blepharophimosis - intellectual disability syndrome, MKB type

Summary

blepharophimosis - intellectual disability syndrome, MKB type (MONDO:0010477) is a disease caused by MED12 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: MED12 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 69
• Phenotypes (HPO): 8

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0000280	Coarse facial features	Frequent (30-79%)
HP:0000325	Triangular face	Frequent (30-79%)
HP:0000414	Bulbous nose	Frequent (30-79%)
HP:0000448	Prominent nose	Frequent (30-79%)
HP:0000581	Blepharophimosis	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0009928	Thick nasal alae	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	blepharophimosis - intellectual disability syndrome, MKB type
Mondo ID	MONDO:0010477
OMIM	300895
Orphanet	293707
SNOMED CT	699297004
UMLS	C3698541
MedGen	785805
GARD	0017341
Is cancer (heuristic)	no

Also known as: blepharophimosis-intellectual disability syndrome, Maat-Kievit-Brunner type · blepharophimosis-mental retardation syndrome, Maat-Kievit-Brunner type · BMRS, Maat-Kievit-Brunner type · BMRS, MKB type · Ohdo syndrome, X-linked · Ohdo syndrome, X-linked, X-linked recessive · OHDOX · X-linked Ohdo syndrome

Data availability: 69 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome-intellectual disability › blepharophimosis - intellectual disability syndrome › Ohdo syndrome and variants › blepharophimosis - intellectual disability syndrome, MKB type

Related subtypes (2): blepharophimosis - intellectual disability syndrome, Ohdo type, blepharophimosis - intellectual disability syndrome, SBBYS type

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

69 retrieved; paginated sample, class counts are floors:

28 uncertain significance, 10 conflicting classifications of pathogenicity, 8 benign/likely benign, 7 likely pathogenic, 5 pathogenic/likely pathogenic, 5 benign, 5 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
452540	NM_005120.3(MED12):c.1547G>A (p.Arg516His)	LOC126863275	Pathogenic	criteria provided, multiple submitters, no conflicts
11520	NM_005120.3(MED12):c.2881C>T (p.Arg961Trp)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1201510	NM_005120.3(MED12):c.3646G>A (p.Val1216Met)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1210242	NM_005120.3(MED12):c.3412C>T (p.Arg1138Trp)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3064230	NM_005120.3(MED12):c.6352C>T (p.Gln2118Ter)	MED12	Pathogenic	criteria provided, single submitter
3382729	NM_005120.3(MED12):c.3129del (p.Ser1044fs)	MED12	Pathogenic	criteria provided, single submitter
382204	NM_005120.3(MED12):c.4831C>T (p.Arg1611Cys)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50280	NM_005120.3(MED12):c.3493T>C (p.Ser1165Pro)	MED12	Pathogenic	no assertion criteria provided
50281	NM_005120.3(MED12):c.5185C>A (p.His1729Asn)	MED12	Pathogenic	no assertion criteria provided
522111	NM_005120.3(MED12):c.887G>A (p.Arg296Gln)	MED12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1210236	NM_005120.3(MED12):c.2669T>A (p.Ile890Asn)	MED12	Likely pathogenic	no assertion criteria provided
1210257	NM_005120.3(MED12):c.6448C>T (p.Gln2150Ter)	MED12	Likely pathogenic	criteria provided, single submitter
1685374	NM_005120.3(MED12):c.1248+3A>G	MED12	Likely pathogenic	criteria provided, single submitter
3897849	NM_005120.3(MED12):c.6439C>T (p.Gln2147Ter)	MED12	Likely pathogenic	criteria provided, single submitter
427070	NM_005120.3(MED12):c.6476A>C (p.Gln2159Pro)	MED12	Likely pathogenic	criteria provided, single submitter
975295	NM_005120.3(MED12):c.5578C>T (p.Pro1860Ser)	MED12	Likely pathogenic	no assertion criteria provided
975296	NM_005120.3(MED12):c.6407A>G (p.Gln2136Arg)	MED12	Likely pathogenic	no assertion criteria provided
1319901	NM_005120.3(MED12):c.439G>A (p.Ala147Thr)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1696529	NM_005120.3(MED12):c.4413G>A (p.Lys1471=)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213624	NM_005120.3(MED12):c.4147G>A (p.Ala1383Thr)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213627	NM_005120.3(MED12):c.6097A>G (p.Met2033Val)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213631	NM_005120.3(MED12):c.1039A>G (p.Ser347Gly)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213632	NM_005120.3(MED12):c.1264C>T (p.Arg422Trp)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
213633	NM_005120.3(MED12):c.1849A>G (p.Thr617Ala)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
50279	NM_005120.3(MED12):c.3443G>A (p.Arg1148His)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
931587	NM_005120.3(MED12):c.1996A>G (p.Met666Val)	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
95246	NM_005120.3(MED12):c.2849+14C>T	MED12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
857059	NM_005120.3(MED12):c.1376C>T (p.Thr459Ile)	LOC126863275	Uncertain significance	criteria provided, single submitter
1200703	NM_005120.3(MED12):c.3760G>A (p.Gly1254Arg)	MED12	Uncertain significance	criteria provided, multiple submitters, no conflicts
1327474	NM_005120.3(MED12):c.823C>G (p.Leu275Val)	MED12	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 5 · 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
MED12	Definitive	X-linked	X-linked intellectual disability with marfanoid habitus	21

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left ovary	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MED12	3,322

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MED12	Q93074	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 1 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
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	215.5×	0.019	MED12
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	196.9×	0.019	MED12
Respiratory Syncytial Virus Infection Pathway	1	196.9×	0.019	MED12
RSV-host interactions	1	156.4×	0.019	MED12
Adipogenesis	1	156.4×	0.019	MED12
Epigenetic regulation by WDR5-containing histone modifying complexes	1	154.3×	0.019	MED12
Regulation of lipid metabolism by PPARalpha	1	141.0×	0.019	MED12
Transcriptional regulation of white adipocyte differentiation	1	129.8×	0.019	MED12
PPARA activates gene expression	1	94.4×	0.024	MED12
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	82.8×	0.024	MED12
Epigenetic regulation of gene expression	1	71.4×	0.025	MED12
Metabolism of lipids	1	31.6×	0.050	MED12
Viral Infection Pathways	1	30.8×	0.050	MED12
Infectious disease	1	24.8×	0.058	MED12
RNA Polymerase II Transcription	1	22.5×	0.059	MED12
Gene expression (Transcription)	1	17.8×	0.070	MED12
Generic Transcription Pathway	1	15.1×	0.077	MED12
Developmental Biology	1	14.5×	0.077	MED12
Disease	1	13.1×	0.080	MED12
Metabolism	1	11.6×	0.086	MED12

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
axis elongation involved in somitogenesis	1	5617.3×	0.003	MED12
embryonic neurocranium morphogenesis	1	1872.4×	0.004	MED12
Schwann cell development	1	1053.2×	0.004	MED12
embryonic brain development	1	802.5×	0.004	MED12
post-anal tail morphogenesis	1	732.7×	0.004	MED12
endoderm development	1	624.1×	0.004	MED12
oligodendrocyte development	1	601.9×	0.004	MED12
spinal cord development	1	510.7×	0.004	MED12
Wnt signaling pathway, planar cell polarity pathway	1	455.5×	0.004	MED12
positive regulation of transcription initiation by RNA polymerase II	1	271.8×	0.006	MED12
somatic stem cell population maintenance	1	247.8×	0.006	MED12
neural tube closure	1	187.2×	0.007	MED12
heart development	1	78.8×	0.016	MED12
protein ubiquitination	1	41.4×	0.028	MED12
positive regulation of DNA-templated transcription	1	27.9×	0.038	MED12
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	MED12

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MED12	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	MED12

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MED12	6	Binding:6

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	MED12

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	1	MED12
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.