Abstract

Background: Apulia and neighbouring Southern Italian regions present a complex genetic stratification shaped by historical migrations. Phenylketonuria (PKU), caused by PAH mutations, serves as an excellent model for molecular epidemiology. This study maps the geographical distribution of PAH variants in a large Southern Italian cohort, evaluating their correlation with clinical phenotypes and long-term Body Mass Index (BMI). Methods: A retrospective cohort study was conducted on 344 patients followed for at least 10 years. Genetic characterization evolved from Sanger to Next-Generation Sequencing, and patients were stratified into micro-geographic clusters. Results: The genetic landscape was dominated by three ancestral variants (c.1208C>T, c.1066-11G>A, c.898G>T), accounting for 58% of the allelic pool. Significant micro-geographic polarization was observed: c.1222C>T clustered in Central–Northern Apulia, mirroring historical Norman-Swabian migration, whereas c.441+5G>T enriched in Southern Apulia. At final follow-up, classic PKU adult patients exhibited a four-fold increased risk of obesity (p < 0.05), driven by severe null alleles that necessitate a lifelong dependency on engineered low-protein foods. Conclusions: PAH mutational stratification serves as a contemporary reflection of historical migratory maps. Incorporating regional and genotypic mapping provides a precision medicine framework to anticipate phenotype severity, optimize therapeutic management, and tailor long-term obesity risk monitoring.

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