Case report: Novel homozygous ACVRL1 missense variant in a family with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension: findings suggest a hypomorphic allele

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder caused by pathogenic variants in genes within the transforming growth factor beta (TGF-β) signaling pathway, such as ACVRL1, leading to haploinsufficiency. Homozygous variants in HHT-related genes are exceptionally rare and have not been reported in ACVRL1-related HHT to date. We report the first known instance of a novel homozygous missense variant in the ACVRL1 gene (c.576C>G; p.Phe192Leu) identified in two siblings from a family of seven, in which three heterozygotes were also present. Comprehensive clinical evaluations revealed striking phenotypic differences between the homozygous and heterozygous family members. Both homozygous individuals exhibited early-onset pulmonary arterial hypertension and diffuse pulmonary arteriovenous malformations. One of them also demonstrated childhood-onset gastrointestinal bleeding-a manifestation unprecedented in HHT that typically has a late-adulthood onset. In contrast, the heterozygotes displayed either mild or equivocal features of HHT, supporting the classification of this variant as a hypomorphic allele. The novel missense variant is located within the intracellular glycine-serine (GS) domain of the protein, suggesting potential impacts on receptor regulation and downstream signaling. Although these findings expand the phenotypic spectrum of ACVRL1-related HHT, they remain limited to clinical observations. Experimental studies, including functional and molecular assays, are therefore essential to confirm the pathogenic impacts of this variant, validate its classification as a hypomorphic allele, and elucidate its effects on BMP-TGF-β signaling.

Keywords: ACVRL1 gene mutation; genotype–phenotype correlation; hereditary hemorrhagic telangiectasia; hypomorphic allele; pulmonary arteriovenous malformations.