Retinal dystrophies, genomic applications in diagnosis and prospects for therapy

Abstract

Retinal dystrophies (RDs) are degenerative diseases of the retina which have marked clinical and genetic heterogeneity. Common presentations among these disorders include night or colour blindness, tunnel vision and subsequent progression to complete blindness. The known causative disease genes have a variety of developmental and functional roles with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even amongst affected individuals within the same family highlighting further levels of complexity. The known disease genes encode proteins involved in retinal cellular structures, phototransduction, the visual cycle, and photoreceptor structure or gene regulation. This review aims to demonstrate the high degree of genetic complexity in both the causative disease genes and their associated phenotypes, highlighting the more common clinical manifestation of retinitis pigmentosa (RP). The review also provides insight to recent advances in genomic molecular diagnosis and gene and cell-based therapies for the RDs.

Keywords: CRISPR/Cas9; Retinal dystrophy (RD); massively parallel sequencing (MPS); retinitis pigmentosa (RP).

Figure 1

Retinal layers and clinical impact of retinal dystrophy. (A) Expansion of retinal region with histology section showing normal retinal layers of the mouse, which has close homology with histology of the human eye. The ONL contains the nuclei of the photoreceptors, and the OS layer contains the outer segments of the photoreceptors; (B) progressive visual field loss as experienced by retinitis pigmentosa patients. Upper image shows normal full visual field, middle image shows constricted field and lower image shows almost no central vision remaining. GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; OS, outer segments of photoreceptors; RPE, retinal pigment epithelium.

Figure 2

Retinitis pigmentosa: fundal images. (A,B) Wide field fundus photography illustrating retinal features of retinitis pigmentosa, including pigmentary changes (arrows), waxy pallor of the optic disc (asterisk) and retinal arteriolar attenuation (arrowheads) in (A), compared with the normal retinal image in (B); (C,D) OCT imaging showing thinning of the rod photoreceptor outer segments in retinitis pigmentosa in (C), compared with normal in (D) (arrows). There is relative preservation of the cone photoreceptor outer segments present in the foveal region in retinitis pigmentosa (arrowhead). OCT, optical coherence tomography.

Figure 3

Cone dystrophy: fundal images. (A,B) Wide field fundus photography illustrating retinal features of cone dystrophy, showing macular atrophy in (A) (arrow), compared with the normal macular appearance present in (B); (C,D) OCT in cone dystrophy illustrates the loss of the foveal photoreceptor outer segments in (C), compared with normal in (D) (arrows). OCT, optical coherence tomography.

Figure 4

Genetic heterogeneity in retinal dystrophies. Diagrammatic representation of overlap between genetic causes of various forms of retinal dystrophy with some example genes shown. Achm, achromatopsia; CSNB, congenital stationary night blindness.