Submission Details

The relationship between ENG and autosomal dominant Hereditary Hemorrhagic Telangiectasia, Type 1 (HHT1) was evaluated using the ClinGen Clinical Validity Framework as of Apr 11, 2019. ENG was first reported in relation to HHT1 in 1994 (McAllister et al., PMID: 7894484). HHT1 is diagnosed by the presence of 3 or more of the Curacao criteria (PMID: 10751092). ENG is an auxiliary component of the TGF-β receptor system and interacts with ACVRL1 in the TGF-β pathway. ACVRL1 is known to cause HHT2. The mechanism for disease is haploinsufficiency (PMID: 15879500, 25312062); however a dominant negative mechanism is also reported (PMID: 25312062), and at least 507 ENG variants, ranging from missense, in-frame indel to nonsense, frameshift, large deletions and whole gene deletions, have been reported in humans (http://www.arup.utah.edu/database/ENG/ENG_welcome.php). Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Variants included in this curation come from 13 probands in 6 publications (PMIDs 7894484, 20414677, 30763665, 17384219, 20364125), and segregated with disease in 13 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. This gene-disease relationship is further supported by animal models and in vitro functional assays. A number of mouse models have been developed for HHT (PMID: 10348742, 20224041, 20364125 ) and interaction with ACVRl1 in the TGF-β pathway has been experimentally demonstrated (PMID: 15702480, 12015308, 25312062). In summary, ENG is definitively associated with autosomal dominant hereditary hemorrhagic telangiectasia, Type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hemostasis/Thrombosis Gene Curation Expert Panel on August 28, 2019 (SOP Version 6). It was reevaluated on 11/28/2022 to update scoring.

Of note, pulmonary arterial hypertension (PAH) is a rare but severe complication of HHT1 that was independently evaluated as of September 22, 2021 by the Pulmonary Hypertension GCEP. At least 13 probands with rare, predicted deleterious variants have been reported (PMIDs: 14684682, 15687131, 23919827, 26387786, 29650961, 31727138). Experimental evidence for a gene-disease relationship for HHT-PAH largely overlaps that for HHT. Spontaneous pulmonary hypertension in an Eng knockout HHT mouse model (PMID: 21859819) adds further support.