Prevalence of ENG Mutations
ENG mutations causing Hereditary Hemorrhagic Telangiectasia (HHT Type 1) occur in approximately 1 in 5,000 to 1 in 10,000 individuals in the general population, though recent genomic data suggest the true prevalence may be substantially higher at 2.1 to 11.9 per 5,000 due to widespread underdiagnosis. 1, 2, 3
Established Prevalence Estimates
Traditional estimates place HHT prevalence at 1 in 5,000 to 1 in 10,000 globally, with geographic variation ranging from 1 in 5,000 to 1 in 18,000 depending on location. 1, 2 Among all HHT cases:
- ENG mutations (HHT Type 1) account for approximately 54-61% of identified HHT families 4, 5
- ACVRL1 mutations (HHT Type 2) account for 37-46% of cases 5
- SMAD4 mutations represent 1-2% of HHT cases 6
This means ENG mutations specifically affect approximately 1 in 9,000 to 1 in 18,000 individuals based on traditional calculations (taking 54-61% of the 1:5,000-1:10,000 overall HHT prevalence). 1, 4, 5
Evidence of Substantial Underdiagnosis
Recent genomic analysis using the Genome Aggregation Database (gnomAD v4.1) reveals HHT prevalence may be 2 to 12 times higher than current estimates, suggesting between 2.1 and 11.9 per 5,000 individuals. 3 This dramatic discrepancy stems from:
- Variable penetrance and clinical manifestations mean not all gene carriers present with obvious symptoms, leading to missed diagnoses 2
- Delays in diagnosis are common, with patients experiencing recurrent symptoms for years before HHT recognition 2
- Clinician unfamiliarity with the Curaçao diagnostic criteria contributes to underrecognition 2
- Nearly 50% of individuals with a single HHT symptom (including three patients reporting only nosebleeds) were found to have pathogenic mutations, indicating many mild cases go undiagnosed 7
Mutation Detection Rates
When genetic testing is performed on clinically diagnosed HHT patients, mutations are identified in 76-85% of families, with the remaining 15-24% potentially harboring mutations in undiscovered genes or mutations too complex to detect with current methods. 8, 5 Specifically:
- Genetic testing identifies causative mutations in 97% of patients with definite clinical diagnosis (3 of 4 Curaçao criteria) 2, 6
- Sensitivity of mutation detection is approximately 80% across all referred families 5
- ENG mutations are widely distributed throughout the gene, while ACVRL1 mutations cluster largely in exons 7 and 8 9
Clinical Implications of Prevalence Data
The higher-than-expected prevalence based on genomic data means HHT should be considered more common than traditionally classified "rare diseases," with important implications:
- Increased clinical suspicion is warranted when evaluating patients with recurrent bilateral epistaxis, even without family history 2, 7
- Screening of asymptomatic family members should be prioritized, as each child of an affected parent has a 50% inheritance risk 6
- Earlier diagnosis allows presymptomatic treatment of pulmonary and cerebral arteriovenous malformations, preventing life-threatening complications including stroke, cerebral abscess, and hemorrhage 2, 6, 4
Geographic and Ethnic Considerations
HHT prevalence appears similar across genetic ancestries based on machine learning analysis of gnomAD variants, suggesting underdiagnosis is a global rather than population-specific phenomenon. 3 Founder effects have been identified in certain regions, which may simplify genetic diagnosis of new patients from those areas. 8