Helicoid Subretinal Fibrosis Associated With a Novel Recessive NR2E3 Mutation p.S44X

Abstract

To describe a unique pattern of helicoid subretinal fibrosis associated with a novel recessive NR2E3 mutation and to highlight how examination of the proband's affected relative allowed appropriate genetic testing. Design: Interventional family study (ophthalmic examination and candidate gene testing). Results: The proband (mother), who complained of poor vision since early childhood, had bilateral helicoid subretinal fibrosis mostly involving the macula. Two children were symptomatic; one had ophthalmic findings similar to her mother while the second had macular retinoschisis, retinal pigment epithelium changes, and refractive accommodative esotropia. The father and third child were asymptomatic and had unremarkable oph-thalmic examination findings. Based on the findings in the second symptomatic child, NR2E3 analysis was performed, which revealed homozygosity for a novel mutation, p.S44X, in all 3 affected individuals and heterozygosity for the mutation in both asymptomatic individuals. Conclusion: Helicoid subretinal fibrosis is another potential phenotypic manifestation of recessive NR2E3 mutation. Clinical Relevance: Examination of affected relatives can be helpful in guiding molecular genetic testing for hereditary eye disease when the proband's diagnosis is unclear.

Next-generation sequencing reveals the mutational landscape of clinically diagnosed Usher syndrome: copy number variations, phenocopies, a predominant target for translational read-through, andPEX26mutated in Heimler syndrome

“…Because the patient's retinal phenotype (deep pigment deposits along the vascular arcades, subretinal fibrosis; delayed, depressed, and simplified scotopic flash response in the ERG) appeared compatible with a recessive NR2E3 ‐related dystrophy (Khan et al. , ), this gene was sequenced. Indeed, a homozygous NR2E3 missense mutation, p.Arg311Gln, previously reported as a pathogenic mutation (Haider et al.…”

Bilateral Helicoid Peri-papillary Sub-retinal Fibrosis Due to a Biallelic NR2E3 Mutation: Describing Variable Expressivity of a Single Genetic Mutation

“…However, in the latter conditions, the brosis is not typically helicoid and usually evidence of underlying systemic disorder or ocular in ammation is accompanied. 3 ESCS was rst described in 1990 by Marmor et al 1 It is unclear that why recessive mutation in NR2E3 gene can cause sub-retinal brosis in a developing retina. In their reported case, Arif O. Khan et al…”

“…These include autosomal recessive Goldmann-Favre syndrome, autosomal recessive or dominant enhanced S-cone syndrome (ESCS), autosomal recessive clumped pigmentary retinal degeneration, autosomal recessive or dominant retinitis pigmentosa, and "torpedo-like" lesions in posterior pole or along the vascular arcades. [2][3][4][5][6][7][8][9][10][11] This mutation has been reported to cause both dominant and recessive form of retinal dystrophy in the same family. These variable presentations of a single genetic mutation make a challenge for establishing the correct diagnosis based on clinical ndings.…”

Differential Dimerization of Variants Linked to Enhanced S-Cone Sensitivity Syndrome (ESCS) Located in the NR2E3 Ligand-Binding Domain

“…A c.166G>A (p.G56R) variant located in the DBD of NR2E3 caused autosomal dominant retinitis pigmentosa (ADRP; MIM# 611131) (Coppieters et al, 2007). Patients with recessive NR2E3 variants often refer to the ophthalmologist for mixed cystoid/schisis-like maculopathy and may exhibit a vast spectrum of signs on funduscopy, including mid-peripheral white/yellow dots and flecks, colocalizing with the rosettes, nummular pigment deposits and helicoidal fibrosis [Jurklies et al, 2001;Marmor, 2006;Bandah et al, 2009;Wang et al, 2009;Khan et al, 2010;Yzer et al, 2013]. The increased number of S-cones results in a pathognomonic increase in the response to blue light, as assessed by spectral electroretinography (ERG), and in a markedly delayed 30-Hz flicker ERG [Marmor et al, 1990;Audo et al, 2008].…”