Telangiectasia, hereditary hemorrhagic, type 1

Summary

Telangiectasia, hereditary hemorrhagic, type 1 (MONDO:0008535) is a disease caused by variants in ENG and GDF2, with 4 cohort genes and 8 clinical trials. Top therapeutic interventions include bevacizumab and pazopanib.

At a glance

• Causal genes: ENG (GenCC Definitive), GDF2 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 446
• Clinical trials: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	telangiectasia, hereditary hemorrhagic, type 1
Mondo ID	MONDO:0008535
OMIM	187300
UMLS	C4551861
MedGen	1643786
GARD	0024627
Is cancer (heuristic)	no

Also known as: ENG-related Hereditary hemorrhagic telangiectasia · hereditary hemorrhagic telangiectasia type 1 · HHT · HHT1 · Osler Weber Rendu syndrome type 1 · telangiectasia, hereditary hemorrhagic, of Rendu, Osler, and Weber · telangiectasia, hereditary hemorrhagic, type 1

Data availability: 446 ClinVar variants · 26 ClinGen variant curations · 5 GenCC gene-disease records.

Disease family

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 › telangiectasia, hereditary hemorrhagic, type 1

Related subtypes (4): 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

446 retrieved; paginated sample, class counts are floors:

136 pathogenic, 94 uncertain significance, 71 conflicting classifications of pathogenicity, 44 likely pathogenic, 36 pathogenic/likely pathogenic, 33 likely benign, 25 benign/likely benign, 7 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1120155	Single allele	ENG	Pathogenic	criteria provided, single submitter
1120156	Single allele	ENG	Pathogenic	criteria provided, single submitter
1120157	Single allele	ENG	Pathogenic	criteria provided, single submitter
1120158	Single allele	ENG	Pathogenic	criteria provided, single submitter
1163030	NM_001114753.3(ENG):c.1429-1G>A	ENG	Pathogenic/Likely 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
1330266	NM_001114753.3(ENG):c.524-1G>A	ENG	Pathogenic	criteria provided, single submitter
1330389	NM_001114753.3(ENG):c.558del (p.Ser187fs)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
1330476	NM_001114753.3(ENG):c.219+2T>C	ENG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330635	NM_001114753.3(ENG):c.1087T>C (p.Cys363Arg)	ENG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330982	NM_001114753.3(ENG):c.465dup (p.Ile156fs)	ENG	Pathogenic	criteria provided, single submitter
1331646	NM_001114753.3(ENG):c.1687-1G>A	ENG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343355	NM_001114753.3(ENG):c.1686+1G>T	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
16668	NM_001114753.3(ENG):c.831C>G (p.Tyr277Ter)	ENG	Pathogenic	criteria provided, single submitter
16669	NM_001114753.3(ENG):c.882_920del (p.Thr295_Asn307del)	ENG	Pathogenic	no assertion criteria provided
16670	NM_001114753.3(ENG):c.1553_1554del (p.Ser518fs)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
16673	NM_001114753.3(ENG):c.2T>C (p.Met1Thr)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
16674	NM_001114753.3(ENG):c.1238G>T (p.Gly413Val)	ENG	Pathogenic	no assertion criteria provided
16676	NM_001114753.3(ENG):c.360C>A (p.Tyr120Ter)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
1678571	NM_001114753.3(ENG):c.934del (p.Ala312fs)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
1678625	NM_001114753.3(ENG):c.1614_1615del (p.Val539fs)	ENG	Pathogenic	criteria provided, single submitter
1701581	NM_001114753.3(ENG):c.1121_1122delinsGC (p.Lys374Ser)	ENG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1703568	GRCh37/hg19 9q34.11(chr9:130581787-130582459)	ENG	Pathogenic	no assertion criteria provided
1733242	NM_001114753.3(ENG):c.361-2A>T	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
1768569	NM_001114753.3(ENG):c.990C>A (p.Cys330Ter)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
1774348	NM_001114753.3(ENG):c.1517T>C (p.Leu506Pro)	ENG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1776434	NM_001114753.3(ENG):c.1613_1614del (p.Thr538fs)	ENG	Pathogenic	criteria provided, multiple submitters, no conflicts
180348	NM_001114753.3(ENG):c.259C>T (p.Gln87Ter)	ENG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1994298	NM_001114753.3(ENG):c.1381_1384del (p.Leu461fs)	ENG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
213210	NM_001114753.3(ENG):c.1312A>T (p.Lys438Ter)	ENG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 13 · 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
ENG	Definitive	Autosomal dominant	telangiectasia, hereditary hemorrhagic, type 1	6
GDF2	Strong	Autosomal dominant	telangiectasia, hereditary hemorrhagic, type 1	8
RASA1	No Known Disease Relationship	Autosomal dominant	telangiectasia, hereditary hemorrhagic, type 1	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
GDF2	Orphanet:275777	Heritable pulmonary arterial hypertension
GDF2	Orphanet:774	Hereditary hemorrhagic telangiectasia
RASA1	Orphanet:693907	RASA1-related capillary malformation-arteriovenous malformation
RASA1	Orphanet:90307	Parkes Weber syndrome
PSEN1	Orphanet:100069	Semantic dementia
PSEN1	Orphanet:100070	Progressive non-fluent aphasia
PSEN1	Orphanet:1020	Early-onset autosomal dominant Alzheimer disease
PSEN1	Orphanet:154	Familial isolated dilated cardiomyopathy
PSEN1	Orphanet:275864	Behavioral variant of frontotemporal dementia

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ENG	HGNC:3349	ENSG00000106991	P17813	Endoglin	gencc,clinvar
GDF2	HGNC:4217	ENSG00000263761	Q9UK05	Growth/differentiation factor 2	gencc
RASA1	HGNC:9871	ENSG00000145715	P20936	Ras GTPase-activating protein 1	gencc
PSEN1	HGNC:9508	ENSG00000080815	P49768	Presenilin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ENG	Endoglin	Vascular endothelium glycoprotein that plays an important role in the regulation of angiogenesis.
GDF2	Growth/differentiation factor 2	Potent circulating inhibitor of angiogenesis.
RASA1	Ras GTPase-activating protein 1	GTPase-activating protein (GAP) that stimulates the intrinsic GTPase activity of Ras proteins, such as NRAS, facilitating their transition from the active GTP-bound state to the inactive GDP-bound state, thereby terminating Ras signaling.
PSEN1	Presenilin-1	Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein).

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

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
Protease	1	9.2×	0.315
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ENG	Other/Unknown	no		TGFBR3/Endoglin-like_N
GDF2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like
RASA1	Scaffold/PPI	no		C2_dom, SH2, SH3_domain
PSEN1	Protease	yes		Peptidase_A22A, Pept_A22A_PS1, Preselin/SPP

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)	1
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cardiac atrium	1
right atrium auricular region	1
right lung	1
cervix squamous epithelium	1
diaphragm	1
skeletal muscle tissue of biceps brachii	1
choroid plexus epithelium	1
endothelial cell	1
placenta	1
C1 segment of cervical spinal cord	1
corpus callosum	1
middle frontal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ENG	265	ubiquitous	marker	right lung, right atrium auricular region, cardiac atrium
GDF2	17	tissue_specific	yes	cervix squamous epithelium, diaphragm, skeletal muscle tissue of biceps brachii
RASA1	298	ubiquitous	marker	endothelial cell, placenta, choroid plexus epithelium
PSEN1	287	ubiquitous	marker	middle frontal gyrus, corpus callosum, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RASA1	4,407
PSEN1	3,732
ENG	3,236
GDF2	1,277

Intra-cohort edges

A	B	Sources
ENG	GDF2	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSEN1	P49768	27
GDF2	Q9UK05	20
RASA1	P20936	15
ENG	P17813	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Noncanonical activation of NOTCH3	1	475.8×	0.013	PSEN1
Regulated proteolysis of p75NTR	1	346.1×	0.013	PSEN1
NOTCH4 Activation and Transmission of Signal to the Nucleus	1	346.1×	0.013	PSEN1
TGFBR3 PTM regulation	1	317.2×	0.013	PSEN1
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	271.9×	0.013	RASA1
NRIF signals cell death from the nucleus	1	237.9×	0.013	PSEN1
VEGFR2 mediated cell proliferation	1	190.3×	0.013	RASA1
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	158.6×	0.013	PSEN1
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	146.4×	0.013	PSEN1
Downstream signal transduction	1	126.9×	0.013	RASA1
Signaling by BMP	1	119.0×	0.013	GDF2
Activated NOTCH1 Transmits Signal to the Nucleus	1	119.0×	0.013	PSEN1
Nuclear signaling by ERBB4	1	115.3×	0.013	PSEN1
EPHB-mediated forward signaling	1	88.5×	0.016	RASA1
EPH-ephrin mediated repulsion of cells	1	73.2×	0.017	PSEN1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	65.6×	0.017	PSEN1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	65.6×	0.017	PSEN1
Regulation of RAS by GAPs	1	64.5×	0.017	RASA1
Degradation of the extracellular matrix	1	39.2×	0.027	PSEN1
Neutrophil degranulation	1	7.7×	0.124	PSEN1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vasculogenesis	3	191.5×	4e-05	ENG, GDF2, RASA1
blood vessel morphogenesis	2	401.2×	7e-04	GDF2, RASA1
negative regulation of endothelial cell proliferation	2	271.8×	8e-04	ENG, GDF2
branching involved in blood vessel morphogenesis	2	263.3×	8e-04	ENG, GDF2
positive regulation of BMP signaling pathway	2	227.7×	9e-04	ENG, GDF2
positive regulation of SMAD protein signal transduction	2	191.5×	0.001	ENG, GDF2
heart looping	2	133.8×	0.002	ENG, PSEN1
BMP signaling pathway	2	100.3×	0.003	ENG, GDF2
positive regulation of L-glutamate import across plasma membrane	1	2106.5×	0.005	PSEN1
Cajal-Retzius cell differentiation	1	2106.5×	0.005	PSEN1
smooth endoplasmic reticulum calcium ion homeostasis	1	2106.5×	0.005	PSEN1
detection of hypoxia	1	2106.5×	0.005	ENG
positive regulation of vascular associated smooth muscle cell differentiation	1	2106.5×	0.005	ENG
positive regulation of angiogenesis	2	57.7×	0.005	ENG, GDF2
negative regulation of neuron apoptotic process	2	55.4×	0.005	PSEN1, RASA1
protein catabolic process at postsynapse	1	1404.3×	0.007	PSEN1
astrocyte activation involved in immune response	1	1053.2×	0.007	PSEN1
cell migration involved in endocardial cushion formation	1	1053.2×	0.007	ENG
obsolete synaptic vesicle targeting	1	1053.2×	0.007	PSEN1
positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation	1	1053.2×	0.007	ENG
atrioventricular canal morphogenesis	1	1053.2×	0.007	ENG
central nervous system vasculogenesis	1	842.6×	0.008	ENG
obsolete sequestering of calcium ion	1	842.6×	0.008	PSEN1
positive regulation of amyloid fibril formation	1	842.6×	0.008	PSEN1
negative regulation of gene expression	2	34.5×	0.008	ENG, PSEN1
cardiac atrium morphogenesis	1	702.2×	0.008	ENG
positive regulation of coagulation	1	702.2×	0.008	PSEN1
regulation of RNA metabolic process	1	702.2×	0.008	RASA1
angiogenesis	2	31.2×	0.008	GDF2, RASA1
venous blood vessel morphogenesis	1	601.9×	0.008	ENG

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) 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
PSEN1	NIROGACESTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSEN1	8	4
ENG	0	0
GDF2	0	0
RASA1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIROGACESTAT	4	PSEN1
TARENFLURBIL	3	PSEN1
SEMAGACESTAT	3	PSEN1
AVAGACESTAT	2	PSEN1
RG-4733	2	PSEN1
BEGACESTAT	2	PSEN1
E-2212	1	PSEN1
MK-0752	1	PSEN1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSEN1	557	Binding:538, Functional:12, ADMET:6, Unclassified:1
GDF2	4	Binding:4

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PSEN1	557

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

8 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)
NIROGACESTAT	4	PSEN1
TARENFLURBIL	3	PSEN1
SEMAGACESTAT	3	PSEN1
AVAGACESTAT	2	PSEN1
RG-4733	2	PSEN1
BEGACESTAT	2	PSEN1
E-2212	1	PSEN1
MK-0752	1	PSEN1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSEN1
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	ENG, GDF2, RASA1

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)
ENG	0	—
GDF2	4	—
RASA1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 8.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE4	1
PHASE2/PHASE3	1
PHASE2	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)
NCT01314274	PHASE2	COMPLETED	Intranasal Submucosal Bevacizumab for Epistaxis in Hereditary Hemorrhagic Telangiectasia (HHT)
NCT04150822	Not specified	ACTIVE_NOT_RECRUITING	CHORUS - Comprehensive HHT Outcomes Registry of the United States (Formerly OUR HHT Registry)
NCT06266624	Not specified	ACTIVE_NOT_RECRUITING	Tourniquet-Test in HHT
NCT06573723	Not specified	RECRUITING	Institutional Registry of Rare Diseases
NCT05550376	Not specified	COMPLETED	Genotype-phenotype Association in Hereditary Hemorrhagic Telangiectasia
NCT06039124	Not specified	COMPLETED	Subsequent Bevacizumab Treatment in Patients With HHT. Follow up BABH

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BEVACIZUMAB	4	3
PAZOPANIB	4	1
CHEMBL4068768	0	1
CHEMBL4171277	0	1
S-ROLIPRAM	0	1