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| Home > Articles > Published articles > New genetic drivers in hemorrhagic hereditary telangiectasia |
(Institut d'Investigació Biomèdica de Bellvitge) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut d'Investigació Biomèdica de Bellvitge) (Institut d'Investigació Biomèdica de Bellvitge) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut d'Investigació Biomèdica de Bellvitge)
| Date: | 2024 |
| Abstract: | Background: Hereditary hemorrhagic telangiectasia (HHT) is a rare vascular disease inherited in an autosomal dominant manner. Disease-causing variants in endoglin (ENG) and activin A receptor type II-like 1 (ACVRL1) genes are detected in around 90% of the patients; also 2% of patients harbor pathogenic variants at SMAD4 and GDF2. Importantly, the genetic cause of 8% of patients with clinical HHT remains unknown. Here, we present new putative genetic drivers of HHT. Methods: To identify new HHT genetic drivers, we performed exome sequencing of 19 HHT patients and relatives with unknown HHT genetic etiology. We applied a multistep filtration strategy to catalog deleterious variants and prioritize gene candidates based on their known relevance in endothelial cell biology. Additionally, we performed in vitro validation of one of the identified variants. Results: We identified variants in the INHA, HIF1A, JAK2, DNM2, POSTN, ANGPTL4, FOXO1 and SMAD6 genes as putative drivers in HHT. We have identified the SMAD6 p. (Glu407Lys) variant in one of the families; this is a loss-of-function variant leading to the activation of the BMP/TGFβ signaling in endothelial cells. Conclusions: Variants in these genes should be considered for genetic testing in patients with HHT phenotype and negative for ACVRL1/ENG mutations. |
| Grants: | Instituto de Salud Carlos III PI17/00669 Instituto de Salud Carlos III PI20/00592 Agencia Estatal de Investigación PID2020-116184RB-110 "la Caixa" Foundation LCF/PR/PR16/51110035 "la Caixa" Foundation LCF/PR/HR19/52160023 "la Caixa" Foundation LCF/BQ/PR20/11770002 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Hereditary hemorrhagic telangiectasia ; Rare diseases ; Genetics ; SMAD6 ; Hypoxia |
| Published in: | European Journal of Internal Medicine, Vol. 119 (january 2024) , p. 99-108, ISSN 1879-0828 |
