The potential of whole genome sequencing in pharmacogenetics: a retrospective health record study in rare disease patients

The clinical relevance of pharmacogenetics (PGx) is becoming increasingly evident as knowledge in this field expands. As of May 2025, 209 clinical guideline annotations are already listed on the internationally recognized ClinPGx website. Nevertheless, except for a few indications, the implementation of PGx in clinical practice currently remains limited in most countries. At the same time, whole genome sequencing (WGS) is increasingly applied in clinical diagnostics, particularly for rare and oncological diseases. These data could also be used for simultaneous PGx analysis. In a retrospective study, we analysed short-read WGS data from 1,000 individuals, including index patients with suspected rare disorders and their relatives. For a subset of 359 individuals, medical reports were reviewed to document drug prescriptions. Guidelines published by PGx consortia on ClinPGx were used for phenotype assignment and interpretation. Clinically relevant PGx variants were detected in 97% (n = 970) of the cohort. Among patients with drug prescriptions (n = 359), 30% (n = 111) had been prescribed at least one medication for which their PGx profile would recommend therapy adjustment. Additionally, CNVs and rare variants were detected, which in 28% (n = 8) resulted in modified therapeutic recommendations. While the most (cost)-efficient strategy for broad PGx implementation remains subject of future research, our findings demonstrate that existing WGS data, such as those generated in the context of rare disease patients, could provide substantial benefits for PGx diagnostics with minimal additional effort.