Novel disease-causing variant in RDH12 presenting with autosomal dominant retinitis pigmentosa

Abstract

Aim: To describe the clinical and molecular features of a novel, autosomal dominant RDH12-retinopathy.

Methods: Retrospective cross-sectional study. Twelve individuals from a four-generation British pedigree underwent ophthalmic examination, genotyping using next generation sequencing, including whole genome sequencing and multimodal retinal imaging including fundus photography, optical coherence tomography (OCT), autofluorescence imaging and adaptive optics (AO) scanning light ophthalmoscopy were performed. Visual electrophysiology was performed in a subset.

Results: Eight family members were confirmed as affected by genotyping heterozygous for RDH12 c.763delG. Visual acuity ranged from -0.1 to 0.2 logMAR. Affected individuals had constricted visual fields. A parafoveal and peripapillary ring of hyper-autofluorescence was seen initially, and with progression the area of perifoveal hypo-autofluorescence increased to involve the parafoveal area. Mild retinal thinning was identified on OCT imaging with reduction in both foveal total retinal and outer nuclear layer thickness. Cone densities along the temporal meridian were reduced in affected individuals compared with normative values at all temporal eccentricities studied. One individual with incomplete penetrance, was identified as clinically affected primarily on the basis of AO imaging. Full-field electroretinography demonstrated a rod-cone pattern of dysfunction and large-field pattern electroretinography identified peripheral macular dysfunction.

Conclusions: This novel heterozygous variant RDH12 c.763delG is associated with a rod-cone dystrophy with variable expression. Determination of the degree of penetrance may depend on the modality employed to phenotypically characterise an individual. This rare and specific heterozygous (dominant) variant is predicted to result in a gain of function, that causes disease in a gene typically associated with biallelic (recessive) variants.

Keywords: dystrophy; genetics; imaging; retina.

Figure 1

Pedigree (GC21021) showing affected index patient (black arrow) and family members over four generations (denoted as M/WT for heterozygotes and WT/WT for those with wild type alleles). Individuals clinically affected with autosomal dominant retinitis pigmentosa are represented in black symbols while unaffected individuals with open symbols. Deceased individual is represented with a slash. Squares represent men and circles represent women. M, c.763delG (p.Val255Serfs*23); WT, wild type. All those examined at Moorfields are marked with an *. Individuals examined at other institutions are marked with a #. Individuals identified as affected by whole genome sequencing, next generation sequencing and targeted sequencing are labelled WGS, NGS and Tgt, respectively, in the pedigree.

Figure 2

Longitudinal fundus autofluorescence (FAF) imaging in minimally symptomatic mother of the index patient (III-12) over a 1.5 years follow-up. Age at baseline was 39 years and 3 months old. Focal area of hyper-autofluorescence temporal macula of left eye and no change noted in this subtle hyper-autofluorescence over the 1.5 years of follow-up. The FAF imaging of right eye was unremarkable.

Figure 3

Multimodal imaging of the right eye of the affected index patient (IV-3) at the age of 14 years. (A) Split-detection AOSLO from the fovea (white asterisk) out to 5° temporally capturing the en face cone photoreceptor inner segments; (B) confocal AOSLO from the fovea (white asterisk) out to 5° temporally capturing the en face cone photoreceptor outer segments; (C) horizontal transfoveal OCT line scan shows loss of inner segment ellipsoid band and outer retinal loss (indicated by arrow). Dashed white lines indicate the location and extent of the AOSLO en face images; (D) fundus autofluorescence image centred on the fovea 55° wide. A ring of parafoveal hyper-autofluorescence, patchy perifoveal hypo-autofluorescence, scattered areas of hypo-autofluorescence along the temporal arcades and in mid-peripheral retina. White dashed line indicates the location and extent of the OCT scan in C; (E) corresponding near infrared reflectance image of the OCT scan (white line) in C. Black dashed rectangle indicates the location and extent of the AOSLO en face images in A and B. AOSLO, adaptive optics scanning light ophthalmoscope; OCT, optical coherence tomography.

Figure 4

Confocal (outer segments) and split-detection (inner segments) adaptive optics scanning light ophthalmoscope images in the index patient (top row) and her parents (middle and bottom rows) across their temporal meridian. Each crop is 55 microns square. Below each row, the bound cells that were used to derive the cone densities as shown in online supplemental file 7, are illustrated by the Voronoi tessellation.