Genotype-phenotype correlations and protein domain-level predictors of cerebrovascular malformations in hereditary hemorrhagic telangiectasia.

BACKGROUND

Hereditary Hemorrhagic Telangiectasia (HHT) exhibits marked phenotypic heterogeneity. Although gene-organ associations are well established for visceral involvement, predictors of cerebrovascular malformations (CVMs), particularly brain arteriovenous malformations (bAVMs), remain incompletely defined. This study aimed to investigate genotype-phenotype correlations and identify predictors of bAVMs in a genetically confirmed HHT cohort.

METHODS

We conducted a retrospective analysis of 142 Caucasian patients with genetically confirmed HHT. Clinical manifestations were systematically assessed and correlated with the mutated gene (ENG, ACVRL1, and SMAD4), variant type (truncating vs. non-truncating), and protein domain location. Multivariable logistic regression was performed to identify independent predictors of bAVMs.

RESULTS

The cohort included 83 (58.5%) ACVRL1 and 53 (37.3%) ENG mutation carriers. Bivariate analysis demonstrated distinct phenotypic patterns. ENG mutations were strongly associated with pulmonary AVMs (p < 0.001) and bAVMs (p < 0.001), with bAVMs observed in 35.8% of ENG carriers compared with 3.6% of ACVRL1 carriers. In contrast, hepatic AVMs were more frequent among ACVRL1 carriers (44.6%), although this did not reach statistical significance (p = 0.086). In the multivariable logistic regression model (overall p < 0.001), younger age emerged as the sole independent predictor of bAVMs (OR 0.968, p = 0.040), whereas the mutated gene did not retain independent significance.

CONCLUSION

ENG mutation carriers display a markedly increased cerebrovascular burden, confirming a gene-specific susceptibility to bAVMs. Younger age independently predicts bAVM presence. These findings support age- and genotype-informed risk stratification and may help refine screening strategies in HHT patients.