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

Am J Hum Genet. 2019 Nov 7;105(5):894-906. doi: 10.1016/j.ajhg.2019.09.010. Epub 2019 Oct 17.

Abstract

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.

Keywords: ACVRL1; ENG; HHT; bi-allelic; biallelic; hereditary hemorrhagic telangiectasia; mosaicism; somatic mutation; two-hit.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Activin Receptors, Type II / genetics*
  • Aged
  • Alleles
  • Arteriovenous Malformations / genetics
  • Endoglin / genetics*
  • Female
  • Genotype
  • Humans
  • Loss of Heterozygosity / genetics
  • Male
  • Mutation / genetics*
  • Phenotype
  • Smad4 Protein / genetics*
  • Telangiectasia, Hereditary Hemorrhagic / genetics*
  • Vascular Malformations / genetics*

Substances

  • ENG protein, human
  • Endoglin
  • Smad4 Protein
  • ACVRL1 protein, human
  • Activin Receptors, Type II