Beyond the SNP: Structural Variants, Copy Number Variation, and Reference Frameworks at Complex Pharmacogenomic Loci

Standard pharmacogenomic genotyping arrays and short-read sequencing were built around common SNPs. They work well at straightforward loci, but at genes like CYP2D6, CYP2A6, CYP2B6, and HLA, where copy number variation, gene duplications, deletions, and hybrid alleles are clinically consequential, they routinely fail. The result is misclassified phenotypes, unresolved diplotypes, and patients assigned to the wrong metaboliser category based on incomplete variant detection.This Research Topic focuses on the genetic complexity that standard PGx workflows miss: structural variants, copy number variants, rare alleles, and the nomenclature and reference frameworks needed to characterise and report them consistently. We invite original research, methods papers, reviews, and perspectives addressing:• Copy number variation at pharmacogenes, including detection, quantification, and phenotypic impact at CYP2D6, CYP2A6, UGT2B17, and related loci• Structural variants, including gene deletions, duplications, and hybrid alleles, and their contribution to variable drug metabolism and response• Rare and novel variant discovery at pharmacogenes and strategies for functional characterisation• Star allele nomenclature: current limitations, evolving definitions, and proposals for standardisation• Haplotype phasing and diplotype assignment at complex loci, including computational and experimental approaches• Reference framework development for pharmacogenes with complex architecture, including pseudogene interference• Benchmarking of genotyping and sequencing platforms for structural variant detection at pharmacogenomic loci• Population-specific variation in structural pharmacogenomic variants and implications for allele frequency databasesSubmissions should connect variant characterisation directly to drug pharmacokinetics, metaboliser phenotype, or clinical drug response. The section does not consider purely methodological studies without a clear pharmacogenomic application. Reports of novel structural variants must include comprehensive characterisation of both the structural alteration and any associated SNVs. Results must be reported separately for each individual sample. Structural variants detected or characterised in pooled samples will not be accepted. Please note: Where patient or genetic data are analysed, submissions should provide a comprehensive description of the study population, relevant clinical information, methods and the rationale for selecting the data studied. Computational and methodological studies should demonstrate a clear pharmacogenomic application and connect variant characterisation to drug pharmacokinetics, metaboliser phenotype or clinical drug response. Studies based solely on public databases or published evidence, without novel pharmacogenomic insight or sufficient validation, will not be considered. Studies related to natural compounds, herbal extracts or traditional medicine products are outside the scope of the Specialty Section Pharmacogenetics & Pharmacogenomics and should be submitted to the Specialty Section Ethnopharmacology. Articles should fit the Journal’s mission and scope. Further information on the Journal’s scope can be accessed following the link https://www.frontiersin.org/journals/pharmacology/aboutDr Korostynski was one of the founders of Intelliseq SA, and Dr George Patrinos holds a patent related to a bioinformatics solution for pharmacogenomic variant annotation. Topic editors: Michal Korostynski, George P Patrinos, Katy Sanchez-Pozos, Hugo Alberto Barrera-Saldaña Source: https://www.frontiersin.org/research-topics/84624/beyond-the-snp-structural-variants-copy-number-variation-and-reference-frameworks-at-complex-pharmacogenomic-loci