A Deep Intronic Substitution in CNGB3 is One of the Major Causes of Achromatopsia among Jewish Patients

Abstract

Purpose : Although most (and perhaps all) genes that can cause achromatopsia (ACHM) when mutated are known, some patients with an ACHM phenotype are still negative for mutations in the coding region of known genes. Our aim was to characterize genetic and clinical aspects of a deep intronic (c.1663-1205G>A, IVS14-1205G>A) CNGB3 variant.

Methods : Clinical evaluation included visual acuity testing, refractive error, color vision testing, full-field electroretinography, and multi-modal retinal imaging. Genetic analysis was performed by Sanger sequencing of PCR products.

Results : Screening for the CNGB3 c.1663-1205G>A variant revealed 17 patients belonging to 12 unrelated families who were either homozygous (7 cases, 5 families) or compound heterozygous (10 cases, 7 families) with another known CNGB3 mutation on the counter allele. All patients were diagnosed with a cone-dominated disease, mainly complete ACHM. In all cases, the disease had an early congenital onset. Visual acuity was markedly impaired, ranging between 0.07 and 0.32 ETDRS (LogMAR +1.18 to +0.50), with a mean visual acuity of 0.15 ETDRS (LogMAR +0.80). Additional typical signs of ACHM including impaired color vision, light aversion, and nystagmus were also noted in all patients. As is common in ACHM, fundus exam was largely unremarkable in the majority of patients, with mild foveal retinal pigment epithelium changes seen in some cases at older ages. Electroretinography was available for 14 out of 17 patients and in all of them cone responses were non-detectable, including infants from the age of 6 months. In a few cases, rod involvement was also evident, with mild reduction of amplitudes. Optical coherence tomography imaging showed irregularity of the ellipsoid zone in the foveal area in some of the patients.

Conclusions : CNGB3 is the most common cause of ACHM in patients of European descent, mainly due to a panethnic founder mutation, c.1148del. Here we report of an intronic CNGB3 variant which is more frequent than the c.1148del mutation in the Jewish population. Among our ACHM cohort, 64% have biallelic CNGA3 mutations and 32% have biallelic CNGB3 mutations. The phenotype of patients harboring the intronic mutation falls largely within the spectrum commonly seen in ACHM. As gene therapy for CNGB3 is currently under investigation, these patients might benefit from this promising therapy.

This is a 2021 ARVO Annual Meeting abstract.