Intrafamilial phenotypic variability in a large family with autosomal dominant RP1 associated Retinitis pigmentosa, and novel RP1 variants in autosomal recessive RP

Abstract

Purpose : Sequence variants in the RP1 gene account for a significant proportion of autosomal dominant (AD) cases, but are also found in autosomal recessive (AR) RP. No gene therapy has been developed so far for RP1 associated RP that shows a varying degree of severity. We investigated the phenotypic and genotypic differences of a large family with AD RP1 associated RP, and a family with compound recessive variants in RP1.

Methods : Clinical data from comprehensive ophthalmic exams, including multi-modal imaging and full-field ERG, were collected for all patients. Whole exome sequencing was performed for genomic analysis. The full length RP1 gene was cloned into an expression plasmid. Reference RP1 and mutant variants were expressed in cells and analyzed by Western blot and confocal microscopy for localization.

Results : The large Swiss family carrying an already described dominant RP1 variant showed varying degree of disease severity from almost complete loss of central vision at age 50 years to conservation of full central function at a similar age. The RP1 family with a recessive trait revealed two novel, compound heterozygous variants . The patient presented a typical RP phenotype with significant nyctalopia in early adulthood, and advanced visual field constriction. Autofluorescence showed a characteristic hyperautofluorescent perifoveal ring. The OCT confirmed retained photoreceptor layers at the fovea, and loss of the photoreceptor and outer nuclear layer outside of it. The father carrying the recessive frameshift variant did not show any signs of RP both clinically and electrophysiologically. The truncated RP1 from the AR family showed an increased nuclear localization, whereas the truncated protein from the AD family seems to be expressed more similar than the reference RP1 within the cell.

Conclusions : Frameshift variants in exon 4 of RP1 appear to not always be disease causing. The variant in the AD family appears to be quite frequent in patients of Swiss origin, and shows a great intrafamilial phenotypic variability. The variant in the AR family did not cause disease in the heterozygous state, but compound heterozygous state. Localization of expressed RP1 variants seems to differ according to their mode of inheritance. These observations are of utmost important when considering future therapeutic approaches.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.