Gene Variants Causing Hereditary Hemorrhagic Telangiectasia
The primary gene variants that cause HHT are mutations in ENG (endoglin, HHT type 1), ACVRL1 (activin receptor-like kinase 1, HHT type 2), SMAD4 (juvenile polyposis-HHT overlap syndrome), and GDF2, with ENG and ACVRL1 mutations accounting for approximately 85-90% of all cases. 1, 2, 3, 4, 5
Primary Disease-Causing Genes
ENG (Endoglin) - HHT Type 1
- Located on chromosome 9, mutations in ENG cause HHT type 1 and are identified in approximately 54% of HHT families 1, 6, 3, 4
- Encodes a transmembrane protein involved in the transforming growth factor-β (TGF-β) signaling pathway expressed on vascular endothelium 6, 3
- Patients with ENG mutations have more frequent and larger pulmonary arteriovenous malformations compared to HHT type 2 6, 7
- Cerebral arteriovenous malformations occur more commonly in HHT1 6
- Hepatic vascular malformations are less common in HHT1 compared to HHT2 6, 7
ACVRL1 (Activin Receptor-Like Kinase 1) - HHT Type 2
- Located on chromosome 12, mutations in ACVRL1 cause HHT type 2 and are identified in approximately 43% of HHT families 1, 7, 3, 4
- Encodes activin receptor-like kinase 1, another component of the TGF-β signaling pathway 3, 4
- Pulmonary arteriovenous malformations occur in only 14% of HHT type 2 patients compared to 40% in HHT type 1 7
- Hepatic involvement is substantially more common and symptomatic in HHT type 2, with marked female predominance 1, 7
SMAD4 (MADH4) - Juvenile Polyposis-HHT Overlap Syndrome
- Mutations in SMAD4 cause a combined syndrome of HHT and juvenile polyposis, occurring in 1-2% of HHT cases 2, 3, 8, 4
- Up to 76% of SMAD4 mutation carriers manifest features of HHT including life-threatening arteriovenous malformations 2
- SMAD4 mutation carriers have significantly higher risk of severe gastric polyposis, and all gastric cancers in one cohort occurred exclusively in SMAD4 carriers 2
- These patients require upper GI tract surveillance every 1-3 years starting at age 18 years 2
GDF2 - Rare HHT Variant
- GDF2 mutations are less frequently responsible for HHT but represent an established disease-causing gene 5
- An HHT3 locus on chromosome 5 (5q31.3-5q32) has also been reported 3
Genetic Testing Approach
Detection Rate and Methodology
- In 97% of patients with a definite clinical diagnosis of HHT, a causative mutation is identified in one of these genes: ENG, ACVRL1, or SMAD4 2, 7
- Simultaneous sequencing and deletion/duplication analysis of both ENG and ACVRL1 genes identifies approximately 96% of mutations when strict Curaçao criteria are applied 2, 9
- Large deletion/duplication analysis is critical, as deletions would be missed if only sequencing is performed 9
Clinical Indications for Testing
- Asymptomatic individuals from families with known HHT represent the strongest indication for genetic testing, allowing for early screening and preventive treatment 2
- SMAD4 testing should be included in the initial panel, particularly when juvenile polyposis features coexist 2
- Genetic testing impacts clinical management because genotype-phenotype correlations exist, and early preventive screening for internal AVMs is recommended prior to the age at which clinical diagnosis can be made 9, 4
Critical Clinical Implications
Inheritance Pattern
- HHT is inherited as an autosomal dominant trait, meaning each child of an affected parent has a 50% chance of inheriting the disease 2, 3, 5
Pathophysiology
- All mutated genes in HHT encode proteins that modulate transforming growth factor-beta superfamily signaling in vascular endothelial cells 3, 5
- These are loss-of-function pathogenic variants in genes encoding proteins of the BMP signaling pathway 5
Phenotypic Variation
- Families with the same mutation exhibit considerable phenotypic variation, making genetic testing alone insufficient for predicting disease severity 8
- The frequency of arteriovenous malformations in particular organs and occurrence of certain rare symptoms are dependent on the specific gene involved 4