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

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.

Hereditary Hemorrhagic Telangiectasia in Pediatric Age: Focus on Genetics and Diagnosis

“…In fact, when a new patient is diagnosed, it is common to experience the subsequent identification of previously undiagnosed relatives. In addition, after the first report of a founder effect in the Netherland Antilles [ 9 ], the same observation has been reported in many different countries, including Italy [ 10 ]. Overall, a reasonable general estimate of the prevalence is 1 in 5000 [ 11 ].…”