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- Title
Hereditary hemorrhagic telangiectasia: First demonstration of a founder effect in Italy; the ACVRL1 c.289_294del variant originated in the country of Bergamo 200 years ago.
- Authors
Sbalchiero, Anna; Abu Hweij, Yasmin; Mazza, Tommaso; Buscarini, Elisabetta; Scotti, Claudia; Pagella, Fabio; Manfredi, Guido; Matti, Elina; Spinozzi, Giuseppe; Olivieri, Carla
- Abstract
Background: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder, affecting 1:5000 individuals worldwide. All the genes associated to the disease (ENG, ACVRL1, SMAD4, GDF2) belong to the TGF‐β/BMPs signaling pathway. We found 19 HHT unrelated families, coming from a Northern Italy region and sharing the ACVRL1 in‐frame deletion c.289_294del (p.H97_N98). Methods: To test the hypothesis of a founder effect, we analyzed 88 subjects from 19 families (66 variant carriers, showing clinical signs of HHT, and 22 non‐carriers, unaffected) using eight microsatellite markers within 3.7 Mb around the ACVRL1 locus. After the haplotype reconstruction, age estimation of the variant was carried out. Results: We observed a common disease haplotype in 16/19 families, while three families showed evidence of recombination around the ACVRL1 locus. The subsequent age estimation analyses suggested that the mutation occurred about 8 generations ago, corresponding to about 200 years ago. We also present novel in silico and modeling data supporting the variant pathogenicity: the deletion alters the protein stability and removes the unique extracellular glycosylation site. Conclusion: We have demonstrated, for the first time, a "founder effect" for a HHT pathogenic variant in Italy.
- Subjects
ITALY; BERGAMO (Italy); NORTHERN Italy; HEREDITARY hemorrhagic telangiectasia; RABBIT diseases; MICROSATELLITE repeats; PROTEIN stability
- Publication
Molecular Genetics & Genomic Medicine, 2022, Vol 10, Issue 8, p1
- ISSN
2324-9269
- Publication type
Article
- DOI
10.1002/mgg3.1972