Hereditary Haemorrhagic Telangiectasia: evidence of a common ancestor in 19 families from Northern Italy.

Introduction: Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant vascular disorder affecting 1:5000-8000 individuals worldwide. The genes associated with HHT (ENG, ACVRL1, SMAD4, GDF2) belong to the TGF-β signalling pathway. Evidence for a “Founder Effect” was demonstrated only few times in the HHT literature. We found 19 HHT unrelated families, coming from the region around Bergamo (Northern Italy) and sharing the same pathogenetic variant: the ACVRL1 in-frame deletion c.289_294del (p.H97-N98). Here we suggest the presence of a common ancestor in whom this variant arose and date its origin about 200 years ago. Materials and Methods: We analysed 88 subjects from 19 families: 66 disease-variant carriers and 22 unaffected. We used eight microsatellite markers spanning 3.7Mb surrounding the ACVRL1 locus. After haplotype reconstruction, the pathogenetic variant's age estimation was carried out with the DMLE+2.3 software package. Results: We observed a common disease haplotype in 16/19 families. Three families showed evidence of recombination around the ACVRL1 locus. Subsequent analyses suggested that the mutation occurred about 8 (95% credible set: 6-11) generations ago, corresponding to about 203 (165-265) years ago. Conclusions: We hypothesise for the first time a “founder effect” for a HHT pathogenetic variant in Italy. This information is also useful to notify the Bergamo Local Health Authority of a higher incidence of a rare, underdiagnosed disease. This will increase HHT patients’ awareness and offer them better clinical care and genetic diagnosis. Grant: CO: Italian Ministry of Education, University and Research to the DMM-University of Pavia “Dipartimenti di Eccellenza (2018-2022)”