Molecular genetic investigations and demonstration of founder effect in Osler-Rendu-Weber disease

R. Gindele1, T. Major2, Z. Szabo1, K. B. Kovács1, G. Pfliegler1, Z. Bereczky1 (1Debrecen, Hungary, 2Eger, Hungary)

Clinical Science
Date: 17.02.2017,
Time: 11:00 - 12:00

Objective: Osler-Rendu-Weber disease (hereditary hemorrhagic telangiectasia; HHT) is a rare autosomal dominant vascular abnormality characterized by mucocutaneous telangiectases and visceral arteriovenous malformations. Many mutations are responsible for the disease, the most commonly involved genes are endoglin (ENG), the activin receptor-like kinase 1 (ACVRL1) and SMAD4, which encode proteins of the transforming growth factor-beta superfamily. Approximately 85 % of HHT cases have heterozygous family-specific mutations either in the ENG or ACVRL1 genes, causing HHT type 1 and 2, respectively. The clinical diagnosis of the disease is based on the Curacao criteria. Our aims were to identify causative mutations of HHT in North-East Hungary and to examine the possibility of a founder effect.

Methods: HHT patients and their relatives were recruited between 2012 and 2016 (n=82). Mutations within ENG and ACVRL1 were detected by direct fluorescent sequencing. Mutation carriers, their spouses and 50 healthy people were genotyped for 8 polymorphic markers around ACVRL1 gene (D12S1677, D12S85, D12S2196, D12S1712, D12S270 and SNPs rs2071219, rs706815 and rs706816). Haplotype analysis was performed to ascertain the possibility of a founder effect. Founder effect was also demonstrated by genealogical study.

Results: Among the 29 HHT index patients, 59% were identified with ENG (11 known and 6 novel) and 28% with ACVRL1 (2 known and 1 novel) mutations. The novel splicing mutation (ACVRL1 c.625+1 G>C) was identified in 5 families. The mutation was absent in 50 healthy subjects. The ACVRL1 c.625+1 G>C mutation was associated with the same haplotype in all carriers (n=14), while different haplotypes were observed in healthy controls that suggested founder effect. The genealogical analysis revealed that the possible common ancestors were married in 1779.

Conclusion: Genetic background of HHT is heterogeneous in our geographical area, however a founder mutation was found in 5 families with the disease. The demonstration of a founder mutation is helpful, since the clinical presentation of the disease becomes more predictable and it might simplify the molecular genetic diagnosis algorithm.