Impact of Variant Type on Genotype–Phenotype Correlations in Hereditary Hemorrhagic Telangiectasia

Background: Hereditary hemorrhagic telangiectasia (HHT) shows substantial phenotypic variability. We investigated genotype-phenotype associations, focusing on variant type and predicted effects on RNA processing. Methods: We conducted a retrospective observational study of genetically confirmed HHT patients carrying ENG or ACVRL1 variants. Clinical manifestations, epistaxis severity, treatment and genetic characteristics were assessed. Variants were classified according to molecular type and predicted RNA-disrupting effect. Results: Seventy-eight patients were included, 28 carrying ENG and 50 ACVRL1 variants. Pulmonary arteriovenous malformations (PAVMs) were more frequent among ENG than ACVRL1 carriers (53.6% vs. 24.0%, p = 0.024), whereas hepatic AVMs showed a nonsignificant predominance in ACVRL1 (44.0% vs. 21.4%, p = 0.072). Moderate-to-severe recent epistaxis was more frequent among ACVRL1 carriers (34.0% vs. 3.6%, p = 0.014). Overall, PAVMs were more frequent in patients carrying RNA-disruptive variants than in those with non-RNA-disruptive variants (60.9% vs. 23.6%, p = 0.004). Importantly, this association persisted within ENG, with PAVMs occurring in 73.7% of patients with RNA-disruptive variants compared with 11.1% of those with non-RNA-disruptive variants (p = 0.004). Among patients with non-RNA-disruptive variants, cerebral vascular malformations were more frequent in ENG than in ACVRL1 carriers (44.4% vs. 8.7%, p = 0.013). Conclusions: Beyond established ENG-ACVRL1 phenotypic differences, variant-level molecular characteristics may contribute to HHT phenotypic heterogeneity.