CLINICAL AND GENETIC EVALUATION IN A COHORT OF PEDIATRIC PATIENTS WITH INHERITED RETINAL DYSTROPHIES

Abstract

Purpose : There are no reports, to the best of our knowledge, that describe genotype phenotype correlations in patients with inherited retinal dystrophies (IRD) with infantile/juvenile onset. The aim of our study is to focus attention on a cohort of Italian IRD patients, performing an extensive clinical evaluation and Next Generation Sequencing (NGS) analysis, in order to select IRD patients with the highest potential of successful outcome of gene therapy-based approaches.

Methods : Thirty-nine Italian patients (representative of 37 different families), aged between 2-18 years, with severe isolated non-syndromic IRD were recruited. Inclusion criteria were: disease onset ≤ 10 years of age, age ≤ 18 years, best corrected visual acuity ≤ 20/70, standard electroretinogram (sERG) abnormalities and macular thickness (MT) ≥100 μm (when sERG and Optical Coherence Tomography were performable). All patients underwent full ophthalmological examinations and targeted NGS-based analysis on a panel, termed RETplex.

Results : Based on ophthalmological assessment, 19 patients were affected by Leber Congenital Amaurosis (LCA) (48.7%), 15 by Early Onset Retinitis Pigmentosa (EORP) (38.5%) and 5 by Achromatopsia (ACHM) (12.8%). The most frequently mutated gene was CEP290. Ellipsoid band (EB) was explorable and carefully analyzed in 28/39 patients (71.8%). The most preserved EB was found in patients with mutations in CEP290, CNGB3, CNGA3, PDE6C genes. We identified causative mutations in 26/39 patients analyzed (66.6%). Causative mutations were found in 11/19 LCA, 10/15 EORP, and in all 5 ACHM patients. Clinical and molecular diagnosis did not always overlap. We found two notable cases of discordance: CEP290 causative of EORP instead of LCA and CNGB3 underlying LCA instead of ACHM. Fourteen patients (35.9%) displayed mutated genes involved in syndromic forms, but their young age masked them.

Conclusions : Our study provides the first detailed clinical/genetic assessment of severe IRDs with infantile/juvenile onset and lays the basis for a standardized protocol to identify the most suitable patients for successful gene replacement therapy. We highlight that the NGS results are very important for a critical re-evaluation of clinical cases in order to better understand and discriminate between diseases.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.