Phenotyping and genotyping inherited retinal diseases: Molecular genetics, clinical and imaging features, and therapeutics of macular dystrophies, cone and cone-rod dystrophies, rod-cone dystrophies, Leber congenital amaurosis, and cone dysfunction syndromes

Abstract

Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population and in children. The scope of this review is to familiarise clinicians and scientists with the current landscape of molecular genetics, clinical phenotype, retinal imaging and therapeutic prospects/completed trials in IRD. Herein we present in a comprehensive and concise manner: (i) macular dystrophies (Stargardt disease (ABCA4), X-linked retinoschisis (RS1), Best disease (BEST1), PRPH2-associated pattern dystrophy, Sorsby fundus dystrophy (TIMP3), and autosomal dominant drusen (EFEMP1)), (ii) cone and cone-rod dystrophies (GUCA1A, PRPH2, ABCA4, KCNV2 and RPGR), (iii) predominant rod or rod-cone dystrophies (retinitis pigmentosa, enhanced S-Cone syndrome (NR2E3), Bietti crystalline corneoretinal dystrophy (CYP4V2)), (iv) Leber congenital amaurosis/early-onset severe retinal dystrophy (GUCY2D, CEP290, CRB1, RDH12, RPE65, TULP1, AIPL1 and NMNAT1), (v) cone dysfunction syndromes (achromatopsia (CNGA3, CNGB3, PDE6C, PDE6H, GNAT2, ATF6), X-linked cone dysfunction with myopia and dichromacy (Bornholm Eye disease; OPN1LW/OPN1MW array), oligocone trichromacy, and blue-cone monochromatism (OPN1LW/OPN1MW array)). Whilst we use the aforementioned classical phenotypic groupings, a key feature of IRD is that it is characterised by tremendous heterogeneity and variable expressivity, with several of the above genes associated with a range of phenotypes.

Keywords: ABCA4; AIPL1; ATF6; Achromatopsia; Autosomal dominant drusen; BEST1; Best disease; Bietti crystalline dystrophy; Blue-cone monochromatism; Bornholm Eye Disease; CEP290; CNGA3; CNGB3; CRB1; CYP4V2; Cone-rod dystrophies; EFEMP1; Early-onset severe retinal dystrophy; Enhanced S-cone syndrome; FAF; GNAT2; GUCA1A; GUCY2D; LCA; Leber congenital amaurosis; NMNAT1, rod-cone dystrophies; NR2E3; OCT; OPN1LW/OPN1MW; Oligocone Trichromacy; PDE6C; PDE6H; PRPH2; Pattern dystrophy; R9AP; RDH12; RGS9; RPE65; RPGR, cone dysfunction syndromes; RS1; Retinal imaging; Retinitis pigmentosa; Sorsby fundus dystrophy; Stargardt disease; TIMP3; TULP1; X-linked retinoschisis.