NR2E3

Inheritance Pattern: AD

Disease ID:MONDO:0012625

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0100288

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0100289

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0012625

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0100289

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0100289

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0012625

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0100288

Submitter: ClinGen

The *NR2E3* gene was first reported in relation to autosomal recessive enhanced S-cone syndrome in 2000 (Haider et al., PMID: 10655056). Subsequent publications expanded the phenotypic spectrum associated with homozygous or compound heterozygous *NR2E3* variants to include related diagnoses such as Goldmann-Favre syndrome (PMID: 18294254), retinitis pigmentosa (PMID: 11071390) and retinoschisis (PMID: 18294254). These cases typically present with night blindness in childhood or adolescence and exhibit progressive loss of visual acuity and slow concentric reduction of the visual field during the subsequent decades, with some retention of vision even in elderly individuals, increased sensitivity to blue light, decreased electroretinogram responses from rods in particular but also from cones, retinal pigment epithelium atrophy with hypopigmented pigment deposits in the peripheral retina, macular schisis, and/or optic disc pallor. The published literature also includes cases of retinitis pigmentosa with a heterozygous *NR2E3* variant, particularly the dominant negative variant p.Gly56Arg. Affected patients typically present with night blindness in late childhood or adolescence, and can exhibit photophobia, progression to undetectable rod function with a relatively late decline in cone function, concentric rings of hyper-autofluorescence surrounding the fovea, vascular arcades, and far periphery, and mixed nummular and bone spicule intraretinal pigmentation in the later stages (PMID: 17564971). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, recessive cases of enhanced S-cone syndrome or autosomal recessive retinitis pigmentosa were compared with dominant cases of retinitis pigmentosa. The shared mode of inheritance, molecular mechanism (biallelic loss-of-function) and phenotypic overlap among recessive cases motivated enhanced S-cone syndrome and autosomal recessive retinitis pigmentosa to be combined for the purposes of this gene curation, with the lumped disease entity referred to as NR2E3-related enhanced S-cone syndrome. On the other hand, cases with overlapping phenotypes but a dominant mode of inheritance differed in their molecular mechanism (dominant negative), in contrast with the unaffected heterozygous carriers from the recessive families. Therefore, dominant cases have been lumped into a separate disease entity, referred to as NR2E3-related dominant retinopathy. Ten suspected disease-causing variants were scored as part of this curation (three frameshift, one canonical splice site variant, five missense variants in the DNA-binding domain, and one short in-frame deletion in the DNA-binding domain), which have been collectively reported in eleven probands in four publications (PMID: 10655056, PMID: 18294254, PMID: 22605927, PMID: 33138239). Ten of the probands scored in this curation harbored the variant allele in the homozygous state, with three reported as consanguineous, while one other proband harbored variants in compound heterozygosity. One large family with evidence of co-segregation of the genotype with affected status contributed to the scoring of the gene-disease relationship (PMID: 11071390). This gene-disease association is also supported by experimental evidence indicating that *NR2E3* is highly specifically expressed in retinal tissues (PMID: 30239781) and encodes a ligand-dependent transcription factor that is involved in photoreceptor differentiation and suppression of cone differentiation in rod photoreceptor cells (PMID: 19379737, PMID: 37510230). The protein product physically interacts with the photoreceptor cell transcription factors NRL and CRX (PMID: 15190009), both of which are encoded by genes that can harbor inherited retinal disease-causing variants. Homozygous loss-of-function of the mouse ortholog *Nr3e2* in the *rd7* model results in enhanced blue cone sensitivity, over-proliferation of ectopic retinal progenitors, increase in blue opsin expressing cone cells, increased expression of cone-associated genes, disrupted outer nuclear layer histology, retinal spotting throughout fundus, late-onset rod and cone cell death, and reduction of outer nuclear layer thickness (PMID: 19379737, PMID: 11487564, PMID: 34561487, PMID: 17266784). These defects can be rescued in young mice by subretinal injection of adeno-associated virus packaged *Nr2e3* (PMID: 32123325). In summary, *NR2E3* is definitively associated with NR2E3-related enhanced S-cone syndrome. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on October 2nd, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0100288

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0100288

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Inheritance Pattern: AD

Disease ID:MONDO:0019118

Submitter: ClinGen

The *NR2E3* gene was first reported in relation to autosomal dominant retinitis pigmentosa in 2007 (Coppetiers et al., PMID: 17564971). Affected patients typically present with night blindness between late childhood and early adulthood, and can exhibit reduced visual acuity, progression to undetectable rod function with a relatively late decline in cone function, concentric rings of hyper-autofluorescence surrounding the fovea, vascular arcades, and far periphery, visual field constriction, cystoid macular degeneration, cataract development, photophobia, and/or mixed nummular and bone spicule intraretinal pigmentation in the later stages (PMID: 17564971). The published literature has also linked *NR2E3* to cases of autosomal recessive enhanced S-cone syndrome that have been reported since 2000 (Haider et al., PMID: 10655056). These recessive cases may alternatively be diagnosed as Goldmann-Favre syndrome (PMID: 18294254), retinitis pigmentosa (PMID: 11071390) or retinoschisis (PMID: 18294254). They typically present with night blindness in childhood or adolescence and exhibit progressive loss of visual acuity and slow concentric reduction of the visual field during the subsequent decades, with some retention of vision even in elderly individuals, increased sensitivity to blue light, decreased electroretinogram responses from rods in particular but also from cones, retinal pigment epithelium atrophy with hypopigmented pigment deposits in the peripheral retina, macular schisis, and/or optic disc pallor. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, dominant cases of retinitis pigmentosa exhibited some overlap in phenotypes with recessive cases of enhanced S-cone syndrome or autosomal recessive retinitis pigmentosa. However, the shared mode of inheritance and molecular mechanism (biallelic loss-of-function) among recessive cases motivated enhanced S-cone syndrome and autosomal recessive retinitis pigmentosa to be combined into a lumped disease entity referred to as *NR2E3*-related enhanced S-cone syndrome, which has been curated separately. Cases with an autosomal dominant mode of inheritance show a unique molecular mechanism (dominant negative), and contrast with the unaffected heterozygous carriers from the recessive families. For the purposes of this curation, dominant cases have been curated as a separate disease entity, referred to as *NR2E3*-related dominant retinopathy. Two suspected disease-causing variants were scored as part of this curation, both of them missense substitutions encoding the dominant negative variant p.Gly56Arg. The NM_014249.4(NR2E3):c.166G>A and NM_014249.4(NR2E3):c.166G>C forms of the variant have collectively been identified and scored in twelve probands in seven publications (PMID: 17564971, PMID: 26910043, ). All of the probands scored in this curation harbored the variant allele in the heterozygous state. Multiple large families with evidence of co-segregation of the genotype with affected status contributed to the scoring of the gene-disease relationship (PMID: 17564971, PMID: 24938718, PMID: 26910043, PMID: 28912962, PMID: 30718709, PMID: 32531858, PMID: 36460718). Functional studies characterizing the effects of the variant are discussed in further detail below. This gene-disease association is also supported by experimental evidence indicating that *NR2E3* is highly specifically expressed in retinal tissues (PMID: 30239781) and encodes a ligand-dependent transcription factor that is involved in photoreceptor differentiation and suppression of cone differentiation in rod photoreceptor cells (PMID: 19379737, PMID: 37510230). The protein product physically interacts with the photoreceptor cell transcription factors NRL and CRX (PMID: 15190009), both of which are encoded by genes that can harbor inherited retinal disease-causing variants. Functional studies characterizing the p.Gly56Arg variant indicate that it preserves interaction with CRX (PMID: 19823680) but disrupts NR2E3 localization (PMID: 33807610) and DNA binding (PMID: 19823680), resulting in aberrant activation of rod-specific genes and repression of cone-specific genes (PMID: 19823680). Antisense oligonucleotide-based or CRISPR/Cas9-based therapeutic strategies for silencing the expression of the p.Gly56Arg variant are in development (PMID: 31083481, PMID: 33807610 ), but rescue experiments have not been scored as part of this gene curation. In summary, *NR2E3* is definitively associated with *NR2E3*-related dominant retinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on November 6th, 2025 (SOP Version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0012625

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0100288

Submitter: Labcorp Genetics (formerly Invitae)