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/BMPs 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). Purpose of the study: To confirm the pathogenicity of the ACVRL1 in-frame deletion c.289_294del (p.H97-N98)and to test the hypothesis of a common origin of the variant.Materials and Methods: Modelling of the extracellular domain of ALK1 (ALK1 EC) carrying the H97_N98del was performed by the Swiss-Model server. Models were visualised with Pymol. Prediction of glycosylation sites was performed by the NetOGlyc 1.0 server. We used eight microsatellite markers spanning 3.7Mb surrounding the ACVRL1 locus. We analysed 88 subjects from 19 families: 66 disease-variant carriers and 22 unaffected. After haplotype reconstruction, the pathogenetic variant's age estimation was carried out with the DMLE+2.3 software package. Results: The variant is not present in GnomAD and it has never been reported in non-Italian families. Online tools predict this variant as “Likely Pathogenic” or “disease-causing”. Structural stability analysis predicts that this deletion is highly deleterious impacting folding, stability and the extracellular localization of the protein. 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.