Hereditary hemorrhagic telangiectasia

Summary

Hereditary hemorrhagic telangiectasia (MONDO:0019180) is a disease (an umbrella term covering 5 Mondo subtypes) caused by ENG (GenCC Strong), with 6 cohort genes and 80 clinical trials. The dominant Reactome pathway is Signaling by BMP (3 cohort genes). Top therapeutic interventions include bevacizumab, propranolol, and timolol.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal gene: ENG (GenCC Strong)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 1,385
• Phenotypes (HPO): 36
• Clinical trials: 80

Clinical features

Epidemiology

Prevalence records

7 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	16	Europe	Validated
Point prevalence	1-5 / 10 000	43.5	France	Validated
Point prevalence	1-9 / 100 000	2.5	United Kingdom	Validated
Point prevalence	1-5 / 10 000	15.6	Denmark	Validated
Point prevalence	1-5 / 10 000	16.25	Japan	Validated
Point prevalence	1-9 / 100 000	6.1	United States	Validated
Point prevalence	1-5 / 10 000	19.4	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000214	Lip telangiectasia	Very frequent (80-99%)
HP:0000227	Tongue telangiectasia	Very frequent (80-99%)
HP:0000421	Epistaxis	Very frequent (80-99%)
HP:0000434	Nasal mucosa telangiectasia	Very frequent (80-99%)
HP:0001009	Telangiectasia	Very frequent (80-99%)
HP:0004406	Spontaneous, recurrent epistaxis	Very frequent (80-99%)
HP:0100579	Mucosal telangiectasiae	Very frequent (80-99%)
HP:0100585	Telangiectasia of the skin	Very frequent (80-99%)
HP:0001409	Portal hypertension	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0002076	Migraine	Frequent (30-79%)
HP:0006548	Pulmonary arteriovenous malformation	Frequent (30-79%)
HP:0006574	Hepatic arteriovenous malformation	Frequent (30-79%)
HP:0011025	Abnormality of cardiovascular system physiology	Frequent (30-79%)
HP:0100026	Arteriovenous malformation	Frequent (30-79%)
HP:0100761	Visceral angiomatosis	Frequent (30-79%)
HP:0000524	Conjunctival telangiectasia	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001342	Cerebral hemorrhage	Occasional (5-29%)
HP:0001394	Cirrhosis	Occasional (5-29%)
HP:0001399	Hepatic failure	Occasional (5-29%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0002040	Esophageal varix	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002105	Hemoptysis	Occasional (5-29%)
HP:0002138	Subarachnoid hemorrhage	Occasional (5-29%)
HP:0002204	Pulmonary embolism	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002326	Transient ischemic attack	Occasional (5-29%)
HP:0002408	Cerebral arteriovenous malformation	Occasional (5-29%)
HP:0002629	Gastrointestinal arteriovenous malformation	Occasional (5-29%)
HP:0004936	Venous thrombosis	Occasional (5-29%)
HP:0007763	Retinal telangiectasia	Occasional (5-29%)
HP:0100659	Abnormality of the cerebral vasculature	Occasional (5-29%)
HP:0100784	Peripheral arteriovenous fistula	Occasional (5-29%)
HP:0200008	Intestinal polyposis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary hemorrhagic telangiectasia
Mondo ID	MONDO:0019180
MeSH	D013683
OMIM	187300
Orphanet	774
DOID	DOID:1270
ICD-10-CM	I78.0
ICD-11	714406192
NCIT	C35064
SNOMED CT	21877004
UMLS	C0039445
MedGen	52657
GARD	0006626
MedDRA	10019883
NORD	1229
Is cancer (heuristic)	no

Also known as: hereditary hemorrhagic telangiectasia · HHT · Osler-Weber-Rendu disease · Rendu-Osler disease · Rendu-Osler-Weber disease · telangiectasia, hereditary Hemorrahagic, of Rendu, Osler · telangiectasia, hereditary hemorrhagic

Data availability: 1,385 ClinVar variants · 6 GenCC gene-disease records · 62 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › hereditary hemorrhagic telangiectasia

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (5): telangiectasia, hereditary hemorrhagic, type 1, telangiectasia, hereditary hemorrhagic, type 2, hereditary hemorrhagic telangiectasia type 3, hereditary hemorrhagic telangiectasia type 4, telangiectasia, hereditary hemorrhagic, type 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

600 retrieved; paginated sample, class counts are floors:

193 likely benign, 156 uncertain significance, 116 pathogenic, 47 conflicting classifications of pathogenicity, 36 pathogenic/likely pathogenic, 27 benign/likely benign, 17 likely pathogenic, 8 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1746471	NM_000020.3(ACVRL1):c.526-7C>G	ACVRL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212794	NM_000020.3(ACVRL1):c.1377+1G>A	ACVRL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
212802	NM_000020.3(ACVRL1):c.998G>T (p.Ser333Ile)	ACVRL1	Pathogenic	reviewed by expert panel
212803	NM_000020.3(ACVRL1):c.200G>A (p.Arg67Gln)	ACVRL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070851	NC_000009.11:g.(?130577951)(130700109_?)del	AK1	Pathogenic	criteria provided, single submitter
1059847	NM_001114753.3(ENG):c.755T>C (p.Ile252Thr)	ENG	Pathogenic	criteria provided, single submitter
1066708	NM_001114753.3(ENG):c.290T>G (p.Leu97Arg)	ENG	Pathogenic	criteria provided, single submitter
1068703	NM_001114753.3(ENG):c.767_786del (p.Pro256fs)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
1068858	NC_000009.11:g.(?130577951)(130582326_?)del	ENG	Pathogenic	criteria provided, single submitter
1070889	NM_001114753.3(ENG):c.657_658del (p.Ile220fs)	ENG	Pathogenic	criteria provided, single submitter
1073414	NM_001114753.3(ENG):c.654_655del (p.Ile220fs)	ENG	Pathogenic	criteria provided, single submitter
1073561	NM_001114753.3(ENG):c.375_378dup (p.Phe127fs)	ENG	Pathogenic	criteria provided, single submitter
1074391	NM_001114753.3(ENG):c.1134G>C (p.Ala378=)	ENG	Pathogenic	criteria provided, single submitter
1074610	NM_001114753.3(ENG):c.523+1G>A	ENG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074831	NM_001114753.3(ENG):c.1687-2A>G	ENG	Pathogenic	criteria provided, single submitter
1074832	NM_001114753.3(ENG):c.1426C>T (p.Gln476Ter)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
1075363	NM_001114753.3(ENG):c.690-1G>C	ENG	Pathogenic	criteria provided, single submitter
1075836	NM_001114753.3(ENG):c.1531del (p.Ala511fs)	ENG	Pathogenic	criteria provided, single submitter
1076004	NM_001114753.3(ENG):c.863_867dup (p.Phe290fs)	ENG	Pathogenic	criteria provided, single submitter
1076795	NM_001114753.3(ENG):c.1687G>T (p.Glu563Ter)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
1076878	NC_000009.11:g.(?130605351)(130616761_?)del	ENG	Pathogenic	criteria provided, single submitter
1076879	NC_000009.11:g.(?130577951)(130581121_?)del	ENG	Pathogenic	criteria provided, single submitter
1076880	NC_000009.11:g.(?_130578090)_130581774del	ENG	Pathogenic	criteria provided, single submitter
1076881	NC_000009.11:g.(?130578196)(130592116_?)del	ENG	Pathogenic	criteria provided, single submitter
1076882	NC_000009.11:g.(?130587069)(130592116_?)del	ENG	Pathogenic	criteria provided, single submitter
1076907	NM_001114753.3(ENG):c.360+1G>C	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
1076967	NM_001114753.3(ENG):c.405dup (p.Thr136fs)	ENG	Pathogenic	criteria provided, single submitter
1163504	NM_001114753.3(ENG):c.397dup (p.Val133fs)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
1163505	NM_001114753.3(ENG):c.132_133del (p.Thr45fs)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
1177295	NM_001114753.3(ENG):c.586T>C (p.Trp196Arg)	ENG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 34 · Orphanet: 14 · 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
ACVRL1	Definitive	Autosomal dominant	telangiectasia, hereditary hemorrhagic, type 2	6
ENG	Definitive	Autosomal dominant	telangiectasia, hereditary hemorrhagic, type 1	6
SMAD4	Definitive	Autosomal dominant	juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	14
GDF2	Strong	Autosomal dominant	telangiectasia, hereditary hemorrhagic, type 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACVRL1	Orphanet:275777	Heritable pulmonary arterial hypertension
ACVRL1	Orphanet:774	Hereditary hemorrhagic telangiectasia
ENG	Orphanet:231160	Familial cerebral saccular aneurysm
ENG	Orphanet:275777	Heritable pulmonary arterial hypertension
ENG	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
ENG	Orphanet:774	Hereditary hemorrhagic telangiectasia
SMAD4	Orphanet:1333	Familial pancreatic carcinoma
SMAD4	Orphanet:2588	Myhre syndrome
SMAD4	Orphanet:329971	Generalized juvenile polyposis/juvenile polyposis coli
SMAD4	Orphanet:774	Hereditary hemorrhagic telangiectasia
SMAD4	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
GDF2	Orphanet:275777	Heritable pulmonary arterial hypertension
GDF2	Orphanet:774	Hereditary hemorrhagic telangiectasia
AK1	Orphanet:86817	Hemolytic anemia due to adenylate kinase deficiency

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACVRL1	HGNC:175	ENSG00000139567	P37023	Activin receptor type-1-like	gencc,clinvar
ENG	HGNC:3349	ENSG00000106991	P17813	Endoglin	gencc,clinvar
SMAD4	HGNC:6770	ENSG00000141646	Q13485	SMAD family member 4	gencc,clinvar
GDF2	HGNC:4217	ENSG00000263761	Q9UK05	Growth/differentiation factor 2	gencc
CCNH	HGNC:1594	ENSG00000134480	P51946	Cyclin-H	clinvar
AK1	HGNC:361	ENSG00000106992	P00568	Adenylate kinase isoenzyme 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACVRL1	Activin receptor type-1-like	Type I receptor for TGF-beta family ligands BMP9/GDF2 and BMP10 and important regulator of normal blood vessel development.
ENG	Endoglin	Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis.
SMAD4	SMAD family member 4	In muscle physiology, plays a central role in the balance between atrophy and hypertrophy.
GDF2	Growth/differentiation factor 2	Potent circulating inhibitor of angiogenesis.
CCNH	Cyclin-H	Regulates CDK7, the catalytic subunit of the CDK-activating kinase (CAK) enzymatic complex.
AK1	Adenylate kinase isoenzyme 1	Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.33

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
Kinase	2	9.2×	0.035
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACVRL1	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ENG	Other/Unknown	no		TGFBR3/Endoglin-like_N
SMAD4	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
GDF2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
CCNH	Other/Unknown	no		Cyclin_N, Cyclin-like_dom, CyclinH/Ccl1
AK1	Kinase	yes	2.7.4.3	Adenylat/UMP-CMP_kin, AK1/5, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

5 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)	1
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lung	2
calcaneal tendon	2
upper lobe of left lung	1
upper lobe of lung	1
cardiac atrium	1
right atrium auricular region	1
ganglionic eminence	1
ventricular zone	1
cervix squamous epithelium	1
diaphragm	1
skeletal muscle tissue of biceps brachii	1
left testis	1
right testis	1
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACVRL1	221	broad	marker	right lung, upper lobe of left lung, upper lobe of lung
ENG	265	ubiquitous	marker	right lung, right atrium auricular region, cardiac atrium
SMAD4	288	ubiquitous	marker	ventricular zone, ganglionic eminence, calcaneal tendon
GDF2	17	tissue_specific	yes	cervix squamous epithelium, diaphragm, skeletal muscle tissue of biceps brachii
CCNH	297	ubiquitous	marker	calcaneal tendon, left testis, right testis
AK1	144	ubiquitous	marker	apex of heart, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD4	7,320
AK1	3,526
ENG	3,236
ACVRL1	2,234
CCNH	2,116
GDF2	1,277

Intra-cohort edges

A	B	Sources
ACVRL1	ENG	intact, string_interaction
ACVRL1	GDF2	biogrid_interaction, intact, string_interaction
ACVRL1	SMAD4	string_interaction
ENG	GDF2	biogrid_interaction, intact, string_interaction
GDF2	SMAD4	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CCNH	P51946	47
GDF2	Q9UK05	20
SMAD4	Q13485	12
ACVRL1	P37023	7
AK1	P00568	5
ENG	P17813	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 107. Enrichment computed across 6 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by BMP	3	214.1×	2e-05	ACVRL1, SMAD4, GDF2
Loss of Function of SMAD4 in Cancer	1	761.3×	0.028	SMAD4
SMAD4 MH2 Domain Mutants in Cancer	1	761.3×	0.028	SMAD4
SMAD2/3 MH2 Domain Mutants in Cancer	1	761.3×	0.028	SMAD4
Signaling by TGFB family members	2	46.1×	0.028	ACVRL1, SMAD4
RUNX3 regulates BCL2L11 (BIM) transcription	1	456.8×	0.035	SMAD4
Loss of Function of SMAD2/3 in Cancer	1	380.7×	0.035	SMAD4
Signaling by TGF-beta Receptor Complex in Cancer	1	380.7×	0.035	SMAD4
RUNX3 regulates CDKN1A transcription	1	326.3×	0.035	SMAD4
Transcriptional regulation of brown and beige adipocyte differentiation	1	228.4×	0.035	SMAD4
RUNX2 regulates bone development	1	163.1×	0.035	SMAD4
Signaling by Activin	1	152.3×	0.035	SMAD4
Formation of definitive endoderm	1	142.8×	0.035	SMAD4
FOXO-mediated transcription of cell cycle genes	1	134.3×	0.035	SMAD4
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	134.3×	0.035	SMAD4
Germ layer formation at gastrulation	1	134.3×	0.035	SMAD4
Transcriptional regulation of pluripotent stem cells	1	108.8×	0.035	SMAD4
Signaling by NODAL	1	99.3×	0.035	SMAD4
Global Genome Nucleotide Excision Repair (GG-NER)	1	91.4×	0.035	CCNH
TGFBR3 expression	1	91.4×	0.035	SMAD4
Cardiogenesis	1	84.6×	0.035	SMAD4
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	1	81.6×	0.035	CCNH
RNA Pol II CTD phosphorylation and interaction with CE	1	81.6×	0.035	CCNH
G1 Phase	1	78.8×	0.035	CCNH
mRNA Capping	1	76.1×	0.035	CCNH
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	76.1×	0.035	SMAD4
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	76.1×	0.035	SMAD4
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	73.7×	0.035	SMAD4
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	73.7×	0.035	SMAD4
Signaling by TGFBR3	1	73.7×	0.035	SMAD4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of SMAD protein signal transduction	4	255.3×	1e-07	ACVRL1, ENG, SMAD4, GDF2
BMP signaling pathway	4	133.8×	7e-07	ACVRL1, ENG, SMAD4, GDF2
cellular response to BMP stimulus	3	280.9×	5e-06	ACVRL1, SMAD4, GDF2
negative regulation of endothelial cell proliferation	3	271.8×	5e-06	ACVRL1, ENG, GDF2
positive regulation of BMP signaling pathway	3	227.7×	6e-06	ACVRL1, ENG, GDF2
dorsal aorta morphogenesis	2	702.2×	8e-05	ACVRL1, ENG
positive regulation of epithelial cell differentiation	2	624.1×	9e-05	ACVRL1, GDF2
positive regulation of bicellular tight junction assembly	2	561.7×	9e-05	ACVRL1, GDF2
transforming growth factor beta receptor signaling pathway	3	79.5×	9e-05	ACVRL1, ENG, SMAD4
positive regulation of endothelial cell differentiation	2	510.7×	9e-05	ACVRL1, GDF2
epithelial to mesenchymal transition involved in endocardial cushion formation	2	468.1×	9e-05	ENG, SMAD4
negative regulation of cell growth	3	72.0×	9e-05	ACVRL1, SMAD4, GDF2
positive regulation of angiogenesis	3	57.7×	2e-04	ACVRL1, ENG, GDF2
activin receptor signaling pathway	2	295.6×	2e-04	SMAD4, GDF2
endocardial cushion morphogenesis	2	280.9×	2e-04	ACVRL1, ENG
negative regulation of endothelial cell migration	2	255.3×	2e-04	ACVRL1, GDF2
negative regulation of blood vessel endothelial cell migration	2	244.2×	3e-04	ACVRL1, GDF2
outflow tract septum morphogenesis	2	216.1×	3e-04	ENG, SMAD4
branching involved in blood vessel morphogenesis	2	175.5×	4e-04	ENG, GDF2
positive regulation of Notch signaling pathway	2	117.0×	1e-03	ACVRL1, GDF2
cellular response to transforming growth factor beta stimulus	2	92.1×	0.001	ACVRL1, SMAD4
vasculogenesis	2	85.1×	0.002	ENG, GDF2
intracellular iron ion homeostasis	2	81.4×	0.002	SMAD4, GDF2
positive regulation of endothelial cell proliferation	2	77.0×	0.002	ACVRL1, GDF2
positive regulation of transcription by RNA polymerase II	4	9.9×	0.002	ACVRL1, ENG, SMAD4, GDF2
obsolete positive regulation of cell proliferation involved in heart valve morphogenesis	1	2808.7×	0.002	SMAD4
female gonad morphogenesis	1	2808.7×	0.002	SMAD4
negative regulation of cardiac myofibril assembly	1	2808.7×	0.002	SMAD4
regulation of DNA-templated transcription	3	15.8×	0.003	ACVRL1, ENG, SMAD4
detection of hypoxia	1	1404.3×	0.004	ENG

Therapeutics

Drugs indicated for this disease

0 approved, 5 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Bevacizumab	Phase 3 (in late-stage trials)
Mupirocin	Phase 3 (in late-stage trials)
Propranolol	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Tranexamic Acid	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Nintedanib, Octreotide, Pazopanib, Pomalidomide, Tamoxifen, Timolol.

Drug target analysis

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

Druggability breadth: 6 of 6 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
ACVRL1	FEDRATINIB
CCNH	ABEMACICLIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CCNH	28	4
ACVRL1	11	4
ENG	0	0
SMAD4	0	0
GDF2	0	0
AK1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	ACVRL1
ENTRECTINIB	4	ACVRL1
VANDETANIB	4	ACVRL1
NINTEDANIB	4	ACVRL1
DASATINIB	4	ACVRL1
ABEMACICLIB	4	CCNH
QUIZARTINIB	4	CCNH
ADAGRASIB	4	CCNH
ALVOCIDIB	3	ACVRL1, CCNH
LESTAURTINIB	3	ACVRL1
DINACICLIB	3	CCNH
LEROCICLIB	3	CCNH
AT-9283	2	ACVRL1
ZILURGISERTIB	2	ACVRL1
TOZASERTIB	2	ACVRL1
SELICICLIB	2	CCNH
ASNUCICLIB	2	CCNH
CYC-065	2	CCNH
ULECACICLIB	2	CCNH
RONICICLIB	2	CCNH
AT-7519	2	CCNH
INIXACICLIB	2	CCNH
ISTISOCICLIB	2	CCNH
MILCICLIB	2	CCNH
ZOTIRACICLIB	2	CCNH
NARAZACICLIB	2	CCNH
CT-7001	2	CCNH
ZEMIRCICLIB	2	CCNH
PF-06952229	1	ACVRL1
PHA-793887	1	CCNH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CCNH	348	Binding:346, Functional:2
ACVRL1	213	Binding:207, Functional:3, Toxicity:2, ADMET:1
SMAD4	6	Binding:6
GDF2	4	Binding:4
AK1	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACVRL1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
AK1	2.7.4.3	adenylate kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ACVRL1	213
CCNH	348

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

29 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)
FEDRATINIB	4	ACVRL1
ENTRECTINIB	4	ACVRL1
VANDETANIB	4	ACVRL1
DASATINIB	4	ACVRL1
ABEMACICLIB	4	CCNH
QUIZARTINIB	4	CCNH
ADAGRASIB	4	CCNH
ALVOCIDIB	3	ACVRL1, CCNH
LESTAURTINIB	3	ACVRL1
DINACICLIB	3	CCNH
LEROCICLIB	3	CCNH
AT-9283	2	ACVRL1
ZILURGISERTIB	2	ACVRL1
TOZASERTIB	2	ACVRL1
SELICICLIB	2	CCNH
ASNUCICLIB	2	CCNH
CYC-065	2	CCNH
ULECACICLIB	2	CCNH
RONICICLIB	2	CCNH
AT-7519	2	CCNH
INIXACICLIB	2	CCNH
ISTISOCICLIB	2	CCNH
MILCICLIB	2	CCNH
ZOTIRACICLIB	2	CCNH
NARAZACICLIB	2	CCNH
CT-7001	2	CCNH
ZEMIRCICLIB	2	CCNH
PF-06952229	1	ACVRL1
PHA-793887	1	CCNH

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ACVRL1, CCNH
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	ENG, SMAD4, GDF2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ENG	0	ACVRL1
GDF2	4	ACVRL1
SMAD4	6	—
AK1	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 80.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	40
PHASE2	19
PHASE1/PHASE2	7
PHASE3	6
PHASE1	5
PHASE2/PHASE3	2
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02389959	PHASE4	COMPLETED	Intranasal Bevacizumab for HHT-Related Epistaxis
NCT03850964	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Effects of Pazopanib on Hereditary Hemorrhagic Telangiectasia Related Epistaxis and Anemia (Paz)
NCT00004654	PHASE3	COMPLETED	Phase III Randomized, Placebo-Controlled, Crossover Study of Soy Protein Isolate for Hereditary Hemorrhagic Telangiectasia
NCT00355108	PHASE3	COMPLETED	ATERO : A Randomised Study With Tranexamic Acid in Epistaxis of Rendu Osler Syndrome
NCT01031992	PHASE3	COMPLETED	Tranexamic Acid and Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)
NCT02106520	PHASE2/PHASE3	TERMINATED	Efficacy of a Bevacizumab Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)
NCT02963129	PHASE3	UNKNOWN	Treatment of Nasal Staphylococcus Aureus Colonization in Patients With HHT
NCT03227263	PHASE3	COMPLETED	BABH Study: Efficacy and Safety of Bevacizumab on Severe Bleedings Associated With Hemorrhagic Hereditary Telangiectasia (HHT).
NCT04113187	PHASE3	COMPLETED	Propranolol for Epistaxis in Hereditary Hemorrhagic Telangiectasia Patients
NCT04404881	PHASE2	ACTIVE_NOT_RECRUITING	Bevacizumab In Hereditary Hemorrhagic Telangiectasia
NCT04976036	PHASE2	RECRUITING	Efficacy of Nintedanib for Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) Patients
NCT05406362	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Assess Safety and Efficacy of VAD044 in HHT Patients
NCT06659640	PHASE1/PHASE2	RECRUITING	A Study to Evaluate ALN-6400 in Healthy Volunteers and Patients With Hereditary Hemorrhagic Telangiectasia (HHT)
NCT07601425	PHASE1/PHASE2	NOT_YET_RECRUITING	Harmony-HHT: ATV-1601 in Participants With Hereditary Hemorrhagic Telangiectasia (HHT)
NCT00004327	PHASE2	COMPLETED	Phase II Pilot Study of Octreotide, a Somatostatin Octapeptide Analog, for Gastrointestinal Hemorrhage in Hormone-Refractory Hereditary Hemorrhagic Telangiectasia and Senile Ectasia
NCT00375622	PHASE2	COMPLETED	Anti-Estrogen Therapy for Hereditary Hemorrhagic Telangiectasia A Double-Blind Placebo-Controlled Clinical Trial
NCT00389935	PHASE2	COMPLETED	Thalidomide Reduces Arteriovenous Malformation Related Gastrointestinal Bleeding
NCT01314274	PHASE2	COMPLETED	Intranasal Submucosal Bevacizumab for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)
NCT01397695	PHASE2	COMPLETED	Topical Bevacizumab for the Management of Recurrent Epistaxis in Patients With Hereditary Hemorrhagic Telangiectasia (HHT)
NCT01402531	PHASE2	COMPLETED	Submucosal Bevacizumab for the Management of Recurrent Epistaxis in Patients With Hereditary Hemorrhagic Telangiectasia (HHT)
NCT01408030	PHASE2	COMPLETED	North American Study of Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)
NCT01408732	PHASE1/PHASE2	COMPLETED	Office-sclerotherapy for Epistaxis Due to Hereditary Hemorrhagic Telangiectasia
NCT01485224	PHASE2	COMPLETED	Efficacy of Thalidomide in the Treatment of Hereditary Hemorrhagic Telangiectasia
NCT01752049	PHASE1/PHASE2	COMPLETED	Topical Anti-angiogenic Therapy for Telangiectasia in HHT: Proof of Concept
NCT02157987	PHASE1/PHASE2	COMPLETED	Treatment of Hereditary Hemorrhagic Telangiectasia of the Nasal Mucosa by Intranasal Bevacizumab : Search for Effective Dose
NCT02204371	PHASE2	TERMINATED	Evaluation of Pazopanib on Bleeding in Subjects With Hereditary Haemorrhagic Telangiectasia
NCT02484716	PHASE2	COMPLETED	Efficacy of a Timolol Nasal Spray as a Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT) - (TEMPO)
NCT02874326	PHASE2	UNKNOWN	Octreotide in Patients With GI Bleeding Due to Rendu-Osler-Weber
NCT03397004	PHASE2	COMPLETED	Doxycycline for Hereditary Hemorrhagic Telangiectasia
NCT03850730	PHASE1/PHASE2	UNKNOWN	Pazopanib for the Treatment of Epistaxis in Hereditary Hemorrhagic Telangiectasia
NCT03910244	PHASE2	COMPLETED	Pomalidomide for the Treatment of Bleeding in HHT
NCT03954782	PHASE2	COMPLETED	Efficacy of Nintedanib Per os as a Treatment for Epistaxis in HHT Disease.
NCT04139018	PHASE2	COMPLETED	Timolol Gel for Epistaxis in Hereditary Hemorrhagic Telangiectasia
NCT04646356	PHASE2	COMPLETED	Tacrolimus Trial for Hereditary Hemorrhagic Telangiectasia (HHT)
NCT05269849	PHASE2	COMPLETED	Sirolimus for Nosebleeds in HHT
NCT01406639	PHASE1	WITHDRAWN	Ranibizumab for the Management of Recurrent Nosebleeds in Patients With Hereditary Hemorrhagic Telangiectasia (HHT)
NCT01507480	PHASE1	COMPLETED	The ELLIPSE Study: A Phase-1 Study Evaluating the Tolerance of Bevacizumab Nasal Spray to Treat Epistaxis in Hereditary Hemorrhagic Telangiectasia
NCT02287558	PHASE1	COMPLETED	Pomalidomide in Hereditary Hemorrhagic Telangiectasia and Transfusion-Dependent Vascular Ectasia: a Phase I Study
NCT02977637	PHASE1	COMPLETED	MRA With Feraheme in HHT
NCT07255846	PHASE1	WITHDRAWN	A Trial of TER-1754 in Patients With Hereditary Hemorrhagic Telangiectasia

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BEVACIZUMAB	4	11
PROPRANOLOL	4	3
TIMOLOL	4	3
DOXYCYCLINE HYCLATE	4	1
ESTRIOL	4	1
MUPIROCIN	4	1
NINTEDANIB	4	1
OCTREOTIDE	4	1
PAZOPANIB	4	1
DEXPROPRANOLOL	2	1
CHEMBL4068768	0	2
CHEMBL4171277	0	2
CHEMBL4793658	0	1
CHEMBL3350037	0	1
CHEMBL1200567	0	1
S-ROLIPRAM	0	1