Characterization of 17 novel endoglin mutations associated with hereditary hemorrhagic telangiectasia

Hum Mutat. 2003 May;21(5):482-92. doi: 10.1002/humu.10203.


Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a vascular dysplasia caused by mutations in the endoglin (ENG) gene and associated with epistaxis, telangiectases, and a high incidence of pulmonary arteriovenous malformations. To efficiently detect deletions and insertions, we optimized a quantitative multiplex polymerase chain reaction (QMPCR) analysis. We report 17 novel mutations, of which six were detected by QMPCR. Three deletions occurring in intronic sequences were associated with a single copy of exons 9a-14, exon 5, and exons 7-8, respectively. A transient 70kDa monomeric mutant protein resulted from the in-frame deletion of exons 7 and 8 but no mutant protein was present in the other cases. Deletion (in exon 10) or insertion (in exon 7) of two nucleotides, as well as a 1-bp deletion in the small exon 9a were found by QMPCR. Sequencing was required to detect single nucleotide deletions/insertions in exons 2, 5, 6, and 8. No mutant proteins were associated with these frame shift mutations. Two novel splice site mutations resulted in skipping of exons 2 and 4, respectively, while a previously reported intron 3 splice mutant was observed as a de novo mutation. We also report five novel nonsense and missense mutations, including one de novo. Review of the 80 HHT1 families reported to date indicates that 10% would not be resolved by sequencing and that an additional 25% could be revealed by QMPCR performed prior to sequencing. Thus the use of QMPCR accelerates genetic screening for HHT1 and resolves mutations affecting whole exons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antigens, CD
  • DNA / chemistry
  • DNA / genetics
  • DNA Mutational Analysis
  • DNA, Complementary / chemistry
  • DNA, Complementary / genetics
  • Endoglin
  • Family Health
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Receptors, Cell Surface
  • Telangiectasia, Hereditary Hemorrhagic / genetics*
  • Telangiectasia, Hereditary Hemorrhagic / pathology
  • Vascular Cell Adhesion Molecule-1 / genetics*


  • Antigens, CD
  • DNA, Complementary
  • ENG protein, human
  • Endoglin
  • Receptors, Cell Surface
  • Vascular Cell Adhesion Molecule-1
  • DNA