Work

Hereditary Hemorrhagic Telangiectasia Prevalence Estimates Calculated From GnomAD Allele Frequencies of Predicted Pathogenic Variants in ENG and ACVRL1

Year: 2025

Type: article

Abstract: Background Hereditary hemorrhagic telangiectasia (HHT) is considered a fully penetrant autosomal dominant disorder characterized by the development of arteriovenous malformations. Up to 96% of HHT cases are caused by heterozygous loss-of-function mutations in ACVRL1 or ENG , which encode proteins that function in bone morphogenetic protein signaling. HHT prevalence is estimated at 1 in 5000 and is accordingly classified as rare. However, HHT is suspected to be underdiagnosed due to variable age of onset and expressivity and lack of awareness of HHT among the medical community. Methods To estimate the true prevalence of HHT, we summed allele frequencies of predicted pathogenic variants in ACVRL1 and ENG using three methods. For method one, we included Genome Aggregation Database (gnomAD v4.1) variants with ClinVar annotations of pathogenic or likely pathogenic, plus unannotated variants with a high probability of causing disease. For method two, we evaluated all ACVRL1 and ENG gnomAD variants using threshold filters based on accessible in silico pathogenicity prediction algorithms. For method three, we developed a machine learning-based classification system to improve the classification of missense variants. Results Based on gnomAD variants, we calculated an HHT prevalence of between 2.1 in 5000 (method 1, most conservative) and 11.9 in 5000 (method 3, least conservative), or roughly 2 to 12-times higher than current estimates. Application of our machine learning-based classification method, which performed with over 97% accuracy, revealed missense variants as the greatest contributor to pathogenic allele frequency and similar HHT prevalence across genetic ancestries. Conclusions Our results support the notion that HHT is underdiagnosed and that HHT may not actually be a ”rare” disease.

Source: Circulation Genomic and Precision Medicine

DOI: 10.1161/circgen.124.005061

Authors: Anthony R. Anzell, Carter White, Brenda Diergaarde, Jenna C. Carlson, Beth L. Roman

Institutions: University of Pittsburgh, UPMC Health System, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center

Language: English

Topic: Vascular Anomalies and Treatments

Subfield: Genetics

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Funders: University of Pittsburgh, National Institutes of Health