A novel EYS c.6192-1G>A variant presents ideal base editing therapeutic opportunities

Causal variants in the EYS gene are a major cause of retinitis pigmentosa (RP). However, treatment development for EYS-RP has been hindered due to the large size of the coding sequence and transcriptional complexity of the mRNA. Recently developed adenine base editors (ABEs), a form of CRISPR gene editing, offer another method to develop treatment for genetic diseases caused by G>A point mutations.

This is a retrospective report describing a 73-year-old female with RP, who underwent clinical examination and retinal imaging. Genetic testing included sequencing of 111 known retinal genes and in silico prediction of pathogenicity of the identified variants. Availability and safety of ABE-mediated approaches to correct the patient variant were analyzed.

Clinical evaluation revealed moderately advanced retinitis pigmentosa which had become symptomatic at 35 years of age. Genetic testing revealed a likely pathogenic homozygous EYS c.6192-1 G>A mutation, disrupting a canonical splice acceptor site. As a result, exon skipping with related frameshift deletion and introduction of a premature stop-codon in the forming mRNA is likely, leading to significantly truncated protein or total abolition of translated EYS. Multiple ABE approaches to correct the variant were detected.

In summary, we report a novel splice site variant in EYS in a patient with classical signs of RP. Further research is needed to develop safe and efficient treatment options for EYS-associated RP.