Microphthalmia, isolated, with coloboma

Summary

Microphthalmia, isolated, with coloboma (MONDO:0000170) is a disease (an umbrella term covering 12 Mondo subtypes) caused by RBP4 (GenCC Strong), with 10 cohort genes.

At a glance

• Prevalence: 1-5 / 10 000 (United Kingdom) [Orphanet-validated]
• Causal gene: RBP4 (GenCC Strong)
• Umbrella term: 12 Mondo subtypes
• Cohort genes: 10
• ClinVar variants: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	19	United Kingdom	Validated
Prevalence at birth	1-5 / 10 000	19	United Kingdom	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	microphthalmia, isolated, with coloboma
Mondo ID	MONDO:0000170
MeSH	C537463
OMIM	300345
Orphanet	98938
ICD-11	1208828500
UMLS	C2931500
MedGen	444071
GARD	0003644
Is cancer (heuristic)	no

Also known as: colobomatous microphthalmia · MAC · MCOPCB1 · microphthalmia associated with colobomatous cyst · microphthalmia with colobomatous cyst · microphthalmia-anophthalmia-coloboma syndrome · microphthalmos bilateral, colobomatous orbital cyst

Data availability: 1 ClinVar variant · 10 GenCC gene-disease records.

Disease family

An umbrella term covering 12 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › isolated microphthalmia › microphthalmia, isolated, with coloboma

Related subtypes (9): microphthalmia, isolated, with cataract 1, isolated microphthalmia 1, isolated microphthalmia 2, isolated microphthalmia 3, isolated microphthalmia 5, isolated microphthalmia 4, isolated microphthalmia 6, isolated microphthalmia 7, isolated microphthalmia 8

Subtypes (12): microphthalmia, isolated, with coloboma 4, microphthalmia with coloboma 2, microphthalmia, isolated, with coloboma 3, microphthalmia, isolated, with coloboma 5, microphthalmia, isolated, with coloboma 6, microphthalmia, isolated, with coloboma 7, microphthalmia, isolated, with coloboma 9, microphthalmia, isolated, with coloboma 10, microphthalmia with coloboma 1, microphthalmia, isolated, with coloboma 8, microphthalmia/coloboma 11, microphthalmia/coloboma 13

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
41942	NM_138425.4(C12orf57):c.1A>G (p.Met1Val)	C12orf57	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 77 · Orphanet: 33 · 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
SHH	Definitive	Autosomal dominant	microphthalmia, isolated, with coloboma 5	16
VSX2	Definitive	Autosomal recessive	microphthalmia, isolated, with coloboma 3	8
RBP4	Strong	Autosomal dominant	microphthalmia, isolated, with coloboma 10	11
TENM3	Strong	Autosomal recessive	microphthalmia, isolated, with coloboma 9	5
ABCB6	Supportive	Autosomal dominant	microphthalmia, isolated, with coloboma	10
GDF3	Supportive	Autosomal dominant	isolated Klippel-Feil syndrome	7
PORCN	Supportive	Autosomal dominant	microphthalmia, isolated, with coloboma	13
STRA6	Supportive	Autosomal dominant	microphthalmia, isolated, with coloboma	5
KIF17	Limited	Autosomal recessive	microphthalmia, isolated, with coloboma	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SHH	Orphanet:220386	Semilobar holoprosencephaly
SHH	Orphanet:280195	Septopreoptic holoprosencephaly
SHH	Orphanet:280200	Microform holoprosencephaly
SHH	Orphanet:476119	Autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome
SHH	Orphanet:485275	Acquired schizencephaly
SHH	Orphanet:93321	Isolated radial hemimelia
SHH	Orphanet:93336	Polydactyly of a triphalangeal thumb
SHH	Orphanet:93405	Syndactyly type 4
SHH	Orphanet:93924	Lobar holoprosencephaly
SHH	Orphanet:93925	Alobar holoprosencephaly
SHH	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
SHH	Orphanet:988	Tibial hemimelia-polysyndactyly-triphalangeal thumb syndrome
SHH	Orphanet:98938	Colobomatous microphthalmia
PORCN	Orphanet:2092	Focal dermal hypoplasia
PORCN	Orphanet:98938	Colobomatous microphthalmia
VSX2	Orphanet:98938	Colobomatous microphthalmia
TENM3	Orphanet:98938	Colobomatous microphthalmia
STRA6	Orphanet:2470	Matthew-Wood syndrome
STRA6	Orphanet:98938	Colobomatous microphthalmia
GDF3	Orphanet:2345	Isolated Klippel-Feil syndrome
GDF3	Orphanet:98938	Colobomatous microphthalmia
ABCB6	Orphanet:241	Dyschromatosis universalis hereditaria
ABCB6	Orphanet:90044	Familial pseudohyperkalemia
ABCB6	Orphanet:98938	Colobomatous microphthalmia
ABCB6	Orphanet:98942	Coloboma of choroid and retina
ABCB6	Orphanet:98943	Coloboma of eye lens
ABCB6	Orphanet:98944	Coloboma of iris
ABCB6	Orphanet:98945	Coloboma of macula
ABCB6	Orphanet:98946	Coloboma of eyelid
ABCB6	Orphanet:98947	Coloboma of optic disc
RBP4	Orphanet:352718	Progressive retinal dystrophy due to retinol transport defect
RBP4	Orphanet:98938	Colobomatous microphthalmia
C12orf57	Orphanet:1777	Temtamy syndrome

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SHH	HGNC:10848	ENSG00000164690	Q15465	Sonic hedgehog protein	gencc
PORCN	HGNC:17652	ENSG00000102312	Q9H237	Protein-serine O-palmitoleoyltransferase porcupine	gencc
KIF17	HGNC:19167	ENSG00000117245	Q9P2E2	Kinesin-like protein KIF17	gencc
VSX2	HGNC:1975	ENSG00000119614	P58304	Visual system homeobox 2	gencc
TENM3	HGNC:29944	ENSG00000218336	Q9P273	Teneurin-3	gencc
STRA6	HGNC:30650	ENSG00000137868	Q9BX79	Receptor for retinol uptake STRA6	gencc
GDF3	HGNC:4218	ENSG00000184344	Q9NR23	Growth/differentiation factor 3	gencc
ABCB6	HGNC:47	ENSG00000115657	Q9NP58	ATP-binding cassette sub-family B member 6	gencc
RBP4	HGNC:9922	ENSG00000138207	P02753	Retinol-binding protein 4	gencc
C12orf57	HGNC:29521	ENSG00000111678	Q99622	Protein C10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SHH	Sonic hedgehog protein	The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity.
PORCN	Protein-serine O-palmitoleoyltransferase porcupine	Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins.
KIF17	Kinesin-like protein KIF17	Together with RAB23 and IFT57, it is required for the localization of specific G protein-coupled receptors, such as dopamime receptor DRD1, to primary cilia.
VSX2	Visual system homeobox 2	Acts as a transcriptional regulator through binding to DNA at the consensus sequence 5’-[TC]TAATT[AG][AG]-3’ upstream of gene promoters.
TENM3	Teneurin-3	Involved in neural development by regulating the establishment of proper connectivity within the nervous system.
STRA6	Receptor for retinol uptake STRA6	Functions as a retinol transporter.
GDF3	Growth/differentiation factor 3	Growth factor involved in early embryonic development and adipose-tissue homeostasis.
ABCB6	ATP-binding cassette sub-family B member 6	ATP-dependent transporter that catalyzes the transport of a broad-spectrum of porphyrins from the cytoplasm to the extracellular space through the plasma membrane or into the vesicle lumen.
RBP4	Retinol-binding protein 4	Retinol-binding protein that mediates retinol transport in blood plasma.
C12orf57	Protein C10	In brain, may be required for corpus callosum development.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 6 · Druggable fraction: 0.2

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
Transporter	1	7.8×	0.607
Scaffold/PPI	1	1.7×	0.725
Enzyme (other)	1	1.2×	0.725
Other/Unknown	6	1.1×	0.725
Transcription factor	1	0.8×	0.725

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SHH	Other/Unknown	no		Hedgehog_signalling_dom, Hedgehog, Hedgehog_Hint
PORCN	Enzyme (other)	yes	2.3.1.250	MBOAT_fam, LPLAT_7/PORCN-like
KIF17	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
VSX2	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
TENM3	Scaffold/PPI	no		EGF, YD, CarboxyPept-like_regulatory
STRA6	Other/Unknown	no		STRA6-like
GDF3	Other/Unknown	no		TGF-b_C, TGF-beta-like, TGFb_CS
ABCB6	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
RBP4	Other/Unknown	no		Lipocln_cytosolic_FA-bd_dom, Retinol-bd/Purpurin, Calycin
C12orf57	Other/Unknown	no		Grcc10

Expression context

Cohort genes with no expression data: 0.

9 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)	1
broad (>20)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
right adrenal gland cortex	2
male germ line stem cell (sensu Vertebrata) in testis	2
primordial germ cell in gonad	2
stromal cell of endometrium	2
type B pancreatic cell	2
left ovary	2
buccal mucosa cell	1
epithelial cell of pancreas	1
lower esophagus mucosa	1
right adrenal gland	1
left testis	1
right testis	1
cortical plate	1
adrenal tissue	1
sural nerve	1
endometrium	1
placenta	1
right hemisphere of cerebellum	1
right ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SHH	131	broad	marker	buccal mucosa cell, right lobe of liver, epithelial cell of pancreas
PORCN	184	ubiquitous	marker	lower esophagus mucosa, right adrenal gland cortex, right adrenal gland
KIF17	177	broad	yes	left testis, right testis, right adrenal gland cortex
VSX2	11	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, cortical plate
TENM3	189	ubiquitous	marker	sural nerve, adrenal tissue, stromal cell of endometrium
STRA6	128	broad	marker	stromal cell of endometrium, endometrium, placenta
GDF3	82	tissue_specific	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, type B pancreatic cell
ABCB6	140	ubiquitous	marker	right ovary, right hemisphere of cerebellum, left ovary
RBP4	244	broad	marker	right lobe of liver, liver, type B pancreatic cell
C12orf57	145	ubiquitous	marker	thymus, left ovary, endocervix

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SHH	4,953
KIF17	1,713
TENM3	1,704
VSX2	1,484
ABCB6	1,480
STRA6	1,448
RBP4	1,143
GDF3	1,113
C12orf57	843
PORCN	802

Intra-cohort edges

A	B	Sources
GDF3	VSX2	string_interaction
RBP4	STRA6	string_interaction
SHH	VSX2	string_interaction
TENM3	VSX2	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 6 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RBP4	P02753	23
SHH	Q15465	20
ABCB6	Q9NP58	16
PORCN	Q9H237	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GDF3	Q9NR23	82.72
C12orf57	Q99622	81.41
STRA6	Q9BX79	78.18
TENM3	Q9P273	77.76
KIF17	Q9P2E2	64.81
VSX2	P58304	61.65

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 47. Enrichment computed across 10 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective visual phototransduction due to STRA6 loss of function	2	1268.9×	3e-05	STRA6, RBP4
The canonical retinoid cycle in rods (twilight vision)	2	173.0×	0.001	STRA6, RBP4
Defective ABCB6 causes MCOPCB7	1	1903.3×	0.006	ABCB6
Retinoid metabolism disease events	1	1903.3×	0.006	RBP4
LGK974 inhibits PORCN	1	951.7×	0.010	PORCN
Mitochondrial ABC transporters	1	475.8×	0.011	ABCB6
Retinoid cycle disease events	1	475.8×	0.011	STRA6
Diseases associated with visual transduction	1	475.8×	0.011	STRA6
Diseases of the neuronal system	1	475.8×	0.011	STRA6
HHAT G278V doesn’t palmitoylate Hh-Np	1	380.7×	0.011	SHH
Formation of lateral plate mesoderm	1	380.7×	0.011	SHH
Release of Hh-Np from the secreting cell	1	237.9×	0.014	SHH
Hh mutants abrogate ligand secretion	1	237.9×	0.014	SHH
Ligand-receptor interactions	1	237.9×	0.014	SHH
Formation of axial mesoderm	1	135.9×	0.022	SHH
Disease	3	6.5×	0.022	SHH, STRA6, ABCB6
Activation of SMO	1	105.7×	0.026	SHH
Developmental Lineage of Multipotent Pancreatic Progenitor Cells	1	100.2×	0.026	SHH
ABC transporter disorders	1	73.2×	0.033	ABCB6
WNT ligand biogenesis and trafficking	1	70.5×	0.033	PORCN
Developmental Lineage of Pancreatic Acinar Cells	1	50.1×	0.044	SHH
Visual phototransduction	1	43.3×	0.044	STRA6
Gastrulation	1	43.3×	0.044	SHH
Assembly and cell surface presentation of NMDA receptors	1	42.3×	0.044	KIF17
Retinoid metabolism and transport	1	41.4×	0.044	RBP4
Hh mutants are degraded by ERAD	1	40.5×	0.044	SHH
Developmental Cell Lineages	1	37.3×	0.046	SHH
Hedgehog ligand biogenesis	1	35.2×	0.047	SHH
Intraflagellar transport	1	33.4×	0.047	KIF17
Class B/2 (Secretin family receptors)	1	31.7×	0.047	SHH

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retinol transport	2	1685.2×	4e-05	STRA6, RBP4
vitamin A import into cell	2	1685.2×	4e-05	STRA6, RBP4
formation of anatomical boundary	2	842.6×	2e-04	SHH, GDF3
lung development	3	59.5×	1e-03	SHH, STRA6, RBP4
smooth muscle tissue development	2	210.7×	0.002	SHH, STRA6
camera-type eye morphogenesis	2	153.2×	0.003	C12orf57, TENM3
polarity specification of anterior/posterior axis	1	1685.2×	0.006	SHH
tetrapyrrole metabolic process	1	1685.2×	0.006	ABCB6
positive regulation of behavior	1	1685.2×	0.006	STRA6
trachea morphogenesis	1	1685.2×	0.006	SHH
right lung development	1	1685.2×	0.006	SHH
left lung development	1	1685.2×	0.006	SHH
primary prostatic bud elongation	1	1685.2×	0.006	SHH
regulation of prostatic bud formation	1	1685.2×	0.006	SHH
obsolete regulation of mesenchymal cell proliferation involved in prostate gland development	1	1685.2×	0.006	SHH
mesenchymal smoothened signaling pathway involved in prostate gland development	1	1685.2×	0.006	SHH
alveolar primary septum development	1	1685.2×	0.006	STRA6
positive regulation of sclerotome development	1	1685.2×	0.006	SHH
tracheoesophageal septum formation	1	1685.2×	0.006	SHH
negative regulation of ureter smooth muscle cell differentiation	1	1685.2×	0.006	SHH
positive regulation of ureter smooth muscle cell differentiation	1	1685.2×	0.006	SHH
negative regulation of kidney smooth muscle cell differentiation	1	1685.2×	0.006	SHH
positive regulation of kidney smooth muscle cell differentiation	1	1685.2×	0.006	SHH
embryonic skeletal system development	2	78.4×	0.006	SHH, RBP4
neuroblast proliferation	2	73.3×	0.006	SHH, VSX2
camera-type eye development	2	71.7×	0.006	SHH, STRA6
eye development	2	70.2×	0.006	GDF3, RBP4
cognition	2	57.1×	0.006	C12orf57, STRA6
heart development	3	23.6×	0.006	SHH, STRA6, RBP4
positive regulation of skeletal muscle cell proliferation	1	842.6×	0.008	SHH

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 7

Druggability breadth: 5 of 10 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SHH	VISMODEGIB
RBP4	RETINOL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RBP4	3	4
PORCN	2	2
SHH	1	4
KIF17	0	0
VSX2	0	0
TENM3	0	0
STRA6	0	0
GDF3	0	0
ABCB6	0	0
C12orf57	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VISMODEGIB	4	SHH
RETINOL	4	RBP4
TINLAREBANT	3	RBP4
FENRETINIDE	3	RBP4
WNT-974	2	PORCN
ETC-159	1	PORCN

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RBP4	32	Binding:29, Functional:3
PORCN	31	Binding:31
SHH	27	Binding:23, Functional:4
ABCB6	3	Functional:3
STRA6	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PORCN	2.3.1.250	[Wnt protein] O-palmitoleoyl transferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

6 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.

Compound	Max phase	Cohort target (bioactivity)
VISMODEGIB	4	SHH
RETINOL	4	RBP4
TINLAREBANT	3	RBP4
FENRETINIDE	3	RBP4
WNT-974	2	PORCN
ETC-159	1	PORCN

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SHH, RBP4
B	Phased (≥1) drug, not yet approved	1	PORCN
C	Druggable family + PDB, no drug	1	ABCB6
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	KIF17, VSX2, TENM3, STRA6, GDF3, C12orf57

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
STRA6	1	RBP4
KIF17	0	—
VSX2	0	—
TENM3	0	—
GDF3	0	—
ABCB6	3	—
C12orf57	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.