Genetic Diagnosis of Hereditary Hemorrhagic Telangiectasia: Four Novel Pathogenic Variations in Turkish Patients

Abstract

Aims: Hereditary hemorrhagic telangiectasia is an autosomaldominant disorder characterized by telangiectasia, epistaxis, andvascular malformations. Pathogenic mutations were found in ENG,AVCRL1, SMAD4, and GDF genes. In this study, we present ourdatabase of patients with hereditary hemorrhagic telangiectasiaregarding the phenotype-genotype relations and discuss two novelENG gene pathogenic variations in two unrelated families.Methods: Next Generation Sequencing analysis was performed onthe peripheral blood of nine patients with hereditary hemorrhagictelangiectasia in four unrelated families. All patients were diagnosedwith hereditary hemorrhagic telangiectasia according to the Curaçaocriteria. Data on treatment and screenings of visceral involvementwere recorded from files.Results: We have found a pathogenic variation in either the ENG orACVRL1 gene in each family. Two novel pathogenic variations in theENG gene, including NM_000118.3 (ENG): c.416delC (p.P139fs*24)and NM_000118.3(ENG): c.1139dupT (p.Leu380PhefsTer16),were found in the same family. The NM_000020.2(ACVRL1):c.1298C>T (p.Pro433Leu) pathogenic variation in the ACVRL1gene in our first family and a novel heterozygous likely pathogenicNM_000020.2(ACVRL1): c.95T>C (p.Val32Ala) variation wasfound in our second family. Seven of the nine patients were treatedwith thalidomide for controlling bleeding episodes. All patientsresponded to thalidomide. In one patient, the response to thalidomidewas lost and switched to bevacizumab.Conclusion: In hereditary hemorrhagic telangiectasia, certain types ofmutations correlate with disease phenotypes and with next generationsequencing methods. New pathogenic variations can be revealed,which might help manage patients with hereditary hemorrhagictelangiectasia