High importance
Sep 13, 2026
To explore differences in expressivity and quantify the degree of phenotypic variability among individuals with hereditary hemorrhagic telangiectasia (HHT) carrying the same pathogenic variant.
Evaluated 60 patients with recurrent ENG and ACVRL1 variants using Shannon entropy indices, Jaccard distances, and a latent variable liability-threshold approach to quantify intra-familial phenotypic heterogeneity.
Substantial phenotypic variability was observed, with cutaneous telangiectasia as the most frequent manifestation. Statistical analysis suggested that the shared variant accounted for only 3.3% of total variance, and age significantly impacted disease severity and symptom manifestations.
The study focused on a relatively small sample size and targeted only specific pathogenic variants, which may limit the generalizability of findings to all HHT patients.
Understanding the phenotypic variability in HHT can help in clinical management and counseling for affected families, highlighting the importance of considering individual-level factors beyond just genetic variants.
Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant vascular disorder primarily caused by pathogenic variants in the ENG and ACVRL1 genes. Although genotype-phenotype correlations are well established at the population level, the degree of phenotypic similarity among relatives sharing the same variant is poorly characterized. Objective: to explore differences in expressivity and quantify the degree of phenotypic variability among individuals with HHT carrying the same pathogenic variant. Methods: We evaluated 60 patients from a reference center with recurrent ENG and ACVRL1 variants, to quantify intra-familial phenotypic heterogeneity using Shannon entropy indices, Jaccard distances, and a latent variable liability-threshold approach. Results: There was substantial phenotypic variability among individuals and families, with cutaneous telangiectasia being the most frequent manifestation. Shannon entropy and Jaccard analyses indicated broadly high variability. The shared variant accounted for only 3.3% of total variance. Age was significantly associated with disease manifestations (β = 0.027, p = 0.002; OR = 1.028, 95% CI 1.010-1.045), with each additional year increasing the odds of severe symptoms by 2.7%, particularly bleeding severity and skin telangiectasias. Conclusions: These findings suggest that the variable expressivity in HHT is predominantly driven by individual-level factors other than the specific pathogenic variant carried by each patient.