Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1.

Published

Journal Article

Hereditary hemorrhagic telangiectasia (HHT) is a Mendelian disease characterized by vascular malformations (VMs) including visceral arteriovenous malformations and mucosal telangiectasia. HHT is caused by loss-of-function (LoF) mutations in one of three genes, ENG, ACVRL1, or SMAD4, and is inherited as an autosomal-dominant condition. Intriguingly, the constitutional mutation causing HHT is present throughout the body, yet the multiple VMs in individuals with HHT occur focally, rather than manifesting as a systemic vascular defect. This disconnect between genotype and phenotype suggests that a local event is necessary for the development of VMs. We investigated the hypothesis that local somatic mutations seed the formation HHT-related telangiectasia in a genetic two-hit mechanism. We identified low-frequency somatic mutations in 9/19 telangiectasia through the use of next-generation sequencing. We established phase for seven of nine samples, which confirms that the germline and somatic mutations in all seven samples exist in trans configuration; this is consistent with a genetic two-hit mechanism. These combined data suggest that bi-allelic loss of ENG or ACVRL1 may be a required event in the development of telangiectasia, and that rather than haploinsufficiency, VMs in HHT are caused by a Knudsonian two-hit mechanism.

Full Text

Duke Authors

Cited Authors

  • Snellings, DA; Gallione, CJ; Clark, DS; Vozoris, NT; Faughnan, ME; Marchuk, DA

Published Date

  • November 7, 2019

Published In

Volume / Issue

  • 105 / 5

Start / End Page

  • 894 - 906

PubMed ID

  • 31630786

Pubmed Central ID

  • 31630786

Electronic International Standard Serial Number (EISSN)

  • 1537-6605

Digital Object Identifier (DOI)

  • 10.1016/j.ajhg.2019.09.010

Language

  • eng

Conference Location

  • United States