Cone dystrophy with supernormal rod response: novel KCNV2 mutations in an underdiagnosed phenotype

Objective: To study the clinical variability and KCNV2 mutation spectrum in cone dystrophy with supernormal rod response (CDSRR) in the Israeli population.

Design: Case series.

Participants: Patients with cone-dominated diseases and unaffected relatives were included. The protocol was approved by the institutional review board and informed consent was obtained from all participants.

Methods: Genomic DNA was extracted and Sanger sequencing was performed on polymerase chain reaction products. Whole genome single nucleotide polymorphism analysis was performed using Affymetrix (Santa Clara, CA) platforms.

Main outcome measures: Single nucleotide polymorphism microarray and homozygosity analysis, DNA sequence analysis, visual function testing, and electroretinography.

Results: Aiming to study the genetics of inherited retinal degenerations in the Israeli and Palestinian populations, we recruited 220 index cases with cone-dominated diseases, of which 2 carried the clinical diagnosis of CDSRR. Mutation screening of KCNV2 revealed 2 compound heterozygous mutations in 2 affected sisters in 1 family and a homozygous mutation in the other family. Inquiring whether KCNV2 is the cause of disease in the remaining patients with cone-dominated diseases, we performed whole genome homozygosity mapping in 52 consanguineous families (of the initial 220), 2 of which had homozygous regions encompassing KCNV2. Mutation analysis revealed a different homozygous mutation in each family. In addition, KCNV2 was screened in 4 families in which review of the clinical data suggested CDSRR misdiagnosis. The analysis revealed 2 compound heterozygous mutations in 1 family. After the genetic analysis and the review of the clinical findings, the diagnosis was revised to CDSRR in all patients with KCNV2 mutations. Clinical data of 13 KCNV2 patients suggested that, although in some cases the classic phenotype of CDSRR was present, others may have dark-adapted electroretinographic responses that are within normal range. The delay in dark-adapted responses may be a more reliable indicator.

Conclusions: This is the first report of genetic and clinical analysis of CDSRR in the Israeli population leading to the identification of 4 novel KCNV2 mutations. Our results support recent studies showing that CDSRR can be misdiagnosed, and therefore screening of KCNV2 for mutations should be considered in patients with cone-dominated diseases, particularly when dark-adapted responses are delayed.