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

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

Methods: Clinical evaluation included visual acuity testing, refractive error, a full clinical eye exam, full-field electroretinography (ffERG), color vision testing, and retinal imaging. Genetic analysis of exons, as well as part of intron 14, was performed by Sanger sequencing of PCR products.

Results: Screening for the c.1663-1205G>A variant revealed 17 patients belonging to 12 unrelated families who were either homozygous for this variant (7 cases, 5 families) or heterozygous in combination with another heterozygous known mutation (10 cases, 7 families). All patients were diagnosed with 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 on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale (logarithm of the minimum angle of resolution [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 exams were largely unremarkable in most patients, with mild foveal RPE changes seen in some cases at older ages. ERG was available for 14 out of 17 patients, and in all of them-including infants from the age of 6 months-cone responses were nondetectable. In a few cases, rod involvement was also evident, with a mild reduction of amplitudes. Optical coherence tomography (OCT) imaging showed irregularity of the ellipsoid zone in the foveal area in some patients.

Conclusions: is the most common cause of ACHM in patients of European descent; this is mainly due to a panethnic founder mutation, c.1148del. Here, we report on an intronic variant that is more frequent than the c.1148del mutation in our cohort of Jewish patients. Among our ACHM cohort, 63.7% of patients had biallelic mutations and 26.4% had biallelic mutations. The phenotype of patients harboring the intronic mutation falls largely within the spectrum commonly seen in ACHM. Since gene therapy for is currently under investigation, these patients might benefit from this promising therapy. Given that this variant is not detectable by current commonly used genetic testing platforms, these patients could easily be missed.