A hypomorphic variant of choroideremia is associated with a novel intronic mutation that leads to exon skipping

ABSTRACT

Introduction

Molecular confirmation of pathogenic sequence variants in the CHM gene is required prior to enrolment in retinal gene therapy clinical trials for choroideremia. Individuals with mild choroideremia have been reported. The molecular basis of genotype–phenotype associations is of clinical relevance since it may impact on selection for retinal gene therapy.

Methods and Materials

Genetic testing and RNA analysis were undertaken in a patient with mild choroideremia to confirm the pathogenicity of a novel intronic variant in CHM and to explore the mechanism underlying the mild clinical phenotype.

Results

A 42-year-old male presented with visual field loss. Fundoscopy and autofluorescence imaging demonstrated mild choroideremia for his age. Genetic analysis revealed a variant at a splice acceptor site in the CHM gene (c.1350-3C > G). RNA analysis demonstrated two out-of-frame transcripts, suggesting pathogenicity, without any detectable wildtype transcripts. One of the two out-of-frame transcripts is present in very low levels in healthy controls.

Discussion

Mild choroideremia may result from +3 or −3 splice site variants in CHM. It is presumed that the resulting mRNA transcripts may be partly functional, thereby preventing the development of the null phenotype. Choroideremia patients with such variants may present challenges for gene therapy since there may be residual transcript activity which could result in long-lasting visual function which is atypical for this disease.

KEYWORDS:

• Choroideremia
• gene therapy
• splice site mutation
• genetic analysis

Acknowledgments

David Bunyan of Salisbury NHS Trust kindly provided RNA and genetics reports.

Disclosure statement

R.E.M is named inventor on a patent titled “Prenylation assay”, a method for determining the activity of REP1 which was filed on behalf of the University of Oxford (US 2022-0380831). No competing financial interests exist for W.J.W, L.J.T, S.S, F.S, C.M.F.C, J.W, P.C, or I.H.Y.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/13816810.2023.2270554.

Additional information

Funding

This project is funded by the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.