State of the Art on Inherited Retinal Dystrophies: Management and Molecular Genetics

Abstract

Inherited retinal dystrophies (IRDs) represent a group of heterogeneous disorders caused by gene mutations primarily affecting retinal photoreceptors. In addition to vision loss, other symptoms may lead to visual impairment, such as altered visual fields, hemeralopia, glare sensitivity, and impaired color vision. These conditions almost always complicate with the onset of cataracts, macular edema or atrophy, glaucoma, etc. A brief overview of key genes involved in the most common and well-known IRDs is provided, followed by clinical and diagnostic implications. The study of IRDs has seen a significant acceleration in recent decades, owing to advances in molecular genetics with the introduction of exome sequencing (WES) and genome-wide association studies (GWASs), which have facilitated the identification of a broad spectrum of genes associated with IRDs. This has led to the classification of five genetic variants, based on the criteria of the American College of Medical Genetics and Genomics (ACMG), serving as a guide for interpreting genetic reports. Next, approaches to genomic editing therapies and research directions regarding artificial intelligence (AI) and machine learning (ML) are discussed. The paper concludes with an examination of the inevitable ethical and regulatory issues, typically driven by regulatory bodies such as the Food and Drug Administration (FDA).

Keywords: gene therapy; genetic counseling; genetic mutations; genome editing; inherited IRDs; inherited retinal diseases; retinitis pigmentosa; sequencing; syndromic inherited retinal dystrophy.

Figure 2

Main forms of inherited retinal dystrophies (IRDs) and their causative genes. The dendrogram summarizes the main forms of IRDs, with a brief description of the clinical phenotype associated with alterations in the main causative genes.

Figure 3

Fundus images of patients with inherited retinal dystrophies (IRDs). (A) Retinitis pigmentosa with bone spicule-like pigment accumulations in the intermediate region of the retinal periphery. Optical coherence tomography (OCT) examination shows optically empty cysts due to the presence of cystoid macular edema (blue arrow). (B) Best disease with yellowish lipofuscin deposits, “egg yolk” type, in the macula. Evident serous detachment of the neuroretina on OCT examination (yellow arrow). (C) The fundus image appears normal, but the OCT scan shows delamination of the outer retina due to cone dystrophy (red arrow). (D) Stargardt’s disease with fundus flavimaculatus for yellowish pisciform lesions on the posterior pole. Marked thinning of the macular outer retina due to atrophy visible on OCT examination (celestial arrows). (E) Butterfly-type bestrophinopathy due to remodeling of the retinal pigmented epithelium in the macular area, more evident in the autofluorescence image (inset).

Figure 1

Ocular anatomy and retinal cell structure.

Figure 4

Overview of the main next-generation sequencing (NGS) analysis methods to support genetic investigations of inherited retinal dystrophies (IRDs). From whole exome sequencing (WES) to modern transcriptomic and epigenomic techniques, these are cutting-edge techniques and technologies that can provide a decisive contribution to translational research and diagnostics of IRD.