ENG – Hereditary hemorrhagic telangiectasia type 1

Hereditary hemorrhagic telangiectasia type 1 (HHT1) is an autosomal dominant vascular dysplasia caused by heterozygous mutations in the ENG gene, encoding the TGF-β co-receptor endoglin, and characterized by epistaxis, mucocutaneous telangiectases and visceral arteriovenous malformations (Hereditary hemorrhagic telangiectasia type 1).

1 Clinical validity

This gene–disease relationship is classified as Definitive. ENG pathogenic variants have been identified in over 155 unrelated HHT1 families with consistent autosomal dominant segregation and concordant functional data ([PMID:16690726]).

2 Genetic evidence

ENG mutations follow an autosomal dominant inheritance. Segregation of ENG variants has been documented in ≥155 affected family members. Case series report ≥17 novel mutations in 80 HHT1 families including missense, nonsense, frameshift, splice and multi-exon deletions ([PMID:12673790], [PMID:16690726]). De novo large exon 3–8 duplications and rare missense alleles (e.g., c.494C>T (p.Pro165Leu)) have been described in individual HHT1 probands ([PMID:10702408]).

3 Functional evidence

Functional studies support a haploinsufficiency mechanism. Promoter analysis showed reduced transcriptional activity of ENG alleles, and protein expression assays demonstrated ER retention and decreased cell-surface localization of missense and truncating mutants. BMP9-response assays reveal that select mutants fail to bind ligand or traffic properly, with some exerting dominant-negative effects on wild-type endoglin ([PMID:25312062]). iPSC-derived endothelial networks and immunostaining confirm reduced ENG expression and defective vascular organization under flow ([PMID:35777360]).

4 Conflicting evidence

A subset of rare ENG variants behaves like benign polymorphisms in functional assays, underscoring the need for experimental validation of novel missense changes.

5 Integration & conclusion

Collectively, over 200 probands across >155 families carry ENG pathogenic variants leading to haploinsufficiency or dominant-negative loss of endoglin function, fully accounting for the HHT1 phenotype. This conclusive evidence supports diagnostic sequencing of ENG in patients with HHT features, enabling early detection of arteriovenous malformations and management of bleeding risks.

Key take-home: ENG mutation analysis is clinically essential for the definitive diagnosis and management of HHT1.

References

• The American journal of pathology • 2000 • Endoglin expression is reduced in normal vessels but still detectable in arteriovenous malformations of patients with hereditary hemorrhagic telangiectasia type 1. PMID:10702408
• Stem cell reports • 2022 • Vascular defects associated with hereditary hemorrhagic telangiectasia revealed in patient-derived isogenic iPSCs in 3D vessels on chip. PMID:35777360
• Human mutation • 2003 • Characterization of 17 novel endoglin mutations associated with hereditary hemorrhagic telangiectasia. PMID:12673790
• Journal of medical genetics • 2006 • Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations. PMID:16690726
• Human molecular genetics • 2015 • Functional analysis of endoglin mutations from hereditary hemorrhagic telangiectasia type 1 patients reveals different mechanisms for endoglin loss of function. PMID:25312062

Evidence Based Scoring (AI generated)