Four ENG variants (three novel frameshift variants and one known splice-site variant) were identified in four HHT1 families with pulmonary arteriovenous malformations, expanding the spectrum of ENG variants and providing insights into the pathogenesis of HHT1.
Key Findings
Results
Four ENG variants were identified across four HHT1 families, three of which are frameshift variants and one is a splice-site variant.
The four variants identified were: c.613del (exon 5) in Family 1, c.1428+2T>C (intron 11) in Family 2, c.1498dup (exon 12) in Family 3, and c.322del (exon 3) in Family 4.
The variants in Families 1, 3, and 4 (c.613delC, c.1498dupC, and c.322delG) are frameshift variants that lead to premature termination of translation.
Clinical evaluations, whole exome sequencing (WES), and Sanger sequencing were performed on probands and their family members across all four families.
Bioinformatics programs were utilized to assess the pathogenicity of the candidate variants.
Results
The splice-site variant c.1428+2T>C causes aberrant ENG mRNA splicing resulting in skipping of exon 11.
The variant c.1428+2T>C, located in intron 11, has been previously reported as pathogenic in ClinVar.
An in vitro minigene assay was conducted to examine the impact of the variant on RNA splicing.
The aberrant splicing leads to exon 11 skipping, producing a shorter protein designated p.Lys438_Gln476del.
Results
The shorter protein produced by the c.1428+2T>C splice-site variant exhibits impaired glycosylation.
Western blot was employed to validate the impact of the variant on protein expression and modification.
The resulting protein p.Lys438_Gln476del demonstrated abnormal glycosylation compared to the wild-type ENG protein.
The combination of exon skipping and impaired glycosylation represents the molecular mechanism by which this variant contributes to HHT1 pathogenesis.
Results
All four HHT1 families presented with pulmonary arteriovenous malformations (PAVMs) as part of their clinical manifestations.
PAVMs were a shared clinical feature across all four families studied.
Clinical manifestations of HHT include PAVMs, recurrent spontaneous nosebleeds, and other related symptoms.
The study focused specifically on HHT1 families, which are caused by pathogenic variants in the ENG gene inherited in an autosomal dominant manner.
Results
The study expands the spectrum of known ENG variants associated with HHT1 by identifying novel pathogenic variants.
The frameshift variants c.613delC (exon 5), c.1498dupC (exon 12), and c.322delG (exon 3) were identified as novel variants in the study.
All three frameshift variants lead to premature termination of translation as their predicted molecular consequence.
The authors state these findings 'expand the spectrum of ENG variants and provides insights into the pathogenesis of HHT1.'
The findings are described as offering 'guidance for the early diagnosis for families affected by HHT1.'
What This Means
This research studied four families affected by a rare inherited blood vessel disorder called Hereditary Hemorrhagic Telangiectasia type 1 (HHT1), which causes abnormal blood vessel formations including dangerous connections between arteries and veins in the lungs (pulmonary arteriovenous malformations, or PAVMs) and recurrent nosebleeds. The researchers used advanced genetic testing (whole exome sequencing) combined with laboratory experiments to identify the specific genetic changes (variants) in the ENG gene that were causing the disease in each family. They found four different variants: three caused the gene's instructions to be cut short prematurely (frameshift variants), while one altered how a section of genetic information is processed (a splice-site variant). For the splice-site variant, laboratory experiments confirmed it causes the cell to skip over an entire section of genetic instructions, producing a shorter, abnormally modified protein that cannot function correctly.
This research matters because HHT1 is a condition where early diagnosis can significantly help patients and their relatives who may be at risk. By identifying new genetic variants that cause the disease, this study helps expand the catalog of known disease-causing changes in the ENG gene. This research suggests that genetic testing using the variants described here can help doctors identify affected family members earlier — before serious complications like PAVMs develop — enabling timely monitoring and treatment. The laboratory work also provides a clearer understanding of exactly how these genetic changes disrupt normal protein function, contributing to our broader knowledge of why this disease occurs.
Gong Y, Zhou T, Fu X, Jiang Y, Wang D, Gu C, et al.. (2026). A Study on the Clinical Phenotypes and Genetic Analysis of ENG Variants in Four Hereditary Hemorrhagic Telangiectasia Type 1 Families.. Human mutation. https://doi.org/10.1155/humu/8307860