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

## TL;DR

This study explores genetic differences in the CYP2D6 gene among northeastern Italian communities and finds unique alleles that could impact drug metabolism.

## Contribution

The study identifies previously unknown and extremely rare CYP2D6 alleles in genetic isolates from northeastern Italy.

## Key findings

- 18 alleles found in the FIC cohort were absent in control cohorts.
- 13 individuals carried the rare CYP2D6*28x2 allele, and one carried the newly identified CYP2D6*34x2 allele.
- Genetic isolates showed slight differentiation from outbred and European populations, offering new insights into CYP2D6 heterogeneity.

## Abstract

The CYP2D6 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 CYP2D6 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 CYP2D6 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 CYP2D6*28x2 allele, whose activity is unknown. Moreover, we identified a carrier of the CYP2D6*34x2 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 CYP2D6 heterogeneity. The findings described here will be relevant to tailoring the treatments in the northeastern Italian population.