Skip to content

Researchers at Moorfields Eye Hospital have reported valuable genotype-phenotype correlations on KCNV2-associated retinopathy  

Researchers have published a study showing that genetic missense alterations on KCNV2-asscociated retinopathy may appear to hold better visual acuity and greater structural integrity (Guimaraes et al., 2023, Br J Ophthalmol., Such data provides important patient prognostication and counselling support, as well as stratification for potential gene therapy trials.  Commenting on their study, their researchers stated that ”due to the inherent clinical heterogeneity of IRDs, establishing genotype–phenotype correlations is a crucial step in counselling and clinical management of these disorders, as it carries direct prognostic implications”.

KCNV2-asscociated retinopathy autosomal recessive cone-rod dystrophy with pathognomonic electroretinogram (ERG) with an estimated frequency of 1/865,000 in the US population, and with an incidence of 5 new cases per year (reported in 1983).  The relevant gene – KCNV2 – encodes Kv8.2, a voltage-gated potassium channel subunit that “acts as a modulator by shifting the activation range of the K+ channels in photoreceptor inner segments”.  KCNV2 is a 2-exon gene encoding a 545 amino acid protein and is predominantly expressed in the heart and retina. As of to date, there are no current treatments available for patients diagnosed of the disorder however, there is significant research in progress, not least of all the collection of data from natural history studies, which will be highly relevant for any future trials.

While the electrophysiology, retinal imaging and clinical course of the disease have been well described in the literature, genotype–phenotype correlations have not been elucidated to date. Results from the study this month has shown that the research team looked at a cohort of 92 patients, catalouging mutations with two loss-of-function changes (TLOF), two missense mutations (TM) or one of each missense and one loss-of-function variants (MLOF), then correlated these genotypes to visual acuity (logMAR BCVA).  Following their evaluation, the clinical researchers stated that, “the most common type of variant combination in our cohort was TLOF variants—present in approximately 60% (n=55) of the 92 patients included in this report. Our analysis suggests a milder phenotype for patients with TM variants, including better BCVA and greater EZ (ellipsoid zone) preservation. The majority of the patients had a disease onset in infancy and at similar ages; even though patients with TLOF variants had the earliest mean age of onset at 3.1 years, this did not reach statistical significance compared with the other groups (p=0.19). Patients with TM variants had an overall statistically significant better BCVA (p=0.03 and 0.035 in right and left eyes, respectively), despite presenting at a similar age. In addition, a smaller proportion of these patients had associated symptoms, such as nyctalopia and photophobia”.  Accordingly, the research paper further commented that, “we provide evidence that individuals with two missense variants in trans had a better best-corrected visual acuity and more preserved structural integrity. Data from this study will arm clinicians with more informed tools for patient prognostication and counselling, as well as assist in patient stratification for future clinical trials”.