Case#: Haider_2000_Proband_6, sex, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.310C>T (p.Arg104Trp) variant in the homozygous state.

ClinVarID: 846973

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00002739 (2 alleles / 73,032 total alleles) in the African / African-American population, with no homozygous occurrences. https://gnomad.broadinstitute.org/variant/chr15-71811830-C-T?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.310C>T (p.Arg104Trp) is a missense variant within the zinc finger / DNA-binding domain of NR2E3,.

CaseAddInfo: It is not clear whether or not the proband comes from a consanguineous family.

CasePMIDs: N/A

Case#: Haider_2000_Proband_1, male, age and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.119-2A>C variant in the homozygous state.

ClinVarID: 191059

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.001359 in the Ashkenazi Jewish population and 0.0007992 in the European (non-Finnish) population (919 / 1,149,942), with no homozygotes observed. https://gnomad.broadinstitute.org/variant/chr15-71811481-A-C?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.119-2A>C is a canonical splice acceptor site variant adjacent to exon 2 of 6, which is an out-of-frame exon that could potentially trigger nonsense-mediated decay if skipped.

CaseAddInfo: The proband is the offspring of 3rd cousins and has an affected sibling and an affected second cousin once removed harboring the variant in the same homozygous genotype (Figure 3c).

CasePMIDs: N/A

Case#: Haider_2000_Proband_3, sex, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.226C>T (p.Arg76Trp) variant in the homozygous state.

ClinVarID: 5529

gnomAD: The variant is not found in gnomAD version 4.1.0 at a frequency of 0.0001124 in the South Asian population (10 alleles / 88,960 total alleles, with no homozygotes) https://gnomad.broadinstitute.org/variant/chr15-71811590-C-T?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.226C>T (p.Arg76Trp) is a missense variant within the zinc finger / DNA-binding domain of NR2E3, and occurs at the same amino acid position as another missense substitution reported in the same article.

CaseAddInfo: It is not clear whether the proband came from a consanguineous family.

CasePMIDs: N/A

Case#: Haider_2000_Proband_2, sex, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.200_208del (p.Cys67_Gly69del) variant in the homozygous state.

ClinVarID: 5531

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_014249.4(NR2E3):c.200_208del (p.Cys67_Gly69del) is a short in-frame deletion variant within the zinc finger / DNA-binding domain of NR2E3.

CaseAddInfo: It is not clear whether the proband came from a consanguineous family.

CasePMIDs: N/A

Case#: Haider_2000_Proband_4, sex, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln) variant in the homozygous state.

ClinVarID: 5530

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0004046 in the South Asian population (36 alleles / 88,984 total alleles, with 1 homozygote) https://gnomad.broadinstitute.org/variant/chr15-71811591-G-A?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln) is a missense variant within the zinc finger / DNA-binding domain of NR2E3, and occurs at the same amino acid position as another missense substitution reported in the same article.

CaseAddInfo: It is not clear whether the proband came from a consanguineous family.

CasePMIDs: N/A

Case#: Haider_2000_Proband_5, female, age, and origin not reported

CasePresentingHPOs: N/A

CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: SSCP analysis of PCR products from NR2E3

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.

Variant: The individual harbors the NM_014249.4(NR2E3):c.290G>A (p.Arg97His) variant in the homozygous state.

ClinVarID: 867089

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00002441 in the European non-Finnish population (28 alleles / 1147036 total alleles, with 0 homozygotes). https://gnomad.broadinstitute.org/variant/chr15-71811810-G-A?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.290G>A (p.Arg97His) is a missense variant within the zinc finger / DNA-binding domain of NR2E3,.

CaseAddInfo: The proband comes from a consanguineous family with mother and father being first cousins, and two similarly affected sisters sharing the same homozygous genotype.

CasePMIDs: N/A

Case#: Kannabiran _2012_Proband_B-2, male, age 10 years at time of report, national origin from India

CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Retinal flecks HP:0012045, Decreased light- and dark-adapted electroretinogram amplitude (rod-cone pattern) HP:0000654, Retinal pigment epithelial atrophy HP:0007722

CaseHPOFreeText: The proband has a diagnosis of autosomal recessive retinitis pigmentosa, with phenotypes highly suggestive of enhanced S-cone syndrome. The proband had gliotic scars in the posterior pole. No OCT was performed, so it is unknown whether macula schisis was present.

CaseNotHPOs: Abnormal optic disc morphology HP:0012795, Abnormal retinal artery morphology HP:0000630, Bone spicule pigmentation of the retina HP:0007737

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping consisted of homozygosity mapping, which established linkage to a 41Mb region of chromosome 15, identifying NR2E3 and RLBP1 as the likely candidate loci.

CaseMethod1: Homozygosity mapping within the family of the proband

CaseMethod2: Sanger sequencing of NR2E3 and RLBP1

CaseGenotypingMethod: Genotyping was performed by homozygosity mapping within the family of the proband, followed by Sanger sequencing of NR2E3 and RLBP1.

Variant: The individual harbors the NM_014249.4(NR2E3):c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA (p.Arg48fs) variant in the homozygous state.

ClinVarID: 183143

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_014249.4(NR2E3):c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA (p.Arg48fs) is a frameshift variant in exon 2 of 8 that is predicted to introduce a premature stop codon and trigger nonsense-mediated decay.

CaseAddInfo: The proband has two unaffected heterozygous parents and an affected sister who shares the same homozygous genotype.

CasePMIDs: N/A

PMID: 11071390

Gene: NR2E3

HGNC: 7974

Disease: enhanced S-cone syndrome

MONDO: 0100288

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of enhanced S cone syndrome is <1 in 1,000,000 (PMID: 30900587).

Penetrance: The penetrance of enhanced S-cone syndrome has been difficult to determine accurately given the rarity of the condition.

ExperimentName: The Nr2e3rd7/rd7 mouse has aberrant proliferation of mitotic progenitors caused by aberrant expression of rod-specific and cone-specific genes such as blue opsin, resulting from failure to suppress the cone generation program and resulting aberrant expression of rod-specific and cone-specific genes.

NonHumanModel: Mus musculus

GeneAlteration: The Rd7 mouse model has been previously described in PMID: 10805811 and PMID: 11487564, and harbors a large out-of-frame deletion within the Nr2e3 locus in the homozygous state.

ModelPhenotype: Abnormal retinal morphology on macular (whorls and rosettes in outer nuclear layer) OCT HP:0030612, Retinal degeneration (late onset) HP:0000546, Retinal thinning HP:0030329

HumanPhenotype: Retinal degeneration HP:0000546, Sensory hypersensitivity (enhanced blue cone sensitivity) HP:5200058

ModelEvidence: The model has been previously published and exhibits ~30x enhanced blue cone sensitivity (PMID: 11487564), retinal spotting throughout the fundus including whorls in the outer nuclear layer (PMID: 11487564), and late onset retinal degeneration characterized by non-apoptotic cell death reduction of outer nuclear layer thickness (PMID: 34561487), and over-proliferation of ectopic retinal progenitors (PMID: 17266784), as well as increased expression of cone-associated genes (Figure 1).

ModelVariant: The model harbors a deletion of 380bp spanning intronic and coding regions, rather than a specific variant from a human patient.

PMID: 19379737

Gene: NR2E3

HGNC: 7974

Disease: enhanced S-cone syndrome

MONDO: 0100288

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of enhanced S cone syndrome is <1 in 1,000,000 (PMID: 30900587).

Penetrance: The penetrance of enhanced S-cone syndrome has been difficult to determine accurately given the rarity of the condition.

Case#: Al-khuzaei_2020_Patient_III, female, 10 years old at presentation of symptoms, 16 years old at time of report, racial origin indicated as Caucasian

CasePresentingHPOs: Photophobia HP:0000613, Photopsia HP:0030786, Nyctalopia HP:0000662, Constriction of peripheral visual field HP:0001133, Yellow/white lesions of the macula HP:0030500, Hyperautofluorescent retinal lesion HP:0025158, Photoreceptor layer loss on macular OCT (ellipsoid zone loss with preservation of the central retina) HP:0030609, Undetectable dark-adapted electroretinogram HP:0030474, Abnormal timing of light-adapted single flash electroretinogram HP:0030482, Abnormal amplitude of light-adapted single flash electroretinogram HP:0030481, Abnormal dark-adapted dim flash electroretinogram HP:0030471, Abnormal amplitude of dark-adapted dim flash electroretinogram HP:0030476, Ring scotoma HP:0030529, Patchy atrophy of the retinal pigment epithelium HP:0007791

CaseHPOFreeText: The proband has a diagnosis of enhanced S-cone sensitivity.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was performed by next-generation sequencing with a 111-gene panel.

CaseMethod1: Next-generation sequencing with a 111-gene panel.

CaseMethod2: Sanger sequencing of NR2E3

CaseGenotypingMethod: Genotyping was performed by next-generation sequencing with a 111-gene panel, followed by Sanger sequencing of NR2E3.

Variant: The individual harbors the maternal NM_014249.4(NR2E3):c.119-2A>C and paternal NM_014249.4(NR2E3):c.639_640insT (p.Pro214fs) variants in the compound heterozygous state.

ClinVarID: 191059, 1455685

gnomAD: The NM_014249.4(NR2E3):c.119-2A>C variant is found in gnomAD version 4.1.0 at a frequency of 0.001359 in the Ashkenazi Jewish population and 0.0007992 in the European (non-Finnish) population (919 / 1,149,942), with no homozygotes observed. https://gnomad.broadinstitute.org/variant/chr15-71811481-A-C?dataset=gnomad_r4 The NM_014249.4(NR2E3):c.639_640insT (p.Pro214fs) variant is found in gnomAD v4.1.1 at a frequency of 0.000008846 (1 allele / 113,042 total alleles) in the European (non-Finnish) population, with 0 homozygotes. https://www.ncbi.nlm.nih.gov/clinvar/variation/1455685/

VariantEvidence: NM_014249.4(NR2E3):c.119-2A>C is a canonical splice acceptor site variant adjacent to exon 2 of 6, which is an out-of-frame exon that could potentially trigger nonsense-mediated decay if skipped. This paper shows mRNA evidence that the variant triggers exon 2 skipping and introduces a premature stop codon in exon 3. NM_014249.4(NR2E3):c.639_640insT (p.Pro214fs) is a frameshift variant in exon 5 of 8 that introduces a premature stop codon and is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband has unaffected heterozygous carrier parents.

CasePMIDs: N/A

Case#: Bernal_2008_Proband_B-256, male, age 13 years at time of report, national origin from Spain

CasePresentingHPOs: Nyctalopia HP:0000662, Progressive visual loss HP:0000529, Reduced visual acuity HP:0007663, Retinoschisis HP:0030502, Nummular pigmentation of the fundus HP:0030505, Undetectable light- and dark-adapted electroretinogram HP:0007688

CaseHPOFreeText: The proband has a diagnosis of Goldmann–Favre syndrome, and had peripheral retinoschisis and macular cysts in both eyes.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3.

Variant: The individual harbors the NM_014249.4(NR2E3):c.932G>A (p.Arg311Gln) variant in the homozygous state.

ClinVarID: 5532

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.003986 in the Ashkenazi Jewish population, with a 118 alleles / 29604 total alleles and 1 homozygote. The variant also has a frequency of 0.0009829 in the Admixed American population. https://gnomad.broadinstitute.org/variant/chr15-71813573-G-A?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.932G>A (p.Arg311Gln) is a missense variant that is a well-known founder and has been reported in patients from multiple studies with diverse presentations. The variant partially disrupts the ability of NR2E3 to form stable dimers (PMID: 11071390).

CaseAddInfo: The proband has two unaffected heterozygous parents.

CasePMIDs: N/A

Case#: Bernal_2008_Proband_B-316, female, age 47 years at time of report, national origin from Spain

CasePresentingHPOs: Nyctalopia HP:0000662, Progressive visual loss HP:0000529, Reduced visual acuity HP:0007663, Severe constriction of peripheral visual field HP:0030526, Undetectable light- and dark-adapted electroretinogram HP:0007688

CaseHPOFreeText: The proband has a diagnosis of retinitis pigmentosa, and had clusters of large, clumped pigment deposits in the midperiphery of both eyes.

CaseNotHPOs: Macular schisis HP:0011511

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3.

Variant: The individual harbors the NM_014249.4(NR2E3):c.1034_1038del (p.Ala344_Leu345insTer) variant in the homozygous state.

ClinVarID: 5534

gnomAD: The variant was not found in gnomAD version 4.1.0.

VariantEvidence: NM_014249.4(NR2E3):c.1034_1038del (p.Ala344_Leu345insTer) is a frameshift variant that introduces a premature stop codon in exon 7 of 8 and is predicted to trigger nonsense-mediated decay.

CaseAddInfo: The proband has two affected siblings who share the same homozygous genotype and one unaffected heterozygous sibling. Parents have not been genotyped, but were indicated as consanguineous.

CasePMIDs: N/A

Case#: Bernal_2008_Proband_B-30, female, age 30 years at time of report, national origin from Spain

CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Reduced visual acuity HP:0007663, Constriction of peripheral visual field HP:0001133

CaseHPOFreeText: The proband has a diagnosis of retinitis pigmentosa, and had hypopigmented clumped lesions in the posterior pole of both eyes.

CaseNotHPOs: N/A

CaseNotHPOFreeText: N/A

CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3.

CaseMethod1: Sanger sequencing of NR2E3

CaseMethod2: N/A

CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3.

Variant: The individual harbors the NM_014249.4(NR2E3):c.119-2A>C variant in the homozygous state.

ClinVarID: 191059

gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.001359 in the Ashkenazi Jewish population and 0.0007992 in the European (non-Finnish) population (919 / 1,149,942), with no homozygotes observed. https://gnomad.broadinstitute.org/variant/chr15-71811481-A-C?dataset=gnomad_r4

VariantEvidence: NM_014249.4(NR2E3):c.119-2A>C is a canonical splice acceptor site variant adjacent to exon 2 of 6, which is an out-of-frame exon that could potentially trigger nonsense-mediated decay if skipped. This paper shows mRNA evidence that the variant triggers exon 2 skipping and introduces a premature stop codon in exon 3.

CaseAddInfo: The proband has an affected sibling who shares the same homozygous genotype.

CasePMIDs: N/A

PMID: 18294254

Gene: NR2E3

HGNC: 7974

Disease: enhanced S-cone syndrome

MONDO: 0100288

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of enhanced S cone syndrome is <1 in 1,000,000 (PMID: 30900587).

Penetrance: The penetrance of enhanced S-cone syndrome has been difficult to determine accurately given the rarity of the condition.

ExperimentName: AAV8-Nr2e3 rescue of rd7/rd7 mice

RescueModel: Mus musculus

GeneAlteration: Rescue was performed by subretinal injection of AAV8-Nr2e3 (or no treatment) into rd7/rd7 mice with homozygous disruption of endogenous Nr2e3

RescueVariant: No variant form of Nr2e3 was studied in this rescue experiment.

RescuePhenotype: The rescued phenotype is retinal spots in the fundus (Figure 3).

RescueMethod: This rescue model has introduction of the virally packaged mouse wild-type Nr2e3 gene.

RescueEvidence: Subretinal administration of the gene results in considerable improvement of the retinal spots in the fundus compared with untreated eyes 3 months post-injection (Figure 3).

ModelVariant: The model harbors homozygous out-of-frame deletion of 380 bp within the coding region of Nr2e3.

ExperimentName: NR2E3 physical interaction with NRL and CRX

InteractingGene: HGNC:8002 (NRL), HGNC:2383 (CRX)

InteractionType: Physical interaction

InteractionMethod: Co-immunoprecipitation

InteractionEvidence: Immunoprecipitation of NR2E3, NRL or CRX from bovine retinal nuclear extract successfully led to co-immunoprecipitation of the others, indicating their presence in a transcriptional regulatory complex (Figure 6).

PMID: 15190009

Gene: NR2E3

HGNC: 7974

Disease: enhanced S-cone syndrome

MONDO: 0100288

InheritancePattern: autosomal recessive

Prevalence: The overall prevalence of enhanced S cone syndrome is <1 in 1,000,000 (PMID: 30900587).

Penetrance: The penetrance of enhanced S-cone syndrome has been difficult to determine accurately given the rarity of the condition.