A Complete Picture of the CYP2D6 Heterogeneity in Northeastern Italian Genetic Isolates

The <i>CYP2D6</i> gene is a highly polymorphic pharmacogene involved in the metabolism of 25% of commonly used drugs. We aim to assess the feasibility of extracting relevant pharmacogenomic information from Whole Genome Sequencing (WGS) data and to highlight any difference in <i>CYP2D6</i> allele frequencies between the northeastern Italian and European populations. To achieve this aim, WGS was performed on two cohorts: 664 individuals from six different isolated communities (FIC) and 123 outbred Italian individuals (FOP). In silico <i>CYP2D6</i> genotyping was performed and allele frequencies from the FIC cohort were compared to those of FOP and European individuals from 1000 Genomes. Interestingly, 18 alleles identified in FIC were absent in the control cohorts. In particular, 13 individuals carried the extremely rare <i>CYP2D6*28x2</i> allele, whose activity is unknown. Moreover, we identified a carrier of the <i>CYP2D6*34x2</i> allele, which has never been described before. The population structure and genetic differentiation of the cohorts were investigated, revealing that the genetic isolates differ only slightly from the outbred and the European populations, but still offer new insight into <i>CYP2D6</i> heterogeneity. The findings described here will be relevant to tailoring the treatments in the northeastern Italian population.