Community-Based SERPINA1 Genotyping in an Isolated Alpine Town Reveals Heterozygous Pi*Mheerlen Carriers:...

Background/Objectives: Alpha-1 antitrypsin deficiency (AATD) is an underdiagnosed hereditary disorder that predisposes individuals to lung and liver disease. While its prevalence is higher in Northern Europe, data from specific, isolated populations in other regions are scarce. This study assessed the prevalence of pathogenic SERPINA1 variants in the adult population of Ponte di Legno, a secluded town in the Italian Alps, to investigate potential founder effects involving rare genotypes. Methods: A cross-sectional community-based screening was conducted. Adult residents without previously diagnosed chronic respiratory diseases were invited to undergo spirometry and provide venous blood samples for serum AAT and CRP measurement. Buccal swabs were collected for genotyping, which was performed using a validated multiplex Luminex xMAP assay detecting 14 common and rare SERPINA1 variants, with isoelectric focusing and Sanger sequencing for further characterization when required. Results: Ninety-one subjects were enrolled (median age 61 years; 37.4% male). Five individuals (5.5%) carried pathogenic SERPINA1 variants: one Pi*MS heterozygote (1.1%), two Pi*MZ heterozygotes (2.2%), and two individuals heterozygous for the rare Pi*Mheerlen variant (Pi*M/Mheerlen) (2.2%). Median serum AAT levels were significantly lower in carriers of deficient alleles compared with Pi*MM individuals (100 mg/dL vs. 125 mg/dL, p = 0.0218). Conclusions: This community-based screening revealed a notable prevalence of AATD carriers in a geographically isolated Italian community, including two cases of the rare Pi*Mheerlen variant, suggesting a possible local founder effect. These findings underscore the value of targeted screening programs using rare variant panels to uncover hidden genetic architectures in isolated populations.