Hum Mutat. 2026 Aug 21;2026:8307860. doi: 10.1155/humu/8307860. eCollection 2026.
ABSTRACT
BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder primarily caused by pathogenic variants in the ENG gene, leading to clinical manifestations including pulmonary arteriovenous malformation (PAVM), recurrent spontaneous nosebleeds, and other related symptoms. This study is aimed at investigating the clinical manifestations of members in four HHT1 families with PAVMs and analyze novel ENG variants.
METHODS: Clinical evaluations, whole exome sequencing (WES), and Sanger sequencing were performed on the probands and their family members from Families 1 to 4. Bioinformatics programs were utilized to assess the pathogenicity of the candidate variants. Additionally, an in vitro minigene assay was conducted to examine the impact of the variant in Family 2 on RNA splicing, and Western blot was employed to validate the impact of the variant on protein expression and modification.
RESULTS: Four ENG variants were identified: c.613del (exon 5), c.1428 + 2 T > C (intron 11), c.1498dup (exon 12), and c.322del (exon 3). The splice-site variant c.1428 + 2 T > C, which has been reported as pathogenic in ClinVar, leads to aberrant ENG mRNA splicing with exon 11 skipping, resulting in a shorter protein (p.Lys438_Gln476del) with impaired glycosylation.
CONCLUSION: The splice-site variant c.1428 + 2 T > C caused aberrant ENG mRNA splicing, leading to exon 11 skipping and producing a shorter protein with abnormal glycosylation (p.Lys438_Gln476del). The variants identified in Families 1, 3, and 4 (c.613delC, c.1498dupC, and c.322delG) are all frameshift variants that lead to premature termination of translation. This study expands the spectrum of ENG variants and provides insights into the pathogenesis of HHT1. These findings offer guidance for the early diagnosis for families affected by HHT1.
PMID:42633037 | PMC:PMC13498851 | DOI:10.1155/humu/8307860