title: Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations.
abstract: 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.
authors.affiliation: HHT Solutions, Toronto Western Hospital, Toronto, Canada.
authors.forename: N L
authors.initials: NL
authors.lastname: Prigoda
authors.forename: S
authors.initials: S
authors.lastname: Savas
authors.forename: S A
authors.initials: SA
authors.lastname: Abdalla
authors.forename: B
authors.initials: B
authors.lastname: Piovesan
authors.forename: D
authors.initials: D
authors.lastname: Rushlow
authors.forename: K
authors.initials: K
authors.lastname: Vandezande
authors.forename: E
authors.initials: E
authors.lastname: Zhang
authors.forename: H
authors.initials: H
authors.lastname: Ozcelik
authors.forename: B L
authors.initials: BL
authors.lastname: Gallie
authors.forename: M
authors.initials: M
authors.lastname: Letarte
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics; D015703:Antigens, CD / Q000235:genetics; D004252:DNA Mutational Analysis; D000071063:Endoglin; D005091:Exons / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D012680:Sensitivity and Specificity; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II