ENG

Inheritance Pattern: AD

Disease ID:MONDO:0017380

Submitter: ClinGen

Juvenile polyposis syndrome (JPS) is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. The term "juvenile" refers to the type of polyp rather than to the age of onset of polyps.ENG was first reported in relation to autosomal dominant JPS in 2005 (Sweet et al., PMID: 16287957). ENG (Endoglin) is a component of the transforming growth factor beta (TGFB) receptor complex and binds TGFB1 with a crucial role in vascular development and angiogenesis. Haploinsufficient variants account for over 85% of patients with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) and have been found to have a Definitive relationship with HHT (see separate curation). Variants in ENG genes were subsequently reported in patients with JPS without overlapped HHT phenotype. Therefore, per the ClinGen Lumping and Splitting Working Group this curation solely focuses on JPS phenotype with regard to curating the limited information available for this split curation. Seven missense variants that have been reported in eight probands in three publications (PMIDs: 16287957, 17204053, 23399955) are included in this curation. All of these JPS associated ENG variants are variants of uncertain pathogenicity (0.3 point). There were two research articles showing endoglin expression was increased in various cancer tissues including colon (1 point). Combination of genetic and experimental evidence has not demonstrated convincing definitive validity of ENG gene in inherited JPS. In summary, there is limited evidence to support this gene-disease relationship.

Inheritance Pattern: AD

Disease ID:MONDO:0008535

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0008535

Submitter: Genomics England PanelApp

Inheritance Pattern: AD

Disease ID:MONDO:0019180

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0008535

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0008535

Submitter: ClinGen

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.

Inheritance Pattern: AD

Disease ID:MONDO:0019180

Submitter: Orphanet