Human Genetics

, Volume 128, Issue 1, pp 61–77 | Cite as

Update on molecular diagnosis of hereditary hemorrhagic telangiectasia

  • Jennifer Richards-Yutz
  • Kathleen Grant
  • Elizabeth C. Chao
  • Susan E. Walther
  • Arupa Ganguly
Original Investigation


Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant, vascular disease hallmarked by the development of arteriovenous malformations (AVMs). Germline mutations in two genes, endoglin (ENG) and activin receptor like kinase 1 (ACVRL1), have been implicated in this disease. This report describes molecular diagnosis in a consecutive series of 600 individuals with clinical features of HHT disease. Each coding exon and flanking intronic regions of ENG and ACVRL1 genes was sequenced. Exonic copy number was quantified in probands without a coding sequence mutation. Novel nonsynonymous variants were further analyzed to predict functional consequences. In addition, common single nucleotide polymorphisms genotypes and haplotypes for the two genes were compared between individuals with and without mutations. The highest mutation detection rate (87% [95% CI 80.2–91.5]) was observed in probands who met all four Curacao criteria (epistaxis, telangiectases, AVMs and family history). More than 30% of identified mutations were novel; however, only 6% were variants of unknown significance. Determining the significance of novel mutations as related to disease presents additional challenges. Detection of multiple alterations in the same proband also requires careful evaluation for disease association. In conclusion, the sensitivity of molecular diagnosis is highest in probands with a clinically confirmed diagnosis of HHT. However, a substantial fraction of probands in this group do not carry an identifiable mutation in the coding exons of these two genes. This suggests alternate mechanisms of gene inactivation or involvement of alternate loci, and it requires further investigation.


Single Nucleotide Polymorphism Molecular Diagnosis Hereditary Hemorrhagic Telangiectasia Nonsynonymous Change Telangiectasis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors are grateful to all physicians submitting requests for molecular diagnosis of HHT. The authors are especially indebted to Kristina Bisacquino and Laurie Brenner for analysis of familial mutations and their respective segregations in pedigrees, and also, Andrew Walther for help with data entry for individual genotypes into our HHT database.


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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Jennifer Richards-Yutz
    • 1
  • Kathleen Grant
    • 1
  • Elizabeth C. Chao
    • 1
  • Susan E. Walther
    • 1
  • Arupa Ganguly
    • 1
  1. 1.Genetic Diagnostic Laboratory, Department of Genetics, School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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