Long-read sequencing of CYP2D6 may improve psychotropic prescribing and treatment outcomes: A systematic review and meta-analysis.

Background: The enzyme expression (i.e. phenotype) of the Cytochrome P450 2D6 (CYP2D6) gene is highly relevant to the metabolism of psychotropic medications, and therefore to precision medicine (i.e. personalised prescribing).

Aims: This review aims to assess the improvement in CYP2D6 phenotyping sensitivity (IPS) and accuracy (IPA) offered by long-read sequencing (LRS), a new genetic testing technology.

Methods: Human DNA samples that underwent LRS genotyping of CYP2D6 in published, peer-reviewed clinical research were eligible for inclusion. A systematic literature search was conducted until 30 September 2023. CYP2D6 genotypes were translated into phenotypes using the international consensus method. IPS was the percentage of non-normal LRS CYP2D6 phenotypes undetectable with FDA-approved testing (AmpliChip). IPA was the percentage of LRS CYP2D6 phenotypes mischaracterised by non-LRS genetic tests (for samples with LRS and non-LRS data).

Results: Six studies and 1411 samples were included. In a meta-analysis of four studies, IPS was 10% overall (95% CI = (2, 18);  = 1385), 20% amongst Oceanians (95% CI = (17, 23);  = 582) and 2% amongst Europeans (95% CI = (1, 4);  = 803). IPA was 4% in a large European cohort (95% CI = (2, 7);  = 567). When LRS was used selectively (e.g. for novel or complex CYP2D6 genotypes), very high figures were observed for IPS (e.g. 88%; 95% CI = (72, 100);  = 17; country = Japan) and IPA (e.g. 76%; 95% CI = (55, 98);  = 17; country = Japan).

Conclusions: LRS improves CYP2D6 phenotyping compared to established genetic tests, particularly amongst Oceanian and Japanese individuals, and those with novel or complex genotypes. LRS may therefore assist in optimising personalised prescribing of psychotropic medications. Further research is needed to determine associated clinical benefits, such as increased medication safety and efficacy.