Menke-Hennekam syndrome 1

Summary

Menke-Hennekam syndrome 1 (MONDO:0020763) is a disease caused by CREBBP (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: CREBBP (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 332

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Menke-Hennekam syndrome 1
Mondo ID	MONDO:0020763
OMIM	618332
UMLS	C5193034
MedGen	1675629
GARD	0025241
Is cancer (heuristic)	no

Also known as: Menke-Hennekam syndrome 1 · MKHK1

Data availability: 332 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Menke-Hennekam syndrome › Menke-Hennekam syndrome 1

Related subtypes (1): Menke-Hennekam syndrome 2

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

332 retrieved; paginated sample, class counts are floors:

160 uncertain significance, 75 conflicting classifications of pathogenicity, 40 benign/likely benign, 26 likely benign, 11 likely pathogenic, 9 pathogenic, 9 pathogenic/likely pathogenic, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
158359	NM_004380.3(CREBBP):c.3779+1G>A	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
158388	NM_004380.3(CREBBP):c.5821C>T (p.Gln1941Ter)	CREBBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684506	NM_004380.3(CREBBP):c.6043dup (p.Ser2015fs)	CREBBP	Pathogenic	criteria provided, single submitter
1685673	NM_004380.3(CREBBP):c.5169C>G (p.Cys1723Trp)	CREBBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1703236	NM_004380.3(CREBBP):c.5558A>C (p.Gln1853Pro)	CREBBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
209145	NM_004380.3(CREBBP):c.5614A>G (p.Met1872Val)	CREBBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
252628	NM_004380.3(CREBBP):c.5615T>C (p.Met1872Thr)	CREBBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265346	NM_004380.3(CREBBP):c.5602C>T (p.Arg1868Trp)	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
3580667	NM_004380.3(CREBBP):c.904_905del (p.Ser302fs)	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
3767134	NM_004380.3(CREBBP):c.5368T>C (p.Cys1790Arg)	CREBBP	Pathogenic	criteria provided, single submitter
3895541	NM_004380.3(CREBBP):c.5227_5229del (p.Val1743del)	CREBBP	Pathogenic	criteria provided, single submitter
429336	NM_004380.3(CREBBP):c.5600G>A (p.Arg1867Gln)	CREBBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
434831	NM_004380.3(CREBBP):c.1237C>T (p.Arg413Ter)	CREBBP	Pathogenic	criteria provided, multiple submitters, no conflicts
521159	NM_004380.3(CREBBP):c.4894TTC[1] (p.Phe1633del)	CREBBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
619090	NM_004380.3(CREBBP):c.5128T>C (p.Cys1710Arg)	CREBBP	Pathogenic	no assertion criteria provided
619094	NM_004380.3(CREBBP):c.5170G>A (p.Glu1724Lys)	CREBBP	Pathogenic	criteria provided, single submitter
871516	NM_004380.3(CREBBP):c.5599C>T (p.Arg1867Trp)	CREBBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9433	NM_004380.3(CREBBP):c.3832G>A (p.Glu1278Lys)	CREBBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066341	NM_004380.3(CREBBP):c.5060C>T (p.Ser1687Phe)	CREBBP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184818	NM_004380.3(CREBBP):c.5609CCA[1] (p.Thr1871del)	CREBBP	Likely pathogenic	no assertion criteria provided
1676444	NM_004380.3(CREBBP):c.5961_5981delinsGCAT (p.Met1988fs)	CREBBP	Likely pathogenic	criteria provided, single submitter
1706589	NM_004380.3(CREBBP):c.5356C>G (p.Arg1786Gly)	CREBBP	Likely pathogenic	criteria provided, single submitter
2582704	NM_004380.3(CREBBP):c.5168G>T (p.Cys1723Phe)	CREBBP	Likely pathogenic	no assertion criteria provided
3382571	NM_004380.3(CREBBP):c.3836+5G>A	CREBBP	Likely pathogenic	criteria provided, single submitter
3777191	NM_004380.3(CREBBP):c.3779+2dup	CREBBP	Likely pathogenic	criteria provided, single submitter
4294502	NM_004380.3(CREBBP):c.1780G>T (p.Glu594Ter)	CREBBP	Likely pathogenic	criteria provided, single submitter
4531607	NM_004380.3(CREBBP):c.5240T>G (p.Leu1747Arg)	CREBBP	Likely pathogenic	criteria provided, single submitter
591453	NM_004380.3(CREBBP):c.5344G>A (p.Ala1782Thr)	CREBBP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
694829	NM_004380.3(CREBBP):c.4991G>A (p.Arg1664His)	CREBBP	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030788	NM_004380.3(CREBBP):c.7184T>C (p.Ile2395Thr)	CREBBP	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
CREBBP	Strong	Autosomal dominant	Menke-Hennekam syndrome 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CREBBP	Orphanet:353277	Rubinstein-Taybi syndrome due to CREBBP mutations
CREBBP	Orphanet:353281	Rubinstein-Taybi syndrome due to 16p13.3 microdeletion
CREBBP	Orphanet:370026	Acute myeloid leukemia with t(8;16)(p11;p13) translocation
CREBBP	Orphanet:592574	Menke-Hennekam syndrome

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
CREBBP	HGNC:2348	ENSG00000005339	Q92793	CREB-binding protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CREBBP	CREB-binding protein	Acetylates histones, giving a specific tag for transcriptional activation.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CREBBP	Transcription factor	no	2.3.1.48	Znf_TAZ, Znf_ZZ, Bromodomain

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
amniotic fluid	1
sural nerve	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CREBBP	297	ubiquitous	marker	sural nerve, tibia, amniotic fluid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CREBBP	6,959

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CREBBP	Q92793	144

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 125. 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
LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production	1	2284.0×	0.007	CREBBP
NFE2L2 regulating inflammation associated genes	1	2284.0×	0.007	CREBBP
NFE2L2 regulating ER-stress associated genes	1	2284.0×	0.007	CREBBP
RUNX1 regulates transcription of genes involved in differentiation of myeloid cells	1	1427.5×	0.007	CREBBP
NFE2L2 regulates pentose phosphate pathway genes	1	1427.5×	0.007	CREBBP
NFE2L2 regulating MDR associated enzymes	1	1427.5×	0.007	CREBBP
Regulation of NFE2L2 gene expression	1	1427.5×	0.007	CREBBP
Regulation of FOXO transcriptional activity by acetylation	1	1142.0×	0.007	CREBBP
Regulation of gene expression by Hypoxia-inducible Factor	1	951.7×	0.007	CREBBP
Activation of the TFAP2 (AP-2) family of transcription factors	1	951.7×	0.007	CREBBP
NFE2L2 regulating tumorigenic genes	1	951.7×	0.007	CREBBP
Cellular response to hypoxia	1	878.5×	0.007	CREBBP
Phosphorylation of CLOCK, acetylation of BMAL1 (ARNTL) at target gene promoters	1	878.5×	0.007	CREBBP
RUNX3 regulates NOTCH signaling	1	815.7×	0.007	CREBBP
TRAF3-dependent IRF activation pathway	1	761.3×	0.007	CREBBP
R-HSA-1368082	1	713.8×	0.007	CREBBP
Regulation of beta-cell development	1	713.8×	0.007	CREBBP
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	713.8×	0.007	CREBBP
FOXO-mediated transcription of cell death genes	1	713.8×	0.007	CREBBP
Maternal to zygotic transition (MZT)	1	713.8×	0.007	CREBBP
The CRY:PER:kinase complex represses transactivation by the BMAL:CLOCK (ARNTL:CLOCK) complex	1	713.8×	0.007	CREBBP
Zygotic genome activation (ZGA)	1	671.8×	0.007	CREBBP
Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors	1	634.4×	0.007	CREBBP
NOTCH4 Intracellular Domain Regulates Transcription	1	571.0×	0.007	CREBBP
Transcriptional Regulation by NPAS4	1	571.0×	0.007	CREBBP
TP53 Regulates Transcription of Cell Death Genes	1	543.8×	0.007	CREBBP
TP53 Regulates Transcription of Genes Involved in Cytochrome C Release	1	543.8×	0.007	CREBBP
NFE2L2 regulating anti-oxidant/detoxification enzymes	1	543.8×	0.007	CREBBP
CD209 (DC-SIGN) signaling	1	519.1×	0.007	CREBBP
Signaling by NOTCH3	1	519.1×	0.007	CREBBP

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
N-terminal peptidyl-lysine acetylation	1	5617.3×	0.003	CREBBP
negative regulation of transcription by RNA polymerase I	1	2407.4×	0.003	CREBBP
homeostatic process	1	1685.2×	0.003	CREBBP
protein acetylation	1	1404.3×	0.003	CREBBP
cAMP/PKA signal transduction	1	1404.3×	0.003	CREBBP
regulation of cellular response to heat	1	1053.2×	0.004	CREBBP
stimulatory C-type lectin receptor signaling pathway	1	732.7×	0.005	CREBBP
regulation of smoothened signaling pathway	1	624.1×	0.005	CREBBP
positive regulation of transforming growth factor beta receptor signaling pathway	1	526.6×	0.005	CREBBP
cellular response to nutrient levels	1	468.1×	0.005	CREBBP
positive regulation of protein localization to nucleus	1	391.9×	0.005	CREBBP
positive regulation of double-strand break repair via homologous recombination	1	383.0×	0.005	CREBBP
canonical NF-kappaB signal transduction	1	366.4×	0.005	CREBBP
embryonic digit morphogenesis	1	300.9×	0.005	CREBBP
cellular response to UV	1	295.6×	0.005	CREBBP
protein destabilization	1	290.6×	0.005	CREBBP
rhythmic process	1	251.5×	0.006	CREBBP
protein-containing complex assembly	1	113.9×	0.012	CREBBP
response to hypoxia	1	95.8×	0.013	CREBBP
regulation of DNA-templated transcription	1	31.6×	0.038	CREBBP
positive regulation of DNA-templated transcription	1	27.9×	0.041	CREBBP
negative regulation of transcription by RNA polymerase II	1	17.7×	0.062	CREBBP
signal transduction	1	16.1×	0.065	CREBBP
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	CREBBP

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

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
CREBBP	COLCHICINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CREBBP	13	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COLCHICINE	4	CREBBP
ALTRETAMINE	4	CREBBP
CURCUMIN	3	CREBBP
PAPAVERINE	3	CREBBP
EPIGALOCATECHIN GALLATE	3	CREBBP
MOLIBRESIB	2	CREBBP
FISETIN	2	CREBBP
ETAZOLATE	2	CREBBP
LUNRESERTIB	2	CREBBP
TRACAZOLATE	2	CREBBP
NOCODAZOLE	2	CREBBP
INOBRODIB	1	CREBBP
AZD-5153	1	CREBBP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CREBBP	687	Binding:644, Functional:43

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CREBBP	2.3.1.48	histone acetyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CREBBP	687

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

13 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)
COLCHICINE	4	CREBBP
ALTRETAMINE	4	CREBBP
CURCUMIN	3	CREBBP
PAPAVERINE	3	CREBBP
EPIGALOCATECHIN GALLATE	3	CREBBP
MOLIBRESIB	2	CREBBP
FISETIN	2	CREBBP
ETAZOLATE	2	CREBBP
LUNRESERTIB	2	CREBBP
TRACAZOLATE	2	CREBBP
NOCODAZOLE	2	CREBBP
INOBRODIB	1	CREBBP
AZD-5153	1	CREBBP

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CREBBP
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.