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Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations
  1. N L Prigoda1,
  2. S Savas2,
  3. S A Abdalla3,
  4. B Piovesan1,
  5. D Rushlow1,
  6. K Vandezande1,
  7. E Zhang1,
  8. H Ozcelik2,
  9. B L Gallie1,
  10. M Letarte4
  1. 1HHT Solutions, Toronto Western Hospital, Toronto, Canada
  2. 2Fred A Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute and Department of Pathology and Laboratory Medicine, Mount Sinai Hospital; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
  3. 3Department of Laboratory Medicine and Pathobiology, St Michael’s Hospital, Toronto, Canada
  4. 4Cancer Research Program, The Hospital for Sick Children, Heart and Stroke Richard Lewar Center of Excellence and Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Canada
  1. Correspondence to:
 Dr Michelle Letarte
 The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8 Canada; mablab{at}


Background: Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder present in 1 in 8000 people and associated with arteriovenous malformations. Genetic testing can identify individuals at risk of developing the disease and is a useful diagnostic tool.

Objective: To present a strategy for mutation detection in families clinically diagnosed with HHT.

Methods: An optimised strategy for detecting mutations that predispose to HHT is presented. The strategy includes quantitative multiplex polymerase chain reaction, sequence analysis, RNA analysis, validation of missense mutations by amino acid conservation analysis for the ENG (endoglin) and ACVRL1 (ALK1) genes, and analysis of an ACVRL1 protein structural model. If no causative ENG or ACVRL1 mutation is found, proband samples are referred for sequence analysis of MADH4 (associated with a combined syndrome of juvenile polyposis and HHT).

Results: Data obtained over the past eight years were summarised and 16 novel mutations described. Mutations were identified in 155 of 194 families with a confirmed clinical diagnosis (80% sensitivity). Of 155 mutations identified, 94 were in ENG (61%), 58 in ACVRL1 (37%), and three in MADH4 (2%).

Conclusions: For most missense variants of ENG and ACVRL1 reported to date, study of amino acid conservation showed good concordance between prediction of altered protein function and disease occurrence. The 39 families (20%) yet to be resolved may carry ENG, ACVRL1, or MADH4 mutations too complex or difficult to detect, or mutations in genes yet to be identified.

  • HHT, hereditary haemorrhagic telangiectasia
  • JPHT, syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia
  • PAVM, pulmonary arteriovenous malformation
  • SIFT, “sorting intolerant from tolerant” program
  • vascular disease
  • endoglin
  • ACVRL1
  • MADH4

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  • Published Online First 11 May 2006

  • Conflicts of interest: none declared