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Condition report · Cardiovascular
Whole genome sequencing identifies ENG, ACVRL1, and SMAD4 variants, distinguishing HHT types with different AVM patterns, and establishes the diagnosis that triggers the pulmonary AVM screening that prevents strokes.
A condition report looks for rare variants known to cause the conditions it covers.
A disorder of angiogenesis leading to arteriovenous dilatations: cutaneo-mucosal hemorrhagic telangiectasias and visceral shunting.
Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant vascular disorder caused by pathogenic variants in genes encoding proteins in the BMP/TGF-β arterial signaling pathway, leading to abnormal blood vessel development with formation of arteriovenous malformations (AVMs). AVMs are direct arteriovenous connections that lack normal capillary beds; they can bleed, cause high-output cardiac failure, and allow venous blood to bypass pulmonary filtration. HHT affects approximately 1 in 5,000-8,000 individuals worldwide. The classic clinical triad (recurrent nosebleeds [epistaxis], mucocutaneous telangiectasias, and AVMs in visceral organs) often allows clinical diagnosis, but AVMs in lung and brain may be asymptomatic until a catastrophic event.
HHT is genetically heterogeneous. Type 1 (ENG: endoglin, chromosome 9q34.11) and type 2 (ACVRL1: activin receptor-like kinase 1, chromosome 12q13.13) each account for approximately 40-45% of molecularly confirmed HHT. SMAD4 pathogenic variants account for approximately 2% and cause a combined juvenile polyposis/HHT syndrome. Rarer variants in RASA1 and EPHB4 cause a related syndrome. ENG variants are associated with higher rates of pulmonary AVMs (present in approximately 60-80% of HHT1 patients) compared to ACVRL1 (30-40% of HHT2 patients). ACVRL1 variants are associated with a higher rate of hepatic AVMs and pulmonary hypertension.
Pulmonary AVMs are the most immediately dangerous manifestation of HHT. Right-to-left shunting allows paradoxical embolism: venous thrombi, bacteria, or air bubbles that would normally be filtered by the pulmonary capillary bed pass directly into the systemic circulation, causing ischemic stroke, brain abscess, or systemic embolism. The risk is proportional to pulmonary AVM size; AVMs with feeding arteries ≥3mm are treated prophylactically by embolotherapy. An estimated 30-40% of HHT patients with pulmonary AVMs have a stroke or TIA as their first neurological event before the diagnosis is established. Pulmonary AVM screening by transthoracic contrast echocardiography or chest CT, combined with embolotherapy for amenable lesions, is life-saving when initiated at diagnosis.
SMAD4 variants cause a combined juvenile polyposis/HHT phenotype. These patients require GI polyposis surveillance in addition to standard HHT management, a clinical need that is only recognized when the specific SMAD4 genotype is identified.
Local dilatation of small vessels resulting in red discoloration of the skin or mucous membranes.
Also known as
telangiectasia
Specific forms also covered
Autosomal dominant
A disorder of angiogenesis leading to arteriovenous dilatations: cutaneo-mucosal hemorrhagic telangiectasias and visceral shunting.
Autosomal dominant
Any hereditary hemorrhagic telangiectasia in which the cause of the disease is a mutation in the GDF2 gene.
Autosomal dominant
Autosomal dominant
Any hereditary hemorrhagic telangiectasia in which the cause of the disease is a mutation in the ACVRL1 gene.
Autosomal dominant
Autosomal dominant
A condition caused by changes in SMAD4 that combines polyps in the digestive tract with the blood vessel abnormalities of hereditary haemorrhagic telangiectasia.
What a diagnosis changes
Knowing about it supports screening for blood vessel malformations in the lungs and brain, and regular bowel and stomach surveillance.
Genes analysed
Also known as
JPHT; polyposis, generalised juvenile, with pulmonary arteriovenous malformation; SMAD4-related juvenile polyposis/hemorrhagic telangiectasia syndrome
ENG and ACVRL1 have distinct clinical profiles and AVM site distributions. SMAD4 causes a combined syndrome requiring GI surveillance. Whole genome sequencing identifies all three genes simultaneously and resolves pathogenic large deletions that standard panel sequencing misses.
HHT type 1 (ENG) carries higher pulmonary AVM prevalence and requires more aggressive screening by both contrast echocardiography and CT chest. HHT type 2 (ACVRL1) carries higher rates of hepatic AVMs and hepatic involvement, with a subset developing high-output cardiac failure and pulmonary hypertension from liver shunting. This clinical distinction guides organ-specific surveillance intensity and influences treatment decisions; bevacizumab has shown particular efficacy in HHT2 hepatic involvement. Knowing which gene is mutated from a complete molecular diagnosis, rather than relying solely on clinical criteria, enables genotype-tailored surveillance from the outset.
Both ENG and ACVRL1 have documented large genomic deletions in approximately 10-20% of molecularly confirmed HHT families. Standard panel sequencing without copy number variant analysis will miss these rearrangements and report a false-negative result in families where a deletion is the causative variant. A false-negative HHT molecular result in a family where the clinical diagnosis of HHT is strong (multiple nosebleed-affected family members, mucocutaneous telangiectasias, and a history of pulmonary AVM) may delay or prevent cascade genetic testing of at-risk relatives, who then do not receive pulmonary AVM screening and remain at stroke risk. Whole genome sequencing provides both point mutation detection and copy number variant analysis in a single test.
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