Abstract
Purpose :
To describe the phenotypic and genotypic findings in two siblings with a severe cone dystrophy and electroretinogram (ERG) findings characteristic of CDSRR.
Methods :
Over 1600 genetic retinopathy patients attending the Genetic Eye Disease Service at the Royal Victoria Eye and Ear Hospital, Dublin, have been recruited prospectively as part of Target 5000. Testing includes: best-corrected visual acuity (BCVA), Goldmann perimetry, Lanthony D15 colour vision, slit-lamp biomicroscopy, ISCEV clinical standard electrodiagnostics, colour and autofluorescence fundus photography and optical coherence tomography. DNA samples undergo exon sequencing of c. 254 candidate genes using target-capture oligo panels or whole exome sequencing in research and/or accredited facilities. Variants of uncertain significance are subjected to in silico analysis.
Results :
Two brothers, 15 and 16 years old respectively, reported life-long reduced vision and photophobia. BCVA was 6/48 and each had red/green colour deficits. ERGs showed delayed rod-isolated responses of low-normal amplitudes and dark-adapted rod-dominated maximal responses of unusually high amplitude. Cone-isolated responses were delayed and markedly reduced in amplitudes. This constellation suggested CDSRR as a likely diagnosis. Genotyping revealed compound heterozygosity for KCNV2 c.1381G>A, p.(Gly461Arg), a known pathogenic variant, and c.1354G>C, p.(Ala452Pro), a previously unreported variant. In silico analyses using SIFT, Mutation Taster and Polyphen 2 predicted the latter to be deleterious.
Conclusions :
KCNV2 (OMIM *607604), causative of CDSRR, encodes the subunit Kv8.2 of a voltage-gated potassium channel in rods and cones. Activation is enabled by complex formation with other subunits and expression influenced by transcription factors CRX and NRL. KCNV2 variants underlie up to 4.3% of cone dystrophies. c.1381G>A, p.(Gly461Arg) is the most commonly reported variant. c.1354G>C, p.(Ala452Pro), a previously unreported missense variant, is absent from the gnomAD database and has not been reported in ClinVAR or HGMD. It affects a highly conserved amino acid in the ion transport domain. Two missense variants affecting a nearby codon have been reported to cause CDSRR. Further functional studies are underway, however, this report provides, to the best of our knowledge, the first evidence for pathogenicity of KCNV2 c.1354G>C, p.(Ala452Pro).
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.