Microphthalmia, syndromic 12

Summary

Microphthalmia, syndromic 12 (MONDO:0014229) is a disease caused by RARB (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RARB (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 62

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		25	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	microphthalmia, syndromic 12
Mondo ID	MONDO:0014229
OMIM	615524
Orphanet	689829
DOID	DOID:0111800
UMLS	C3809803
MedGen	816133
GARD	0013235
Is cancer (heuristic)	no

Also known as: MCOPS12 · microphthalmia, syndromic 12 · microphthalmia, syndromic type 12 · RARB syndromic microphthalmia · syndromic microphthalmia caused by mutation in RARB · syndromic microphthalmia-12

Data availability: 62 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic microphthalmia › microphthalmia, syndromic 12

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, syndromic microphthalmia type 5, microphthalmia-brain atrophy syndrome, oculoauricular syndrome, microphthalmia, syndromic 11, 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

62 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 13 likely benign, 10 likely pathogenic, 8 benign, 4 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 3 pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
218339	NM_000965.5(RARB):c.638T>C (p.Leu213Pro)	RARB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
809439	NM_000965.5(RARB):c.1210C>T (p.Gln404Ter)	RARB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88760	NM_000965.5(RARB):c.355C>T (p.Arg119Ter)	RARB	Pathogenic	no assertion criteria provided
88761	NM_000965.5(RARB):c.1205_1206dup (p.Ile403fs)	RARB	Pathogenic	no assertion criteria provided
88762	NM_000965.5(RARB):c.1159C>T (p.Arg387Cys)	RARB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88763	NM_000965.5(RARB):c.1159C>A (p.Arg387Ser)	RARB	Pathogenic	no assertion criteria provided
988355	NM_000965.5(RARB):c.1193C>G (p.Ser398Ter)	RARB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338852	NM_000965.5(RARB):c.881G>T (p.Gly294Val)	RARB	Likely pathogenic	criteria provided, single submitter
218338	NM_000965.5(RARB):c.887G>C (p.Gly296Ala)	RARB	Likely pathogenic	criteria provided, single submitter
3376953	NM_000965.5(RARB):c.640G>T (p.Asp214Tyr)	RARB	Likely pathogenic	criteria provided, single submitter
3377400	NM_000965.5(RARB):c.1199C>T (p.Pro400Leu)	RARB	Likely pathogenic	criteria provided, single submitter
3776082	NM_000965.5(RARB):c.1205_1206del (p.Leu402fs)	RARB	Likely pathogenic	criteria provided, single submitter
4755515	NM_000965.5(RARB):c.674C>A (p.Ala225Asp)	RARB	Likely pathogenic	criteria provided, single submitter
559901	NM_000965.5(RARB):c.872A>T (p.His291Leu)	RARB	Likely pathogenic	criteria provided, single submitter
800775	NM_000965.5(RARB):c.1180G>T (p.Glu394Ter)	RARB	Likely pathogenic	no assertion criteria provided
870386	NM_000965.5(RARB):c.835T>G (p.Phe279Val)	RARB	Likely pathogenic	criteria provided, single submitter
988076	NM_000965.5(RARB):c.1151G>A (p.Gly384Asp)	RARB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2423443	NC_000003.11:g.(?25470223)(25824881_?)del	NGLY1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1102389	NM_000965.5(RARB):c.264A>T (p.Ser88=)	RARB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2721928	NM_000965.5(RARB):c.1250C>G (p.Thr417Ser)	RARB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1035194	NM_000965.5(RARB):c.224dup (p.Arg76fs)	RARB	Uncertain significance	criteria provided, single submitter
1328391	NM_000965.5(RARB):c.1181A>G (p.Glu394Gly)	RARB	Uncertain significance	no assertion criteria provided
1706544	NM_000965.5(RARB):c.602A>G (p.Tyr201Cys)	RARB	Uncertain significance	criteria provided, single submitter
1969155	NM_000965.5(RARB):c.634C>T (p.Arg212Ter)	RARB	Uncertain significance	criteria provided, single submitter
2687511	NM_000965.5(RARB):c.157+1895G>A	RARB	Uncertain significance	criteria provided, single submitter
2770133	NM_000965.5(RARB):c.158-1G>A	RARB	Uncertain significance	criteria provided, single submitter
2801261	NM_000965.5(RARB):c.646G>A (p.Gly216Ser)	RARB	Uncertain significance	criteria provided, multiple submitters, no conflicts
2807006	NM_000965.5(RARB):c.545A>G (p.Glu182Gly)	RARB	Uncertain significance	criteria provided, single submitter
2841110	NM_000965.5(RARB):c.683G>T (p.Cys228Phe)	RARB	Uncertain significance	criteria provided, single submitter
3775945	NM_000965.5(RARB):c.683G>A (p.Cys228Tyr)	RARB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
RARB	Definitive	Autosomal dominant	microphthalmia, syndromic 12	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RARB	Orphanet:689829	Microphthalmia-motor delay-language delay-brain anomalies-diaphragmatic hernia syndrome
NGLY1	Orphanet:404454	Alacrimia-choreoathetosis-liver dysfunction syndrome

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
RARB	HGNC:9865	ENSG00000077092	P10826	Retinoic acid receptor beta	gencc,clinvar
NGLY1	HGNC:17646	ENSG00000151092	Q96IV0	Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RARB	Retinoic acid receptor beta	Receptor for retinoic acid.
NGLY1	Peptide-N(4)-(N-acetyl-beta-glucosaminyl)asparagine amidase	Specifically deglycosylates the denatured form of N-linked glycoproteins in the cytoplasm and assists their proteasome-mediated degradation.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Nuclear receptor	1	192.9×	0.010
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RARB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
NGLY1	Enzyme (other)	yes	3.5.1.52	Transglutaminase-like, Peptide_N_glycanase_PAW_dom, Galactose-bd-like_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
buccal mucosa cell	1
choroid plexus epithelium	1
palpebral conjunctiva	1
male germ cell	1
right testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RARB	210	ubiquitous	marker	choroid plexus epithelium, palpebral conjunctiva, buccal mucosa cell
NGLY1	290	ubiquitous	marker	sperm, male germ cell, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RARB	2,185
NGLY1	1,442

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RARB	P10826	9
NGLY1	Q96IV0	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	211.5×	0.010	NGLY1
Signaling by Retinoic Acid	1	203.9×	0.010	RARB
Nuclear Receptor transcription pathway	1	100.2×	0.013	RARB
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	45.7×	0.022	RARB

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
glandular epithelial cell development	1	1685.2×	0.006	RARB
ventricular cardiac muscle cell differentiation	1	1203.7×	0.006	RARB
growth plate cartilage development	1	1053.2×	0.006	RARB
embryonic eye morphogenesis	1	766.0×	0.006	RARB
striatum development	1	561.7×	0.006	RARB
glycoprotein catabolic process	1	526.6×	0.006	NGLY1
embryonic digestive tract development	1	495.6×	0.006	RARB
regulation of myelination	1	443.5×	0.006	RARB
negative regulation of stem cell proliferation	1	421.3×	0.006	RARB
negative regulation of chondrocyte differentiation	1	337.0×	0.006	RARB
neural precursor cell proliferation	1	337.0×	0.006	RARB
outflow tract septum morphogenesis	1	324.1×	0.006	RARB
retinoic acid receptor signaling pathway	1	324.1×	0.006	RARB
embryonic hindlimb morphogenesis	1	290.6×	0.007	RARB
ureteric bud development	1	227.7×	0.007	RARB
positive regulation of BMP signaling pathway	1	227.7×	0.007	NGLY1
stem cell proliferation	1	156.0×	0.010	RARB
neurogenesis	1	104.0×	0.014	RARB
multicellular organism growth	1	68.5×	0.021	RARB
protein folding	1	51.7×	0.026	NGLY1
positive regulation of apoptotic process	1	28.4×	0.045	RARB
negative regulation of apoptotic process	1	17.4×	0.070	RARB
cell differentiation	1	14.6×	0.077	RARB
apoptotic process	1	14.3×	0.077	RARB
negative regulation of transcription by RNA polymerase II	1	8.9×	0.118	RARB
signal transduction	1	8.0×	0.125	RARB
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	RARB

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
RARB	BEXAROTENE
NGLY1	DACTINOMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RARB	18	4
NGLY1	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEXAROTENE	4	RARB
AMOXICILLIN	4	RARB
ADAPALENE	4	RARB
TOLCAPONE	4	RARB
KETOCONAZOLE	4	RARB
CYCLOSPORINE	4	RARB
TAZAROTENE	4	RARB
TAMIBAROTENE	4	RARB
TRIFAROTENE	4	RARB
TRETINOIN	4	RARB
TROGLITAZONE	4	RARB
TROVAFLOXACIN	4	RARB
ALPROSTADIL	4	RARB
IBUPROFEN	4	RARB
ZAFIRLUKAST	4	RARB
ALITRETINOIN	4	RARB
DACTINOMYCIN	4	NGLY1
CONESSINE	2	RARB
GLIQUIDONE	2	RARB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
RARB	278	Binding:199, Functional:78, ADMET:1
NGLY1	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NGLY1	3.5.1.52	peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RARB	278

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

19 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)
BEXAROTENE	4	RARB
AMOXICILLIN	4	RARB
ADAPALENE	4	RARB
TOLCAPONE	4	RARB
KETOCONAZOLE	4	RARB
CYCLOSPORINE	4	RARB
TAZAROTENE	4	RARB
TAMIBAROTENE	4	RARB
TRIFAROTENE	4	RARB
TRETINOIN	4	RARB
TROGLITAZONE	4	RARB
TROVAFLOXACIN	4	RARB
ALPROSTADIL	4	RARB
IBUPROFEN	4	RARB
ZAFIRLUKAST	4	RARB
ALITRETINOIN	4	RARB
DACTINOMYCIN	4	NGLY1
CONESSINE	2	RARB
GLIQUIDONE	2	RARB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	RARB, NGLY1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.