Isolated optic nerve hypoplasia

Summary

Isolated optic nerve hypoplasia (MONDO:0008136) is a disease with 3 cohort genes and 2 clinical trials. Top therapeutic interventions include melatonin and setmelanotide.

At a glance

• Cohort genes: 3
• ClinVar variants: 12
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated optic nerve hypoplasia
Mondo ID	MONDO:0008136
OMIM	165550
Orphanet	137902, 637061
DOID	DOID:0111531
ICD-11	609162974
SNOMED CT	724999003
UMLS	C1833797
MedGen	322281
GARD	0008419
NORD	1528
Is cancer (heuristic)	no

Also known as: familial bilateral optic nerve hypoplasia · Optic Nerve Hypoplasia · optic nerve hypoplasia, bilateral · optic nerve hypoplasia, familial bilateral

Data availability: 12 ClinVar variants · 1 GenCC gene-disease record · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › hereditary optic neuropathy › isolated optic nerve hypoplasia

Related subtypes (7): Leber hereditary optic neuropathy, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome, retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome, morning glory syndrome, autosomal recessive osteopetrosis, autosomal dominant optic atrophy, OPA1-related optic atrophy with or without extraocular features

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

12 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 pathogenic, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 2 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3474	NM_001368894.2(PAX6):c.1310A>T (p.Ter437Leu)	ELP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
279862	NM_001368894.2(PAX6):c.823C>T (p.Arg275Ter)	PAX6	Pathogenic	criteria provided, multiple submitters, no conflicts
3471	NM_001368894.2(PAX6):c.419T>A (p.Val140Asp)	PAX6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3476	NM_001368894.2(PAX6):c.655C>T (p.Gln219Ter)	PAX6	Pathogenic	criteria provided, multiple submitters, no conflicts
522379	NM_000280.4:c.1267A>T	PAX6	Likely pathogenic	criteria provided, single submitter
3769638	NM_152730.6(TBC1D32):c.1551del (p.Asn517fs)	TBC1D32	Likely pathogenic	no assertion criteria provided
2920693	NM_001368894.2(PAX6):c.400G>A (p.Val134Met)	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
800413	NM_001368894.2(PAX6):c.256G>C (p.Gly86Arg)	PAX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1385887	NM_001368894.2(PAX6):c.556_564del (p.Pro186_Gln188del)	PAX6	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382303	NM_001368894.2(PAX6):c.535G>T (p.Gly179Trp)	PAX6	Uncertain significance	criteria provided, single submitter
3769637	NM_152730.6(TBC1D32):c.3169+5C>A	TBC1D32	Uncertain significance	no assertion criteria provided
1652503	NM_001368894.2(PAX6):c.1221A>C (p.Ser407=)	PAX6	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 14 · 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
PAX6	Supportive	Autosomal dominant	isolated optic nerve hypoplasia	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAX6	Orphanet:1065	Aniridia-cerebellar ataxia-intellectual disability syndrome
PAX6	Orphanet:2253	Foveal hypoplasia-presenile cataract syndrome
PAX6	Orphanet:2334	Autosomal dominant keratitis
PAX6	Orphanet:250923	Isolated aniridia
PAX6	Orphanet:35737	Morning glory disc anomaly
PAX6	Orphanet:708	Peters anomaly
PAX6	Orphanet:893	WAGR syndrome
PAX6	Orphanet:98942	Coloboma of choroid and retina
PAX6	Orphanet:98943	Coloboma of eye lens
PAX6	Orphanet:98944	Coloboma of iris
PAX6	Orphanet:98945	Coloboma of macula
PAX6	Orphanet:98946	Coloboma of eyelid
PAX6	Orphanet:98947	Coloboma of optic disc
TBC1D32	Orphanet:141007	Orofaciodigital syndrome type 9

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
PAX6	HGNC:8620	ENSG00000007372	P26367	Paired box protein Pax-6	gencc,clinvar
ELP4	HGNC:1171	ENSG00000109911	Q96EB1	Elongator complex protein 4	clinvar
TBC1D32	HGNC:21485	ENSG00000146350	Q96NH3	Protein broad-minded	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAX6	Paired box protein Pax-6	Transcription factor with important functions in the development of the eye, nose, central nervous system and pancreas.
ELP4	Elongator complex protein 4	Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).
TBC1D32	Protein broad-minded	Required for high-level Shh responses in the developing neural tube.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.0

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
Transcription factor	1	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PAX6	Transcription factor	no		HD, Paired_dom, Homeodomain-like_sf
ELP4	Other/Unknown	no		Elongator_complex_protein_4, P-loop_NTPase
TBC1D32	Other/Unknown	no		BROMI_M, Rab-GAP_TBC_sf, PHAF1/BROMI

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	2
primordial germ cell in gonad	2
palpebral conjunctiva	1
type B pancreatic cell	1
calcaneal tendon	1
adrenal tissue	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAX6	201	broad	marker	palpebral conjunctiva, type B pancreatic cell, ventricular zone
ELP4	250	ubiquitous	marker	ventricular zone, calcaneal tendon, primordial germ cell in gonad
TBC1D32	208	ubiquitous	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAX6	4,971
ELP4	1,740
TBC1D32	919

Intra-cohort edges

A	B	Sources
ELP4	PAX6	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAX6	P26367	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBC1D32	Q96NH3	80.84
ELP4	Q96EB1	74.49

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Formation of the anterior neural plate	1	519.1×	0.006	PAX6
Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP)	1	439.2×	0.006	PAX6
Regulation of gene expression in beta cells	1	259.6×	0.006	PAX6
Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1)	1	259.6×	0.006	PAX6
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	45.7×	0.025	PAX6
HATs acetylate histones	1	39.6×	0.025	ELP4

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
lens development in camera-type eye	2	249.7×	0.002	PAX6, TBC1D32
pancreatic A cell development	1	5617.3×	0.003	PAX6
oligodendrocyte cell fate specification	1	5617.3×	0.003	PAX6
forebrain-midbrain boundary formation	1	5617.3×	0.003	PAX6
somatic motor neuron fate commitment	1	5617.3×	0.003	PAX6
habenula development	1	1872.4×	0.006	PAX6
regulation of asymmetric cell division	1	1404.3×	0.006	PAX6
regulation of timing of cell differentiation	1	1404.3×	0.006	PAX6
smoothened signaling pathway involved in dorsal/ventral neural tube patterning	1	1404.3×	0.006	TBC1D32
ventral spinal cord interneuron specification	1	936.2×	0.006	PAX6
commitment of neuronal cell to specific neuron type in forebrain	1	936.2×	0.006	PAX6
salivary gland morphogenesis	1	802.5×	0.006	PAX6
cerebral cortex regionalization	1	802.5×	0.006	PAX6
type B pancreatic cell differentiation	1	702.2×	0.006	PAX6
forebrain dorsal/ventral pattern formation	1	702.2×	0.006	PAX6
lacrimal gland development	1	702.2×	0.006	PAX6
ventral spinal cord development	1	624.1×	0.006	PAX6
positive regulation of epithelial cell differentiation	1	624.1×	0.006	PAX6
iris morphogenesis	1	624.1×	0.006	PAX6
retinal pigment epithelium development	1	561.7×	0.006	TBC1D32
dorsal/ventral axis specification	1	510.7×	0.006	PAX6
spinal cord motor neuron cell fate specification	1	510.7×	0.006	PAX6
cornea development in camera-type eye	1	432.1×	0.007	PAX6
tRNA wobble uridine modification	1	401.2×	0.007	ELP4
negative regulation of neuroblast proliferation	1	401.2×	0.007	PAX6
embryonic camera-type eye morphogenesis	1	374.5×	0.007	PAX6
cell fate determination	1	312.1×	0.009	PAX6
eye photoreceptor cell development	1	280.9×	0.009	PAX6
neuron fate commitment	1	267.5×	0.009	PAX6
astrocyte differentiation	1	255.3×	0.009	PAX6

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PAX6	0	0
ELP4	0	0
TBC1D32	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	PAX6, ELP4, TBC1D32

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)
PAX6	0	—
ELP4	0	—
TBC1D32	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06760546	PHASE3	RECRUITING	A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
NCT00825591	EARLY_PHASE1	COMPLETED	Biological Clock Dysfunction in Optic Nerve Hypoplasia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MELATONIN	4	1
SETMELANOTIDE	4	1
CHEMBL4067491	0	1