of RP1-Associated Retinal Dystrophies in a Multicenter Korean Cohort.

PURPOSE: To define the allelic architecture and phenotypic spectrum of RP1-associated retinal dystrophies in a large Korean cohort, emphasizing recurrent truncating alleles, phasing of linked variants, and mobile-element insertions (MEIs) underdetected by standard next-generation sequencing.

METHODS

This retrospective multicenter study included 143 patients with RP1-associated retinopathy sequenced at eight centers in Korea (2002-2025). Clinical findings, multimodal imaging, and electrophysiology were evaluated. Structural variants and allelic phase were assessed using an integrative genomics viewer-based soft-clipping review, Alu-PCR, and long-read whole-genome sequencing (lrWGS) in selected cases. Patients were classified as autosomal-dominant retinitis pigmentosa (AD-RP), autosomal-recessive RP (AR-RP), or recessive macular or cone(-rod) dystrophies.

RESULTS

Twenty-seven RP1 variants were identified, including nine novel alleles. All AD-RP cases were explained by seven exon 4 truncations within the dominant cluster. AR disease was dominated by three highly recurrent truncating alleles: c.4196del (p.Cys1399Leufs*5, carried by 32.2% of patients), the hypomorphic truncation c.5797C>T (p.Arg1933*, 30.8%), and c.6181del (p.Ile2061Serfs*12, 31.5%). The downstream missense variant c.6353G > A (p.Ser2118Asn) was consistently observed in cis with c.4196del, whereas c.4196del also occurred independently; this phase relationship was confirmed by lrWGS. The Alu insertion c.4052_4053ins328 (p.Tyr1352Alafs*9) was carried by 14% of patients. AR-RP presented earlier (mean onset 16.9 vs. 33.5 years, P < 0.001) and had poorer baseline worse-eye best-corrected visual acuity (logMAR, 1.05 vs. 0.44, P = 0.002) than AD-RP.

CONCLUSIONS

This large ancestry-specific RP1-associated retinal dystrophy cohort refines the allelic landscape and underscores the importance of phasing and MEI-aware testing strategies, revealing broad phenotypic expansion to macular and cone(-rod) dystrophies and genotype-dependent severity profiles.