Novel Pathogenic Sequence Variants in NR2E3 and Clinical Findings in Three Patients

Abstract

A retrospective review of the clinical records of patients seen at the Oxford Eye Hospital identified as having NR2E3 mutations was performed. The data included symptoms, best-corrected visual acuity, multimodal retinal imaging, visual fields and electrophysiology testing. Three participants were identified with biallelic NR2E3 pathogenic sequence variants detected using a targeted NGS gene panel, two of which were novel. Participant I was a Nepalese male aged 68 years, and participants II and III were white Caucasian females aged 69 and 10 years old, respectively. All three had childhood onset nyctalopia, a progressive decrease in central vision, and visual field loss. Patients I and III had photopsia, patient II had photosensitivity and patient III also had photophobia. Visual acuities in patients I and II were preserved even into the seventh decade, with the worst visual acuity measured at 6/36. Visual field constriction was severe in participant I, less so in II, and fields were full to bright targets targets in participant III. Electrophysiology testing in all three demonstrated loss of rod function. The three patients share some of the typical distinctive features of NR2E3 retinopathies, as well as a novel clinical observation of foveal ellipsoid thickening.

Keywords: Goldmann–Favre syndrome; NR2E3; autosomal recessive and autosomal dominant retinitis pigmentosa; ellipsoid zone; enhanced S-cone syndrome; inherited retinal degeneration; pigmentary clumping; retinal dystrophy.

Figure 1

Schematic diagram of NR2E3 genomic locus, structure of the encoded protein and location of identified mutations. The top panel shows the NR2E3 gene on 15q23 which consists of 8 exons and spans approximately 7.7 kb of genomic DNA. Exons are shown as boxes and introns as lines; all are to scale. The middle panel shows which domains each exon contributes to the protein structure. The gene encodes a predicted 410 amino acid protein which shows the characteristic structure of a nuclear hormone receptor (lower panel) and consists of 5 domains: the N-terminal A/B domain (regions 1 and 2, shown in dark blue), a DNA binding domain (light grey) which contains 2 Zn-fingers (region 3, dark grey), a hinge region (region 4, green) and the ligand binding domain at the C-terminal end (region 5, light blue). The position of the β-sheets, α-helices and the activator function region 2 are also shown (in red, blue and darker blue, respectively). The positions of the mutations described in this report are also shown. Figure adapted from Mollena et al. [22].

Figure 2

Family trees and colour imaging, fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT) imaging of patients I, II and III. The top panel shows the pedigrees of each family, the arrow indicates the proband. (A) Imaging of Patient I showing a dense concentric band of pigment and atrophy, extending from the arcades into the mid peripheral retina (i,ii); increased autofluorescence signal at both maculae (iii,iv), and central preservation of the retina on optical coherence tomography (v,vi). (B) Imaging of Patient II showing concentric pigment clumping in the mid peripheral retina that is more pronounced in the temporal and nasal regions (i,ii); mildly increased AF at both maculae and decreased AF extending from the vascular arcades into the midperiphery (iii,iv); significant focal thickening at the fovea in the ellipsoid zone (EZ) and, in the right eye, an incipient lamellar hole (v,vi). (C) Imaging of patient III shows a concentric band of atrophy, pigment, and white dots extending from the arcades into the mid peripheral retina (i,ii); with an increased autofluorescence signal at both maculae (iii,iv), and central preservation of the retina on optical coherence tomography (v,vi). (vii–viii) in each panel are OCT images with segmentation highlighting the ganglion cell layer in purple and the inner plexiform layer in blue (see Supplementary Table S2 for measurements).

Figure 3

Electrophysiology results for patients compared to a control eye. Patient 1 has widespread loss in all systems with residual S-cone response. Patient 2 has extinguished rod, reduced cone but large S-cone responses. Patient 3 has reduced responses affecting rods more than cones. DA 0.01 is the dark-adapted rod response, and DA 10 is the dark adapted maximal response. At DA 10, both the single flash response and oscillatory potentials are shown. LA 30 Hz is light adapted 30 Hz flicker response and LA 3 is the light adapted standard flash as per International Society of Electrophysiology of Vision (ISCEV) guidelines. The S-cone response isolates the S-cone response using a blue flash. The pattern electroretinogram (PERG) reflects macular function.