Expanding the phenotypic spectrum in RDH12-associated retinal disease

Abstract

Retinol dehydrogenase 12, RDH12, plays a pivotal role in the visual cycle to ensure the maintenance of normal vision. Alterations in activity of this protein result in photoreceptor death and decreased vision beginning at an early age and progressing to substantial vision loss later in life. Here we describe 11 patients with retinal degeneration that underwent next-generation sequencing (NGS) with a targeted panel of all currently known inherited retinal degeneration (IRD) genes and whole-exome sequencing to identify the genetic causality of their retinal disease. These patients display a range of phenotypic severity prompting clinical diagnoses of macular dystrophy, cone-rod dystrophy, retinitis pigmentosa, and early-onset severe retinal dystrophy all attributed to biallelic recessive mutations in RDH12 We report 15 causal alleles and expand the repertoire of known RDH12 mutations with four novel variants: c.215A > G (p.Asp72Gly); c.362T > C (p.Ile121Thr); c.440A > C (p.Asn147Thr); and c.697G > A (p.Val233Ille). The broad phenotypic spectrum observed with biallelic RDH12 mutations has been observed in other genetic forms of IRDs, but the diversity is particularly notable here given the prior association of RDH12 primarily with severe early-onset disease. This breadth emphasizes the importance of broad genetic testing for inherited retinal disorders and extends the pool of individuals who may benefit from imminent gene-targeted therapies.

Keywords: central scotoma; cone-rod dystrophy; macular dystrophy; peripheral visual field loss; pigmentary retinal degeneration; progressive central visual loss; progressive visual field defects; severe visual impairment.

Figure 1.

RDH12 protein and alignment. (A) Mutations identified in this study listed with gene and protein structure. Novel mutations appear in red; variants that have been functionally validated previously are in bold. The RDH12 gene (top) with coding exons is shaded in blue. Protein (below) is shown with dashed lines demarcating exon boundaries with amino acids numbered. NAD(P)H binding is shown in the dark green square (46–52 aa); the area in green shows the short-chain dehydrogenase/reductase homology (40–243) with active site (175 aa) and proton acceptor (200 aa) in dark green. Proposed signal peptide shown in yellow (1–27 aa). Domains and motifs defined by https://www.ebi.ac.uk/interpro/protein/Q96NR8 and http://pfam.xfam.org/protein/Q96NR8. (B) The protein alignment of the substituted amino acids resulting from novel mutations. (B, From blast.ncbi.nlm.nih.gov/.)

Figure 2.

Clinical phenotypes of RDH12-associated patients. Widefield fundus photography, fundus autofluorescence imaging, and optical coherence tomography to demonstrate degree of retinal dystrophy in patients. (A–C) OGI519-1068, age 14; (D–F) OGI3079-4672, age 33; (G–I) OGI3076-4666, age 14; (J–L) OGI2356-3915, age 11; (M–O) OGI1242-2406, age 31; (P–R) OGI3077-4669, age 29.