Famililal cerebral cavernous malformations

Summary

Famililal cerebral cavernous malformations (MONDO:0031037) is a disease (an umbrella term covering 5 Mondo subtypes) with 3 cohort genes and 6 clinical trials. Top therapeutic interventions include propranolol.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 3
• ClinVar variants: 3
• Phenotypes (HPO): 25
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	15	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0033522	Cerebral cavernous malformation	Obligate (100%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001342	Cerebral hemorrhage	Very frequent (80-99%)
HP:0002315	Headache	Very frequent (80-99%)
HP:0001028	Hemangioma	Frequent (30-79%)
HP:0001048	Cavernous hemangioma	Frequent (30-79%)
HP:0001324	Muscle weakness	Frequent (30-79%)
HP:0002516	Increased intracranial pressure	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0012748	Focal T2 hyperintense brainstem lesion	Frequent (30-79%)
HP:0012749	Focal T2 hypointense brainstem lesion	Frequent (30-79%)
HP:0030430	Neuroma	Frequent (30-79%)
HP:0033748	Hypoesthesia	Frequent (30-79%)
HP:0100561	Spinal cord lesion	Occasional (5-29%)
HP:0002572	Episodic vomiting	Occasional (5-29%)
HP:0007872	Choroidal hemangioma	Occasional (5-29%)
HP:0011276	Vascular skin abnormality	Occasional (5-29%)
HP:0011513	Retinal cavernous angioma	Occasional (5-29%)
HP:0012721	Venous malformation	Occasional (5-29%)
HP:0100543	Cognitive impairment	Occasional (5-29%)
HP:0002858	Meningioma	Very rare (<1-4%)
HP:0009588	Vestibular schwannoma	Very rare (<1-4%)
HP:0009592	Astrocytoma	Very rare (<1-4%)
HP:0010512	Adrenal calcification	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	famililal cerebral cavernous malformations
Mondo ID	MONDO:0031037
OMIM	116860
Orphanet	221061
SNOMED CT	717003001
UMLS	C2931263
MedGen	419031
GARD	0013641
Is cancer (heuristic)	no

Also known as: CCM · cerebral cavernous malformations · familial brain cavernous angioma · familial brain cavernous hemangioma · familial cerebral cavernoma · familial cerebral cavernous malformation · famililal cerebral cavernous malformations · hereditary brain cavernous angioma · hereditary brain cavernous hemangioma · hereditary cerebral cavernoma · hereditary cerebral cavernous malformation

Data availability: 3 ClinVar variants · 3 GenCC gene-disease records · 7 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › cerebral cavernous malformation › famililal cerebral cavernous malformations

Subtypes (5): cerebral cavernous malformation 2, cerebral cavernous malformation 3, cerebral cavernous malformation 1, cerebral cavernous malformation 4, cerebral cavernous malformations 5

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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
265214	NM_194454.3(KRIT1):c.152_155del (p.Lys51fs)	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
372398	NM_194454.3(KRIT1):c.1201_1204del (p.Gln401fs)	KRIT1	Pathogenic	criteria provided, multiple submitters, no conflicts
468331	NM_007217.4(PDCD10):c.474+5G>A	PDCD10	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 3 · 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
CCM2	Definitive	Autosomal dominant	cerebral cavernous malformation 2	4
KRIT1	Definitive	Autosomal dominant	cerebral cavernous malformation 1	6
PDCD10	Definitive	Autosomal dominant	cerebral cavernous malformation 3	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KRIT1	Orphanet:221061	Familial cerebral cavernous malformation
PDCD10	Orphanet:221061	Familial cerebral cavernous malformation
CCM2	Orphanet:221061	Familial cerebral cavernous malformation

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KRIT1	HGNC:1573	ENSG00000001631	O00522	Krev interaction trapped protein 1	gencc,clinvar
PDCD10	HGNC:8761	ENSG00000114209	Q9BUL8	Programmed cell death protein 10	gencc,clinvar
CCM2	HGNC:21708	ENSG00000136280	Q9BSQ5	Cerebral cavernous malformations 2 protein	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KRIT1	Krev interaction trapped protein 1	Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity.
PDCD10	Programmed cell death protein 10	Promotes cell proliferation.
CCM2	Cerebral cavernous malformations 2 protein	Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KRIT1	Scaffold/PPI	no		FERM_domain, Ankyrin_rpt, PH-like_dom_sf
PDCD10	Other/Unknown	no		PDCD10, PDC10_dimerisation_sf, PDCD10_N
CCM2	Other/Unknown	no		PTB/PI_dom, PH-like_dom_sf, Malcavernin

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
corpus callosum	1
colonic mucosa	1
jejunal mucosa	1
mucosa of sigmoid colon	1
anterior cingulate cortex	1
nucleus accumbens	1
putamen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KRIT1	138	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
PDCD10	295	ubiquitous	marker	jejunal mucosa, mucosa of sigmoid colon, colonic mucosa
CCM2	243	ubiquitous	marker	putamen, nucleus accumbens, anterior cingulate cortex

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PDCD10	1,792
CCM2	1,600
KRIT1	1,290

Intra-cohort edges

A	B	Sources
CCM2	KRIT1	biogrid_interaction, intact, string_interaction
CCM2	PDCD10	intact, string_interaction
KRIT1	PDCD10	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRIT1	O00522	15
PDCD10	Q9BUL8	10
CCM2	Q9BSQ5	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
endothelium development	3	1296.3×	2e-08	KRIT1, PDCD10, CCM2
regulation of angiogenesis	3	421.3×	3e-07	KRIT1, PDCD10, CCM2
intrinsic apoptotic signaling pathway in response to hydrogen peroxide	1	1872.4×	0.006	PDCD10
endothelial cell development	1	1404.3×	0.006	CCM2
blood vessel endothelial cell differentiation	1	1123.5×	0.006	CCM2
Golgi reassembly	1	1123.5×	0.006	PDCD10
angiogenesis	2	41.6×	0.006	KRIT1, PDCD10
venous blood vessel morphogenesis	1	802.5×	0.006	CCM2
negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis	1	702.2×	0.006	PDCD10
establishment of Golgi localization	1	624.1×	0.006	PDCD10
pericardium development	1	624.1×	0.006	CCM2
endothelial tube morphogenesis	1	624.1×	0.006	CCM2
integrin activation	1	468.1×	0.007	KRIT1
positive regulation of protein serine/threonine kinase activity	1	432.1×	0.007	PDCD10
wound healing, spreading of cells	1	374.5×	0.008	PDCD10
negative regulation of cell migration involved in sprouting angiogenesis	1	330.4×	0.008	PDCD10
regulation of establishment of cell polarity	1	312.1×	0.008	KRIT1
positive regulation of stress-activated MAPK cascade	1	267.5×	0.009	PDCD10
negative regulation of endothelial cell migration	1	255.3×	0.009	KRIT1
positive regulation of peptidyl-serine phosphorylation	1	255.3×	0.009	PDCD10
stress-activated MAPK cascade	1	234.1×	0.009	CCM2
positive regulation of intracellular protein transport	1	224.7×	0.009	PDCD10
positive regulation of MAP kinase activity	1	216.1×	0.009	PDCD10
cell-cell junction organization	1	208.1×	0.009	CCM2
negative regulation of endothelial cell proliferation	1	181.2×	0.010	KRIT1
negative regulation of endothelial cell apoptotic process	1	165.2×	0.010	KRIT1
inner ear development	1	124.8×	0.013	CCM2
positive regulation of Notch signaling pathway	1	117.0×	0.013	PDCD10
cell redox homeostasis	1	114.6×	0.013	KRIT1
vasculogenesis	1	85.1×	0.017	CCM2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KRIT1	0	0
PDCD10	0	0
CCM2	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
PDCD10	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	KRIT1, PDCD10, CCM2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KRIT1	0	—
PDCD10	1	—
CCM2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03474614	PHASE2	TERMINATED	Effect of Oral Propranolol on mRNA Expresssion in Symptomatic Cavernous Malformation
NCT01764451	EARLY_PHASE1	TERMINATED	Permeability MRI in Cerebral Cavernous Malformations Type 1 in New Mexico: Effects of Statins
NCT01764529	Not specified	ACTIVE_NOT_RECRUITING	Modifiers of Disease Severity in Cerebral Cavernous Malformations
NCT06983132	Not specified	RECRUITING	Natural History of Familial Cerebral Cavernous Malformations: the CCM_Italia Cohort Study
NCT03467295	Not specified	UNKNOWN	Treatments and Outcomes of Untreated Cerebral Cavernous Malformations in CHina.
NCT03652181	Not specified	COMPLETED	CASH (Cavernous Angiomas With Symptomatic Hemorrhage) Trial Readiness

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
PROPRANOLOL	4	1