Hereditary haemorrhagic telangiectasia (HHT) is diagnosed clinically by the Curaçao Criteria of
spontaneous recurrent nosebleeds, mucocutaneous telangiectasia at characteristic sites, visceral involvement (arteriovenous malformations [AVMs]; gastrointestinal telangiectasia), and family history. [1] Early diagnosis is important to enable AVM screening and preventative
treatments.[2-5] HHT is caused by loss-of-function DNA variants in ENG, ACVRL1 ̧ SMAD4 or GDF2,[6-9] though older manuscripts describing linkage to additional loci[10,11] continue to be referenced heavily. In whole genome sequencing performed prospectively for HHT “gene negative” patients recruited to the NHS 100,000 Genomes Project,[12] no candidate variants were identified in the HHT3 or HHT4 loci. “HHT gene negative” families receiving a clinical positive test result included the original HHT3 family, and a family diagnosed with a related vasculopathy (CM-AVM2[13]), due to a heterozygous variant in EPHB4 that lies on the same chromosome as the HHT4 locus. Clinically, we conclude that molecular testing is advisable to confirm HHT as it is possible to meet three Curaçao Criteria without having HHT. For some HHT family members who meet 3 criteria ‘only’ through nosebleeds, telangiectasia and family
history, a designation of “likely” not “definite” HHT may be preferred. Scientifically, reference to early linkage studies unsupported by confirmatory sequence identification of a causal gene is discouraged, and there is no longer evidence for an independent HHT3 locus.