Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype

Hum Mutat. 2006 Jul;27(7):667-75. doi: 10.1002/humu.20342.


Hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu disease) is an autosomal dominant disease characterized by arteriovenous malformations ranging from cutaneous and mucous membrane telangiectasias to more severe pulmonary, gastrointestinal, and cerebral arteriovenous malformations (AVMs). Acute complications from bleeding or pulmonary shunting may be catastrophic. However, when diagnosed early, the complications can usually be prevented. Mutations in two genes, Endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1 or ALK1) have been associated with HHT. We describe the results of mutation analysis on a consecutive series of 200 individuals undergoing clinical genetic testing for HHT. The observed sensitivity of mutation detection was similar to that in other series with strict ascertainment criteria. A total of 127 probands were found, with sequence changes consisting of 103 unique alterations, 68 of which were novel. In addition, eight intragenic rearrangements in the ENG gene and two in the ACVRL1 gene were identified in a subset of coding sequence mutation-negative individuals. Most individuals tested could be categorized by the number of HHT diagnostic criteria present. Surprisingly, almost 50% of the cases with a single symptom were found to have a significant sequence alteration; three of these reported only nosebleeds. Genetic testing can confirm the clinical diagnosis in individuals and identify presymptomatic mutation carriers. As many of the complications of HHT disease can be prevented, a confirmed molecular diagnosis provides an opportunity for early detection of AVMs and management of the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / chemistry
  • Activin Receptors, Type II / genetics*
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antigens, CD / chemistry
  • Antigens, CD / genetics*
  • Blotting, Southern
  • Child
  • Child, Preschool
  • Chromosome Aberrations
  • DNA Mutational Analysis
  • Endoglin
  • Exons
  • Female
  • Genetic Testing*
  • Genotype
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mutation*
  • Phenotype
  • Protein Structure, Tertiary
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / genetics*
  • Telangiectasia, Hereditary Hemorrhagic / diagnosis*
  • Telangiectasia, Hereditary Hemorrhagic / genetics


  • Antigens, CD
  • ENG protein, human
  • Endoglin
  • Receptors, Cell Surface
  • ACVRL1 protein, human
  • Activin Receptors, Type II