Syndromic microphthalmia type 5

Summary

Syndromic microphthalmia type 5 (MONDO:0012413) is a disease caused by OTX2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: OTX2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 51

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	syndromic microphthalmia type 5
Mondo ID	MONDO:0012413
MeSH	C566441
OMIM	610125
Orphanet	178364
DOID	DOID:0111806
SNOMED CT	718761007
UMLS	C1864690
MedGen	350491
GARD	0003692
Is cancer (heuristic)	no

Also known as: MCOPS5 · microphthalmia syndromic 5 · microphthalmia, syndromic 5 · microphthalmia, syndromic type 5 · OTX2 syndromic microphthalmia · OTX2-related eye disorders · syndromic microphthalmia caused by mutation in OTX2 · syndromic microphthalmia type 5 · syndromic microphthalmia/anophthalmia due to OTX2 mutation

Data availability: 51 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic microphthalmia › syndromic microphthalmia type 5

Related subtypes (18): anophthalmia/microphthalmia-esophageal atresia syndrome, COFS syndrome, microphthalmia, syndromic 2, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, microphthalmia, syndromic 1, linear skin defects with multiple congenital anomalies, Matthew-Wood syndrome, MMEP syndrome, microphthalmia with brain and digit anomalies, microphthalmia-brain atrophy syndrome, oculoauricular syndrome, microphthalmia, syndromic 11, microphthalmia, syndromic 12, colobomatous microphthalmia-rhizomelic dysplasia syndrome, microphthalmia, Lenz type, Behrens Baumann dust syndrome, microphthalmia microtia fetal akinesia, RAB18 deficiency

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

51 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 19 pathogenic, 6 likely pathogenic, 3 benign/likely benign, 2 conflicting classifications of pathogenicity, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1184455	NM_021728.4(OTX2):c.634_640del (p.Tyr212fs)	OTX2	Pathogenic	no assertion criteria provided
1320211	NM_021728.4(OTX2):c.728dup (p.Ala244fs)	OTX2	Pathogenic	criteria provided, single submitter
190249	NM_021728.4(OTX2):c.316del (p.Gln106fs)	OTX2	Pathogenic	no assertion criteria provided
190250	NM_021728.4(OTX2):c.289C>T (p.Arg97Ter)	OTX2	Pathogenic	criteria provided, single submitter
2444436	NM_021728.4(OTX2):c.591T>G (p.Tyr197Ter)	OTX2	Pathogenic	criteria provided, multiple submitters, no conflicts
30024	NM_021728.4(OTX2):c.428_429dup (p.Ser144fs)	OTX2	Pathogenic	no assertion criteria provided
30025	NM_021728.4(OTX2):c.437C>G (p.Ser146Ter)	OTX2	Pathogenic	no assertion criteria provided
30026	NM_021728.4(OTX2):c.245_260del (p.Lys82fs)	OTX2	Pathogenic	no assertion criteria provided
30027	NM_021728.4(OTX2):c.586G>T (p.Gly196Ter)	OTX2	Pathogenic	criteria provided, single submitter
30028	NM_021728.4(OTX2):c.294A>T (p.Arg98Ser)	OTX2	Pathogenic	no assertion criteria provided
500507	NM_172337.2(OTX2):c.402dup (p.Ser135Leufs)	OTX2	Pathogenic	criteria provided, multiple submitters, no conflicts
545433	NM_021728.4(OTX2):c.781_784del (p.Thr261fs)	OTX2	Pathogenic	criteria provided, single submitter
561071	NM_021728.4(OTX2):c.673del (p.Ala225fs)	OTX2	Pathogenic	criteria provided, single submitter
666555	NM_021728.4(OTX2):c.749del (p.Gly250fs)	OTX2	Pathogenic	criteria provided, single submitter
812111	NM_021728.4(OTX2):c.811del (p.Thr271fs)	OTX2	Pathogenic	criteria provided, single submitter
9515	NM_021728.4(OTX2):c.487_488dup (p.Ser164fs)	OTX2	Pathogenic	no assertion criteria provided
9516	NM_021728.4(OTX2):c.289C>G (p.Arg97Gly)	OTX2	Pathogenic	no assertion criteria provided
9517	NM_021728.4(OTX2):c.81del (p.Ser28fs)	OTX2	Pathogenic	no assertion criteria provided
9518	NM_021728.4(OTX2):c.561T>A (p.Tyr187Ter)	OTX2	Pathogenic	criteria provided, single submitter
3338471	GRCh37/hg19 14q22.2-22.3(chr14:54866611-57272174)x1	ATG14	Likely pathogenic	no assertion criteria provided
1332784	NM_021728.4(OTX2):c.278G>T (p.Trp93Leu)	OTX2	Likely pathogenic	criteria provided, single submitter
190251	NM_021728.4(OTX2):c.259G>A (p.Glu87Lys)	OTX2	Likely pathogenic	criteria provided, single submitter
3062100	NM_021728.4(OTX2):c.150G>C (p.Arg50Ser)	OTX2	Likely pathogenic	criteria provided, single submitter
3382712	NM_021728.4(OTX2):c.706_725del (p.Thr236fs)	OTX2	Likely pathogenic	criteria provided, single submitter
4292789	NM_021728.4(OTX2):c.761C>G (p.Ser254Ter)	OTX2	Likely pathogenic	criteria provided, single submitter
288894	NM_021728.4(OTX2):c.641C>A (p.Thr214Asn)	OTX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
803030	NM_021728.4(OTX2):c.425C>G (p.Pro142Arg)	OTX2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1417039	NM_021728.4(OTX2):c.380G>A (p.Arg127Gln)	OTX2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1687464	NM_021728.4(OTX2):c.278G>C (p.Trp93Ser)	OTX2	Uncertain significance	criteria provided, single submitter
2412735	NM_021728.4(OTX2):c.677_678insTGTG (p.Leu227fs)	OTX2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 7 · 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
OTX2	Definitive	Autosomal dominant	syndromic microphthalmia type 5	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OTX2	Orphanet:178364	Syndromic microphthalmia type 5
OTX2	Orphanet:3157	Septo-optic dysplasia spectrum
OTX2	Orphanet:35612	Nanophthalmos
OTX2	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
OTX2	Orphanet:98938	Colobomatous microphthalmia
OTX2	Orphanet:990	Agnathia-holoprosencephaly-situs inversus syndrome
OTX2	Orphanet:99001	Butterfly-shaped pigment dystrophy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OTX2	HGNC:8522	ENSG00000165588	P32243	Homeobox protein OTX2	gencc,clinvar
ATG14	HGNC:19962	ENSG00000126775	Q6ZNE5	Beclin 1-associated autophagy-related key regulator	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OTX2	Homeobox protein OTX2	Transcription factor probably involved in the development of the brain and the sense organs.
ATG14	Beclin 1-associated autophagy-related key regulator	Required for both basal and inducible autophagy.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OTX2	Transcription factor	no		HD, Otx2_TF, Otx_TF
ATG14	Enzyme (other)	yes	2.7.1.137	UV_resistance/autophagy_Atg14

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
secondary oocyte	2
pigmented layer of retina	1
gluteal muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OTX2	62	broad	marker	secondary oocyte, oocyte, pigmented layer of retina
ATG14	292	ubiquitous	marker	secondary oocyte, oocyte, gluteal muscle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OTX2	2,368
ATG14	2,086

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATG14	Q6ZNE5	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OTX2	P32243	60.99

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 2 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 posterior neural plate	1	571.0×	0.015	OTX2
Formation of the anterior neural plate	1	519.1×	0.015	OTX2
Dengue virus modulates apoptosis	1	356.9×	0.015	ATG14
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	196.9×	0.020	ATG14
Autophagy	1	74.2×	0.039	ATG14
SARS-CoV-2-host interactions	1	59.5×	0.039	ATG14
Macroautophagy	1	57.7×	0.039	ATG14
SARS-CoV-2 activates/modulates innate and adaptive immune responses	1	44.6×	0.044	ATG14
SARS-CoV-2 Infection	1	40.2×	0.044	ATG14
Class I MHC mediated antigen processing & presentation	1	35.0×	0.045	ATG14
SARS-CoV Infections	1	27.7×	0.052	ATG14
Viral Infection Pathways	1	15.4×	0.081	ATG14
Adaptive Immune System	1	14.9×	0.081	ATG14
Infectious disease	1	12.4×	0.090	ATG14
Disease	1	6.5×	0.148	ATG14
Immune System	1	6.5×	0.148	ATG14

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to mitochondrial depolarisation	1	1404.3×	0.006	ATG14
autophagosome membrane docking	1	1203.7×	0.006	ATG14
regulation of fibroblast growth factor receptor signaling pathway	1	1203.7×	0.006	OTX2
positive regulation of gastrulation	1	1203.7×	0.006	OTX2
regulation of triglyceride metabolic process	1	1053.2×	0.006	ATG14
primitive streak formation	1	702.2×	0.007	OTX2
phosphatidylinositol-3-phosphate biosynthetic process	1	648.1×	0.007	ATG14
positive regulation of embryonic development	1	561.7×	0.007	OTX2
regulation of protein complex stability	1	526.6×	0.007	ATG14
post-transcriptional regulation of gene expression	1	324.1×	0.007	ATG14
early endosome to late endosome transport	1	324.1×	0.007	ATG14
protein targeting to lysosome	1	312.1×	0.007	ATG14
regulation of smoothened signaling pathway	1	312.1×	0.007	OTX2
dopaminergic neuron differentiation	1	312.1×	0.007	OTX2
midbrain development	1	300.9×	0.007	OTX2
negative regulation of protein phosphorylation	1	290.6×	0.007	ATG14
forebrain development	1	175.5×	0.010	OTX2
autophagosome maturation	1	175.5×	0.010	ATG14
endosome to lysosome transport	1	168.5×	0.010	ATG14
cellular response to glucose starvation	1	168.5×	0.010	ATG14
mitophagy	1	159.0×	0.010	ATG14
regulation of macroautophagy	1	147.8×	0.010	ATG14
positive regulation of protein phosphorylation	1	138.1×	0.011	ATG14
macroautophagy	1	120.4×	0.012	ATG14
autophagosome assembly	1	112.3×	0.012	ATG14
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	105.3×	0.012	ATG14
cellular response to starvation	1	96.8×	0.013	ATG14
protein-containing complex assembly	1	56.9×	0.021	OTX2
axon guidance	1	45.3×	0.026	OTX2
defense response to virus	1	34.7×	0.032	ATG14

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
OTX2	0	0
ATG14	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ATG14	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATG14	2.7.1.137	phosphatidylinositol 3-kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	ATG14
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	OTX2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
OTX2	0	—
ATG14	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.