Toward an elucidation of the molecular genetics of inherited retinal degenerations

Abstract

While individually classed as rare diseases, hereditary retinal degenerations (IRDs) are the major cause of registered visual handicap in the developed world. Given their hereditary nature, some degree of intergenic heterogeneity was expected, with genes segregating in autosomal dominant, recessive, X-linked recessive, and more rarely in digenic or mitochondrial modes. Today, it is recognized that IRDs, as a group, represent one of the most genetically diverse of hereditary conditions - at least 260 genes having been implicated, with 70 genes identified in the most common IRD, retinitis pigmentosa (RP). However, targeted sequencing studies of exons from known IRD genes have resulted in the identification of candidate mutations in only approximately 60% of IRD cases. Given recent advances in the development of gene-based medicines, characterization of IRD patient cohorts for known IRD genes and elucidation of the molecular pathologies of disease in those remaining unresolved cases has become an endeavor of the highest priority. Here, we provide an outline of progress in this area.

Figure 1

SLC24A1 causative of an autosomal recessive retinal degeneration. Panel A: Fundus photograph of the right eye of the proband with an SLC24A1 mutation indicating mild optic disc pallor, moderate arteriolar attenuation and quite extensive thinning of the retinal pigment epithelium in the retinal mid-periphery with abundant bone spicule intra-retinal pigment deposits, typically seen in patients with Retinitis Pigmentosa. Panel B: Goldmann kinetic perimetry of the left eye. Marked concentric constriction is evident, even to the large IV4e target (red), with preservation of an inferior island of field. This pattern of visual field loss is very typical of that seen in Retinitis Pigmentosa. Panel C: Optical Coherence Tomography (OCT) image of the left macula showing preservation of retinal structures, consistent with the normal appearance of the macula in Panel A and the patient’s good best-corrected visual acuity of 6/6.

Figure 2

Frequencies with which different genes were found to harbour disease-causing mutations in the Target 5000 study in Ireland (Carrigan et al. 2016), counted as number of independent pedigrees. Genes that were observed less than four times, could not be cleanly visually represented, and so are listed below. Three observations: ADGRV1, CERKL, CRX, EYS, KLHL7 Two observations: CNGB3, CRB1, NRL, PROM1, PRPF8, RP2, SNRNP200, TRPM1 One observation: ABCC6, ABHD12, AIPL1, BBS10, BBS4, BBS9, C2ORF71, CDH23, CLRN1, CNGA1, ELOVL4, EMC1, FZD4, GNAT1, GUCY2D, HK1, HMCN1, IFT140, IMPDH1, IQCB1, LCA5, MFN2, MFRP, NMNAT1, NYX, OAT, PDE6A, PRPF31, RDH5, SDCCAG8, SLC24A1.