Abstract
We performed a clinical and genetic characterization of a pediatric cohort of patients with inherited retinal dystrophy (IRD) to identify the most suitable cases for gene therapy. The cohort comprised 43 patients, aged between 2 and 18 years, with severe isolated IRD at the time of presentation. The ophthalmological characterization also included assessment of the photoreceptor layer integrity in the macular region (ellipsoid zone (EZ) band). In parallel, we carried out a targeted, next-generation sequencing (NGS)-based analysis using a panel that covers over 150 genes with either an established or a candidate role in IRD pathogenesis. Based on the ophthalmological assessment, the cohort was composed of 24 Leber congenital amaurosis, 14 early onset retinitis pigmentosa, and 5 achromatopsia patients. We identified causative mutations in 58.1% of the cases. We also found novel genotype-phenotype correlations in patients harboring mutations in the CEP290 and CNGB3 genes. The EZ band was detectable in 40% of the analyzed cases, also in patients with genotypes usually associated with severe clinical manifestations. This study provides the first detailed clinical-genetic assessment of severe IRDs with infantile onset and lays the foundation of a standardized protocol for the selection of patients that are more likely to benefit from gene replacement therapeutic approaches.
Highlights
Inherited retinal dystrophies (IRD) are a clinically and genetically heterogeneous group of disorders that affect the retina, and mainly photoreceptor cells
Based on a first-level ophthalmological assessment, this cohort was composed of 24 patients affected by Leber congenital amaurosis (LCA) (55.8%), 14 by early onset retinitis pigmentosa (EORP) (32.6%), and 5 by ACHM (11.6%) (Figure 1a)
In analyzing the macular region, we considered the presence of a relevant Macular thickness (MT) and of the ellipsoid zone (EZ) bands as two important criteria for successful gene therapy [9]
Summary
Inherited retinal dystrophies (IRD) are a clinically and genetically heterogeneous group of disorders that affect the retina, and mainly photoreceptor cells. They represent the most frequent cause of blindness of genetic origin in the Western population [1]. IRDs are characterized by a notable extent of genetic heterogeneity with approximately 200 responsible genes identified to date (http://www.sph.uth.tmc.edu/RetNet/). It is currently possible to determine the molecular defect underlying IRDs in about 50–70% of patients [4,5,6], which suggests the existence of additional genes responsible for these conditions
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
