Virulence Genes Of Hereditary Hemorrhagic Telangiectasia In China

Hereditary hemorrhagic telangiectasia （HHT） is an autosomal dominantvascular disease, with the incidence rate1：5000~8000in North America. HHT ischaracterized by cutaneous or mucosal telangiectasia and visceral arteriovenousmalformations. Epistaxis and gastrointestinal bleeding are common mucosalmanifestation. Involved organs include the lungs, liver and brain. Clinical diagnosis ismainly based on the clinical manifestation of HHT： nose bleeding, capillary skinmucous membrane expansion, visceral arteriovenous malformations and family history.Molecular diagnosis is made according to the detection of endoglin （ENG） gene,activin receptor-like kinase-1（ACVRL1） gene and mothers against decapentaplegichomolog4（SMAD4） gene. Mutations detection rate in clinically diagnosed patientswas68-78%. Genetic testing can confirm the clinical diagnosis in individuals andidentify presymptomatic mutation carriers.Objective： To study the etiology and pathogenesis of hereditary hemorrhagictelangiectasia, evaluate the molecular test sensitivity and understand mutationspectrum of HHT patients in China.Methods：80patients with HHT from10families were enrolled in our study. Weevaluated the patients by history, examination, screening for vascular malformations.Whole genomic DNA was extracted from peripheral blood. Polymerase chain reactionamplification and sequencing were performed to detect mutation in gene ENG,ACVRL1and SMAD4. The evolutionary conservation of mutations was caculatedamong species. Mutation screening was carried out in100normal controls. The mutantprotein three-dimensional structure was modelled to analysis of its pathogenicity. Result：We found mutations in6of the8definitely diagnosed kindreds（75%）analyzed-14%were in ENG and86%were in ACVRL1. The observed sensitivity ofmutation detection was similar to that in other series with strict ascertainment criteria.We detected a total of14different mutations in the two genes. Twelve mutations wereidentified in the ACVRL1gene, five of which were novel and comprised missensemutation in exons3, insertion in exons8, intronic deletion in intron5and singlenucleotide variants （SNVs） in intron1and9. One of two mutations identified in theENG gene were novel single base pair substitutions in exons7.Conclusion：1. The method developed proved to be very sensitive for mutation detection inboth ENG and ALK1.2. ALK1mutations （HHT2） were predominant over ENG mutations （HHT1）in Chinese population, different to Northern Europe or North America.3. To distinguish benign from pathogenic mutations is of great significance.4. It will remain challenging to improve our understanding of the non-codingpart of our genome.