Microphthalmia with brain and digit anomalies

Summary

Microphthalmia with brain and digit anomalies (MONDO:0011936) is a disease caused by BMP4 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: BMP4 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 208
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000528	Anophthalmia	Very frequent (80-99%)
HP:0000568	Microphthalmia	Very frequent (80-99%)
HP:0000482	Microcornea	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000567	Chorioretinal coloboma	Frequent (30-79%)
HP:0000612	Iris coloboma	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000556	Retinal dystrophy	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000647	Sclerocornea	Occasional (5-29%)
HP:0000864	Abnormality of the hypothalamus-pituitary axis	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001830	Postaxial foot polydactyly	Occasional (5-29%)
HP:0002164	Nail dysplasia	Occasional (5-29%)
HP:0006101	Finger syndactyly	Occasional (5-29%)
HP:0007068	Inferior vermis hypoplasia	Occasional (5-29%)
HP:0009623	Proximal placement of thumb	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	microphthalmia with brain and digit anomalies
Mondo ID	MONDO:0011936
MeSH	C566440
OMIM	607932
Orphanet	139471
DOID	DOID:0111805
SNOMED CT	721878003
UMLS	C1864689
MedGen	355268
GARD	0003645
Is cancer (heuristic)	no

Also known as: anophthalmia clinical with micrognathia malformed ears digital anomalies and abnormal external genitalia · Bakrania-Ragge syndrome · MCOPS6 · microphthalmia syndromic 6 · microphthalmia with brain and digit anomalies · microphthalmia, syndromic 6 · microphthalmia, syndromic type 6 · syndromic microphthalmia type 6

Data availability: 208 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic microphthalmia › microphthalmia with brain and digit anomalies

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, syndromic microphthalmia type 5, 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

208 retrieved; paginated sample, class counts are floors:

112 uncertain significance, 40 likely benign, 25 conflicting classifications of pathogenicity, 10 benign, 8 benign/likely benign, 7 pathogenic, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071168	NC_000014.8:g.(?_54416336)_54418690del	BMP4	Pathogenic	criteria provided, single submitter
1458344	NM_001202.6(BMP4):c.205_214del (p.Arg69fs)	BMP4	Pathogenic	criteria provided, single submitter
17700	NM_001202.6(BMP4):c.226_227del (p.Ser76fs)	BMP4	Pathogenic	no assertion criteria provided
29615	NC_000014.9:g.(53815591_53825260)_(53983697_53984391)del	BMP4	Pathogenic	no assertion criteria provided
29616	NM_001202.6(BMP4):c.592C>T (p.Arg198Ter)	BMP4	Pathogenic	criteria provided, multiple submitters, no conflicts
29617	NM_001202.6(BMP4):c.171dup (p.Glu58fs)	BMP4	Pathogenic	no assertion criteria provided
1455396	NC_000014.8:g.(?54416750)(55369403_?)del	SAMD4A	Pathogenic	criteria provided, single submitter
3236711	NM_001202.6(BMP4):c.371-2A>G	BMP4	Likely pathogenic	no assertion criteria provided
3370344	NM_001202.6(BMP4):c.602del (p.Asp201fs)	BMP4	Likely pathogenic	criteria provided, single submitter
3899988	NM_001202.6(BMP4):c.323dup (p.Arg109fs)	BMP4	Likely pathogenic	no assertion criteria provided
4291771	NM_001202.6(BMP4):c.253del (p.Asp85fs)	BMP4	Likely pathogenic	criteria provided, single submitter
4813345	NM_001202.6(BMP4):c.533T>G (p.Ile178Arg)	BMP4	Likely pathogenic	criteria provided, single submitter
4819603	NM_001202.6(BMP4):c.187del (p.Gln63fs)	BMP4	Likely pathogenic	criteria provided, single submitter
1195040	NM_001202.6(BMP4):c.677G>A (p.Arg226Gln)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1311100	NM_001202.6(BMP4):c.351G>A (p.Val117=)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1331305	NM_001202.6(BMP4):c.766C>T (p.Arg256Ter)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1381981	NM_001202.6(BMP4):c.118G>A (p.Gly40Ser)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1595389	NM_001202.6(BMP4):c.485G>A (p.Arg162Gln)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1691786	NM_001202.6(BMP4):c.863G>A (p.Arg288Gln)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
17703	NM_001202.6(BMP4):c.272C>G (p.Ser91Cys)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2063217	NM_001202.6(BMP4):c.838C>T (p.Arg280Trp)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2205310	NM_001202.6(BMP4):c.1099A>C (p.Ser367Arg)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225304	NM_001202.6(BMP4):c.751C>T (p.His251Tyr)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2927135	NM_001202.6(BMP4):c.461C>T (p.Ser154Phe)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
29618	NM_001202.6(BMP4):c.362A>G (p.His121Arg)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3026515	NM_001202.6(BMP4):c.856C>T (p.Arg286Ter)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
313354	NM_001202.6(BMP4):c.215A>G (p.Gln72Arg)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
388306	NM_001202.6(BMP4):c.898C>T (p.Arg300Trp)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424492	NM_001202.6(BMP4):c.512G>A (p.Trp171Ter)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
468357	NM_001202.6(BMP4):c.76T>C (p.Leu26=)	BMP4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 4 · 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
BMP4	Definitive	Autosomal dominant	microphthalmia with brain and digit anomalies	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BMP4	Orphanet:139471	Microphthalmia with brain and digit anomalies
BMP4	Orphanet:199306	Cleft lip/palate
BMP4	Orphanet:828	Stickler syndrome
BMP4	Orphanet:93100	Renal agenesis, unilateral

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
BMP4	HGNC:1071	ENSG00000125378	P12644	Bone morphogenetic protein 4	gencc,clinvar
SAMD4A	HGNC:23023	ENSG00000020577	Q9UPU9	Protein Smaug homolog 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BMP4	Bone morphogenetic protein 4	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including neurogenesis, vascular development, angiogenesis and osteogenesis.
SAMD4A	Protein Smaug homolog 1	Acts as a translational repressor of SRE-containing messengers.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BMP4	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
SAMD4A	Other/Unknown	no		SAM, SAM/pointed_sf, PHAT_dom_sf

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
pigmented layer of retina	1
rectum	1
retina	1
dorsal motor nucleus of vagus nerve	1
heart right ventricle	1
inferior olivary complex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BMP4	189	ubiquitous	marker	pigmented layer of retina, retina, rectum
SAMD4A	288	ubiquitous	marker	dorsal motor nucleus of vagus nerve, inferior olivary complex, heart right ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BMP4	4,425
SAMD4A	1,078

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SAMD4A	Q9UPU9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BMP4	P12644	79.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 2 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
Formation of lateral plate mesoderm	1	2284.0×	0.004	BMP4
Formation of intermediate mesoderm	1	1427.5×	0.004	BMP4
Specification of primordial germ cells	1	878.5×	0.004	BMP4
Kidney development	1	815.7×	0.004	BMP4
Germ layer formation at gastrulation	1	671.8×	0.004	BMP4
Formation of the nephric duct	1	634.4×	0.004	BMP4
Specification of the neural plate border	1	634.4×	0.004	BMP4
Formation of the ureteric bud	1	496.5×	0.005	BMP4
Formation of paraxial mesoderm	1	407.9×	0.005	BMP4
Elastic fibre formation	1	335.9×	0.006	BMP4
Molecules associated with elastic fibres	1	308.6×	0.006	BMP4
Gastrulation	1	259.6×	0.006	BMP4
Reproduction	1	190.3×	0.008	BMP4
Post-translational protein phosphorylation	1	100.2×	0.014	BMP4
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.015	BMP4
Extracellular matrix organization	1	63.1×	0.019	BMP4
Post-translational protein modification	1	19.2×	0.058	BMP4
Developmental Biology	1	14.5×	0.073	BMP4
Metabolism of proteins	1	12.4×	0.081	BMP4

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
intermediate mesodermal cell differentiation	1	8426.0×	0.002	BMP4
positive regulation of cardiac muscle fiber development	1	8426.0×	0.002	BMP4
bronchus development	1	8426.0×	0.002	BMP4
bud dilation involved in lung branching	1	8426.0×	0.002	BMP4
mammary gland formation	1	8426.0×	0.002	BMP4
negative regulation of mesenchymal cell proliferation involved in ureter development	1	8426.0×	0.002	BMP4
negative regulation of glomerulus development	1	8426.0×	0.002	BMP4
regulation of mesodermal cell differentiation	1	8426.0×	0.002	BMP4
negative regulation of metanephric S-shaped body morphogenesis	1	8426.0×	0.002	BMP4
negative regulation of metanephric comma-shaped body morphogenesis	1	8426.0×	0.002	BMP4
tendon cell differentiation	1	4213.0×	0.002	BMP4
positive regulation of branching involved in lung morphogenesis	1	4213.0×	0.002	BMP4
negative regulation of glomerular mesangial cell proliferation	1	4213.0×	0.002	BMP4
negative regulation of branching involved in ureteric bud morphogenesis	1	4213.0×	0.002	BMP4
positive regulation of primary miRNA processing	1	4213.0×	0.002	BMP4
mesodermal cell fate determination	1	2808.7×	0.002	BMP4
specification of animal organ position	1	2808.7×	0.002	BMP4
regulation of cell fate commitment	1	2808.7×	0.002	BMP4
deltoid tuberosity development	1	2808.7×	0.002	BMP4
trachea development	1	2808.7×	0.002	BMP4
glomerular capillary formation	1	2808.7×	0.002	BMP4
nephric duct formation	1	2808.7×	0.002	BMP4
positive regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis	1	2808.7×	0.002	BMP4
lens induction in camera-type eye	1	2106.5×	0.002	BMP4
prostatic bud formation	1	2106.5×	0.002	BMP4
epithelial-mesenchymal cell signaling	1	2106.5×	0.002	BMP4
negative regulation of prostatic bud formation	1	2106.5×	0.002	BMP4
regulation of protein import into nucleus	1	1685.2×	0.002	BMP4
negative regulation of striated muscle tissue development	1	1685.2×	0.002	BMP4
regulation of smooth muscle cell differentiation	1	1685.2×	0.002	BMP4

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
BMP4	0	0
SAMD4A	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
BMP4	2	Binding:2

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	BMP4, SAMD4A

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)
BMP4	2	—
SAMD4A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.