enhanced S-cone syndrome

Summary

enhanced S-cone syndrome (MONDO:0100288) is a disease caused by variants in NR2E3 and NRL, with 3 cohort genes and 1 clinical trial.

At a glance

• Causal genes: NR2E3 (GenCC Definitive), NRL (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 265
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	enhanced S-cone syndrome
Mondo ID	MONDO:0100288
MeSH	C564835
OMIM	268100
DOID	DOID:0090059
UMLS	C1849394
MedGen	341446
GARD	0026125
Is cancer (heuristic)	no

Also known as: enhanced S-cone syndrome · ESCS

Data availability: 265 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › vitreous body disorder › vitreous disorder › vitreous syneresis › vitreoretinal degeneration › enhanced S-cone syndrome

Related subtypes (8): Wagner disease, snowflake vitreoretinal degeneration, X-linked retinoschisis, Stickler syndrome, exudative vitreoretinopathy, CAPN5-related vitreoretinopathy, BEST1-related vitreoretinochoroidopathy, Knobloch syndrome

Subtypes (2): Goldmann-Favre syndrome, enhanced S-cone syndrome 2

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

265 retrieved; paginated sample, class counts are floors:

100 uncertain significance, 42 likely pathogenic, 38 conflicting classifications of pathogenicity, 35 pathogenic/likely pathogenic, 26 likely benign, 13 pathogenic, 6 benign, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068080	NM_014249.4(NR2E3):c.925C>G (p.Arg309Gly)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068708	NM_014249.4(NR2E3):c.241dup (p.Tyr81fs)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072667	NM_014249.4(NR2E3):c.250C>T (p.Gln84Ter)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1361677	NM_014249.4(NR2E3):c.119-2A>G	NR2E3	Pathogenic	criteria provided, multiple submitters, no conflicts
143147	NM_014249.4(NR2E3):c.364C>T (p.Arg122Cys)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1445894	NM_014249.4(NR2E3):c.731del (p.Leu244fs)	NR2E3	Pathogenic	criteria provided, multiple submitters, no conflicts
1452315	NM_014249.4(NR2E3):c.874del (p.Arg292fs)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452924	NM_014249.4(NR2E3):c.645C>A (p.Cys215Ter)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453001	NM_014249.4(NR2E3):c.1042C>T (p.Gln348Ter)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456422	NM_014249.4(NR2E3):c.131C>A (p.Ser44Ter)	NR2E3	Pathogenic	criteria provided, multiple submitters, no conflicts
183143	NM_014249.4(NR2E3):c.143_144delinsAGTGTGCCTCCAGTGCCTCGCTCCA (p.Arg48fs)	NR2E3	Pathogenic	criteria provided, multiple submitters, no conflicts
191059	NM_014249.4(NR2E3):c.119-2A>C	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191060	NM_014249.4(NR2E3):c.373C>T (p.Arg125Ter)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1928679	NM_014249.4(NR2E3):c.612_642del (p.Pro205fs)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1931456	NM_014249.3(NR2E3):c.1101delG	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1942248	NM_014249.4(NR2E3):c.996_997del	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137726	NM_014249.4(NR2E3):c.1095C>G (p.Pro365=)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137727	NM_014249.4(NR2E3):c.1220T>A (p.Met407Lys)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2155106	NM_014249.4(NR2E3):c.302_325del (p.Gln101_Cys108del)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677356	NM_014249.4(NR2E3):c.583del (p.Ile195fs)	NR2E3	Pathogenic	criteria provided, multiple submitters, no conflicts
2677357	NM_014249.4(NR2E3):c.336del (p.Gly112_Met113insTer)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677366	NM_014249.4(NR2E3):c.225_245+6del	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677369	NM_014249.4(NR2E3):c.803G>A (p.Trp268Ter)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2677371	NM_014249.4(NR2E3):c.119-2A>T	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2861010	NM_014249.4(NR2E3):c.1127del (p.Pro376fs)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438227	NM_014249.4(NR2E3):c.305C>A (p.Ala102Asp)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438228	NM_014249.4(NR2E3):c.311G>A (p.Arg104Gln)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438229	NM_014249.4(NR2E3):c.767C>A (p.Ala256Glu)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4815622	NM_014249.4(NR2E3):c.919_920del (p.Ile307fs)	NR2E3	Pathogenic	criteria provided, single submitter
551852	NM_014249.4(NR2E3):c.194_202del (p.Asn65_Cys67del)	NR2E3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 6 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NR2E3	Definitive	Autosomal recessive	enhanced S-cone syndrome	10
NRL	Definitive	Autosomal recessive	enhanced S-cone syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NR2E3	Orphanet:53540	Goldmann-Favre syndrome
NR2E3	Orphanet:791	Retinitis pigmentosa
NRL	Orphanet:791	Retinitis pigmentosa
SLC17A5	Orphanet:309324	Free sialic acid storage disease, infantile form
SLC17A5	Orphanet:309331	Intermediate severe Salla disease
SLC17A5	Orphanet:309334	Salla disease

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NR2E3	HGNC:7974	ENSG00000278570	Q9Y5X4	Photoreceptor-specific nuclear receptor	gencc,clinvar
NRL	HGNC:8002	ENSG00000129535	P54845	Neural retina-specific leucine zipper protein	gencc,clinvar
SLC17A5	HGNC:10933	ENSG00000119899	Q9NRA2	Sialin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NR2E3	Photoreceptor-specific nuclear receptor	Orphan nuclear receptor of retinal photoreceptor cells.
NRL	Neural retina-specific leucine zipper protein	Acts as a transcriptional activator which regulates the expression of several rod-specific genes, including RHO and PDE6B.
SLC17A5	Sialin	Multifunctional anion transporter that operates via two distinct transport mechanisms, namely proton-coupled anion cotransport and membrane potential-dependent anion transport.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Nuclear receptor	1	128.6×	0.023
Transporter	1	25.9×	0.057
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NR2E3	Nuclear receptor	yes		Retinoid-X_rcpt/HNF4, Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt
NRL	Transcription factor	no		bZIP_Maf, bZIP, TF_DNA-bd_sf
SLC17A5	Transporter	yes		MFS, MFS_dom, MFS_trans_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
buccal mucosa cell	1
secondary oocyte	1
cortical plate	1
hindlimb stylopod muscle	1
corpus epididymis	1
mucosa of sigmoid colon	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NR2E3	156	tissue_specific	marker	buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte
NRL	129	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, hindlimb stylopod muscle, cortical plate
SLC17A5	264	ubiquitous	marker	corpus epididymis, stromal cell of endometrium, mucosa of sigmoid colon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NR2E3	1,319
SLC17A5	1,170
NRL	937

Intra-cohort edges

A	B	Sources
NR2E3	NRL	biogrid_interaction, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC17A5	Q9NRA2	7
NR2E3	Q9Y5X4	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NRL	P54845	72.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC17A5 causes Salla disease (SD) and ISSD	1	5710.0×	0.003	SLC17A5
Organic anion transport by SLC5/17/25 transporters	1	713.8×	0.011	SLC17A5
Hyaluronan degradation	1	356.9×	0.015	SLC17A5
Sialic acid metabolism	1	163.1×	0.020	SLC17A5
Synthesis of substrates in N-glycan biosythesis	1	146.4×	0.020	SLC17A5
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	103.8×	0.020	SLC17A5
SLC transporter disorders	1	102.0×	0.020	SLC17A5
Nuclear Receptor transcription pathway	1	100.2×	0.020	NR2E3
Disorders of transmembrane transporters	1	69.6×	0.025	SLC17A5
R-HSA-425393	1	64.9×	0.025	SLC17A5
Asparagine N-linked glycosylation	1	30.1×	0.045	SLC17A5
SLC-mediated transmembrane transport	1	29.6×	0.045	SLC17A5
Transport of small molecules	1	12.6×	0.096	SLC17A5
Post-translational protein modification	1	9.6×	0.116	SLC17A5
Disease	1	6.5×	0.155	SLC17A5
Metabolism of proteins	1	6.2×	0.155	SLC17A5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sialic acid transport	1	5617.3×	0.003	SLC17A5
carbohydrate derivative transport	1	2808.7×	0.003	SLC17A5
visual perception	2	53.0×	0.003	NR2E3, NRL
neurotransmitter loading into synaptic vesicle	1	936.2×	0.005	SLC17A5
retinal rod cell development	1	561.7×	0.006	NRL
monoatomic anion transport	1	468.1×	0.006	SLC17A5
positive regulation of gene expression	2	25.8×	0.006	NR2E3, NRL
eye photoreceptor cell development	1	280.9×	0.009	NR2E3
phototransduction	1	165.2×	0.013	NR2E3
amino acid transport	1	104.0×	0.019	SLC17A5
retina development in camera-type eye	1	85.1×	0.021	NR2E3
positive regulation of transcription by RNA polymerase II	2	9.9×	0.022	NR2E3, NRL
response to bacterium	1	64.6×	0.024	SLC17A5
monoatomic ion transport	1	52.0×	0.027	SLC17A5
cell population proliferation	1	34.2×	0.037	NR2E3
neuron differentiation	1	33.4×	0.037	NR2E3
negative regulation of cell population proliferation	1	14.0×	0.082	NR2E3
negative regulation of transcription by RNA polymerase II	1	5.9×	0.178	NR2E3
signal transduction	1	5.3×	0.185	NR2E3
regulation of transcription by RNA polymerase II	1	3.9×	0.236	NRL

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR2E3	0	0
NRL	0	0
SLC17A5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
SLC17A5	14	Binding:14
NR2E3	6	Functional:5, Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	NR2E3, SLC17A5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NRL

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NR2E3	6	—
NRL	0	—
SLC17A5	14	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry