Norrie disease

Summary

Norrie disease (MONDO:0010691) is a disease caused by NDP (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NDP (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 40
• Phenotypes (HPO): 64

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		400	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

64 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000400	Macrotia	Very frequent (80-99%)
HP:0000446	Narrow nasal bridge	Very frequent (80-99%)
HP:0000490	Deeply set eye	Very frequent (80-99%)
HP:0000518	Cataract	Very frequent (80-99%)
HP:0000532	Chorioretinal abnormality	Very frequent (80-99%)
HP:0000568	Microphthalmia	Very frequent (80-99%)
HP:0000601	Hypotelorism	Very frequent (80-99%)
HP:0000618	Blindness	Very frequent (80-99%)
HP:0000647	Sclerocornea	Very frequent (80-99%)
HP:0007676	Hypoplasia of the iris	Very frequent (80-99%)
HP:0007833	Anterior chamber synechiae	Very frequent (80-99%)
HP:0007957	Corneal opacity	Very frequent (80-99%)
HP:0008046	Abnormal retinal vascular morphology	Very frequent (80-99%)
HP:0100012	Neoplasm of the eye	Very frequent (80-99%)
HP:0100742	Vascular neoplasm	Very frequent (80-99%)
HP:0000375	Abnormal cochlea morphology	Frequent (30-79%)
HP:0000541	Retinal detachment	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000709	Psychosis	Frequent (30-79%)
HP:0000733	Abnormal repetitive mannerisms	Frequent (30-79%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0004327	Abnormal vitreous humor morphology	Frequent (30-79%)
HP:0005293	Venous insufficiency	Frequent (30-79%)
HP:0006887	Intellectual disability, progressive	Frequent (30-79%)
HP:0007968	Remnants of the hyaloid vascular system	Frequent (30-79%)
HP:0008063	Aplasia/Hypoplasia of the lens	Frequent (30-79%)
HP:0100639	Erectile dysfunction	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000233	Thin vermilion border	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000272	Malar flattening	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000411	Protruding ear	Occasional (5-29%)
HP:0000501	Glaucoma	Occasional (5-29%)
HP:0000615	Abnormal pupil morphology	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0000717	Autism	Occasional (5-29%)
HP:0000738	Hallucinations	Occasional (5-29%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)
HP:0000823	Delayed puberty	Occasional (5-29%)
HP:0001083	Ectopia lentis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0002076	Migraine	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Norrie disease
Mondo ID	MONDO:0010691
MeSH	C537849
OMIM	310600
Orphanet	649
DOID	DOID:0060844
ICD-11	676214590
NCIT	C118634
SNOMED CT	15228007
UMLS	C0266526
MedGen	75615
GARD	0007224
MedDRA	10069760
NORD	1514
Is cancer (heuristic)	no

Also known as: Anderson-Warburg syndrome · atrophia bulborum hereditaria · Episkopi blindness · fetal iritis syndrome · foetal iritis syndrome · ND · NDP · Norrie disease · Norrie disease, X-linked recessive · Norrie syndrome · Norrie-Warburg disease · Norrie-Warburg syndrome · pseudoglioma

Data availability: 40 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital vitreoretinal dysplasia › Norrie disease

Related subtypes (8): osteoporosis-pseudoglioma syndrome, Coats disease, incontinentia pigmenti, spondylo-ocular syndrome, Coats plus syndrome, trisomy 13, retinal capillary malformation, persistent hyperplastic primary vitreous

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

40 retrieved; paginated sample, class counts are floors:

19 pathogenic, 11 likely pathogenic, 5 uncertain significance, 3 pathogenic/likely pathogenic, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
224624	NM_012193.4(FZD4):c.313A>G (p.Met105Val)	FZD4	Pathogenic	criteria provided, multiple submitters, no conflicts
10683	NM_000266.4(NDP):c.287G>A (p.Cys96Tyr)	NDP	Pathogenic	no assertion criteria provided
10686	NM_000266.4(NDP):c.384C>A (p.Cys128Ter)	NDP	Pathogenic	criteria provided, multiple submitters, no conflicts
10687	NM_000266.4(NDP):c.1A>G (p.Met1Val)	NDP	Pathogenic	criteria provided, multiple submitters, no conflicts
10689	NM_000266.4(NDP):c.38T>G (p.Leu13Arg)	NDP	Pathogenic	no assertion criteria provided
10690	NM_000266.4(NDP):c.181C>T (p.Leu61Phe)	NDP	Pathogenic	criteria provided, multiple submitters, no conflicts
10691	NM_000266.4(NDP):c.125A>G (p.His42Arg)	NDP	Pathogenic	criteria provided, multiple submitters, no conflicts
10693	NM_000266.4(NDP):c.313G>A (p.Ala105Thr)	NDP	Pathogenic	no assertion criteria provided
10696	NM_000266.4(NDP):c.288C>G (p.Cys96Trp)	NDP	Pathogenic	no assertion criteria provided
10698	NM_000266.4(NDP):c.218C>A (p.Ser73Ter)	NDP	Pathogenic	no assertion criteria provided
10699	NM_000266.4(NDP):c.302C>T (p.Ser101Phe)	NDP	Pathogenic	no assertion criteria provided
1213861	NM_000266.4(NDP):c.58G>T (p.Gly20Ter)	NDP	Pathogenic	criteria provided, single submitter
167326	NM_000266.4(NDP):c.220C>T (p.Arg74Cys)	NDP	Pathogenic	criteria provided, multiple submitters, no conflicts
1805040	NM_000266.4(NDP):c.223_224dup (p.Glu76fs)	NDP	Pathogenic	criteria provided, single submitter
285413	NM_000266.4(NDP):c.155T>A (p.Leu52Ter)	NDP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
92699	NM_000266.4(NDP):c.109C>T (p.Arg37Ter)	NDP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10681	NM_000266.4(NDP):c.179T>A (p.Val60Glu)	NDP-AS1	Pathogenic	no assertion criteria provided
10685	NM_000266.4(NDP):c.206G>C (p.Cys69Ser)	NDP-AS1	Pathogenic	no assertion criteria provided
10688	NM_000266.4(NDP):c.361C>T (p.Arg121Trp)	NDP-AS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10692	NM_000266.4(NDP):c.103del (p.Asp35fs)	NDP-AS1	Pathogenic	no assertion criteria provided
10697	NM_000266.4(NDP):c.134T>A (p.Val45Glu)	NDP-AS1	Pathogenic	no assertion criteria provided
236067	NM_012338.4(TSPAN12):c.542G>T (p.Cys181Phe)	TSPAN12	Pathogenic	criteria provided, multiple submitters, no conflicts
10680	NM_000266.4(NDP):c.224C>G (p.Ser75Cys)	NDP	Likely pathogenic	criteria provided, single submitter
10682	NM_000266.4(NDP):c.131A>G (p.Tyr44Cys)	NDP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172720	NM_000266.4(NDP):c.355A>C (p.Thr119Pro)	NDP	Likely pathogenic	criteria provided, single submitter
1339550	NM_000266.4(NDP):c.242T>C (p.Phe81Ser)	NDP	Likely pathogenic	criteria provided, single submitter
1705321	NM_000266.4(NDP):c.131_132del (p.Tyr44fs)	NDP	Likely pathogenic	criteria provided, single submitter
1805158	NM_000266.4(NDP):c.307C>G (p.Leu103Val)	NDP	Likely pathogenic	criteria provided, single submitter
3242164	NM_000266.4(NDP):c.181C>A (p.Leu61Ile)	NDP	Likely pathogenic	criteria provided, single submitter
3382646	NM_000266.4(NDP):c.334_349dup (p.Thr117fs)	NDP	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 9 · 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
NDP	Definitive	X-linked	Norrie disease	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NDP	Orphanet:190	Coats disease
NDP	Orphanet:649	Norrie disease
NDP	Orphanet:891	Familial exudative vitreoretinopathy
NDP	Orphanet:90050	Retinopathy of prematurity
NDP	Orphanet:91495	Persistent hyperplastic primary vitreous
TSPAN12	Orphanet:891	Familial exudative vitreoretinopathy
FZD4	Orphanet:891	Familial exudative vitreoretinopathy
FZD4	Orphanet:90050	Retinopathy of prematurity
FZD4	Orphanet:91495	Persistent hyperplastic primary vitreous

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NDP	HGNC:7678	ENSG00000124479	Q00604	Norrin	gencc,clinvar
TSPAN12	HGNC:21641	ENSG00000106025	O95859	Tetraspanin-12	clinvar
NDP-AS1	HGNC:40395	ENSG00000236276		NDP antisense RNA 1	clinvar
FZD4	HGNC:4042	ENSG00000174804	Q9ULV1	Frizzled-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDP	Norrin	Activates the canonical Wnt signaling pathway through FZD4 and LRP5 coreceptor.
TSPAN12	Tetraspanin-12	Regulator of cell surface receptor signal transduction.
FZD4	Frizzled-4	Receptor for Wnt proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
GPCR	1	6.0×	0.314
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NDP	Other/Unknown	no		Norrie_dis, Cys_knot_C, Glyco_hormone_CN
TSPAN12	Other/Unknown	no		Tetraspanin_animals, Tetraspanin_EC2_sf, Tetraspanin/Peripherin
NDP-AS1	Other/Unknown	no
FZD4	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM

Expression context

Cohort genes with no expression data: 0.

2 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
caudate nucleus	1
cranial nerve II	1
decidua	1
nephron tubule	1
oocyte	1
secondary oocyte	1
endometrium	1
ganglionic eminence	1
ventricular zone	1
adipose tissue	1
right lung	1
subcutaneous adipose tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDP	197	broad	yes	cranial nerve II, decidua, caudate nucleus
TSPAN12	267	ubiquitous	marker	oocyte, nephron tubule, secondary oocyte
NDP-AS1	67		yes	ganglionic eminence, ventricular zone, endometrium
FZD4	243	ubiquitous	marker	adipose tissue, subcutaneous adipose tissue, right lung

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FZD4	1,869
NDP	1,461
TSPAN12	686
NDP-AS1	0

Intra-cohort edges

A	B	Sources
FZD4	NDP	biogrid_interaction, intact, string_interaction
FZD4	TSPAN12	string_interaction
NDP	TSPAN12	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NDP	Q00604	12
FZD4	Q9ULV1	11
TSPAN12	O95859	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 4 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by RNF43 mutants	1	1268.9×	0.005	FZD4
WNT5A-dependent internalization of FZD4	1	761.3×	0.005	FZD4
Regulation of FZD by ubiquitination	1	519.1×	0.005	FZD4
Asymmetric localization of PCP proteins	1	203.9×	0.007	FZD4
Class B/2 (Secretin family receptors)	1	190.3×	0.007	FZD4
Ca2+ pathway	1	178.4×	0.007	FZD4
Cargo recognition for clathrin-mediated endocytosis	1	104.8×	0.011	FZD4
Clathrin-mediated endocytosis	1	85.2×	0.012	FZD4

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
Norrin signaling pathway	3	3370.4×	9e-10	NDP, TSPAN12, FZD4
extracellular matrix-cell signaling	2	2246.9×	7e-06	NDP, FZD4
retinal blood vessel morphogenesis	2	1605.0×	1e-05	NDP, FZD4
establishment of blood-brain barrier	2	936.2×	2e-05	NDP, FZD4
endothelial cell differentiation	2	749.0×	3e-05	NDP, FZD4
angiogenesis	3	62.4×	5e-05	NDP, TSPAN12, FZD4
retina layer formation	2	432.1×	7e-05	NDP, TSPAN12
canonical Wnt signaling pathway	2	102.1×	0.001	NDP, FZD4
cerebellum vasculature morphogenesis	1	5617.3×	0.001	FZD4
progesterone secretion	1	2808.7×	0.002	FZD4
retina blood vessel maintenance	1	2808.7×	0.002	NDP
re-entry into mitotic cell cycle	1	1872.4×	0.003	NDP
Wnt signaling pathway, calcium modulating pathway	1	1404.3×	0.003	FZD4
cone retinal bipolar cell differentiation	1	1404.3×	0.003	NDP
retina vasculature morphogenesis in camera-type eye	1	1123.5×	0.004	FZD4
glycine metabolic process	1	936.2×	0.004	NDP
regulation of vascular endothelial growth factor receptor signaling pathway	1	936.2×	0.004	FZD4
establishment of blood-retinal barrier	1	936.2×	0.004	NDP
locomotion involved in locomotory behavior	1	802.5×	0.004	FZD4
positive regulation of neuron projection arborization	1	702.2×	0.005	FZD4
retinal rod cell differentiation	1	624.1×	0.005	NDP
microglial cell proliferation	1	624.1×	0.005	NDP
ubiquitin-dependent endocytosis	1	624.1×	0.005	NDP
retinal pigment epithelium development	1	561.7×	0.005	NDP
L-serine metabolic process	1	561.7×	0.005	NDP
vacuole organization	1	510.7×	0.005	NDP
microglia differentiation	1	510.7×	0.005	NDP
optic nerve development	1	401.2×	0.006	NDP
dendritic spine development	1	401.2×	0.006	NDP
negative regulation of cell-substrate adhesion	1	351.1×	0.006	FZD4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NDP	0	0
TSPAN12	0	0
NDP-AS1	0	0
FZD4	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
FZD4	7	Functional:6, 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	1	FZD4
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	NDP, TSPAN12, NDP-AS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NDP	0	—
TSPAN12	0	—
NDP-AS1	0	—
FZD4	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.