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- Alle Frequency Distribution Of Clinicaly Relevant Pharmacogenetic Variants In Genes With CPIC Guidelines Across European Populations: A Scoping ReviewPublication . Simões, Raquel; Cardoso, Maria Luis; Martiniano, Hugo F. M. C.; Vicente, Astrid MouraIntroduction: Pharmacogenetics (PGx) is the study of how genetic variants affect drug response. PGx variants can affect either pharmacokinetics – the processes of drug absorption, distribution, metabolism, and elimination – or pharmacodynamics – the biochemical and physiological effects of drugs and their mechanisms of action. Pharmacokinetics gene variants often define haplotypes, which are described using the star (*) allele nomenclature for genes such as those in the Cytochrome P450 (CYP450) family. This results in phenotypes of normal, rapid, ultrarapid, or poor metabolisers, leading to various drug responses (1). In recognition of the importance of understanding the clinical impact of PGx variants, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed guidelines that translate PGx test results into clinical recommendations for drug selection and dosing (2). Reports in the literature on ancestry‑related differences in drug response highlight the need for a broader investigation of PGx variants, namely in CYP450 genes, across diverse groups(3).
- Allele frequency distribution of clinically relevant pharmacogenetic variants across European populations: A Scoping ReviewPublication . Simões, Raquel D.; Cardoso, Maria L.; Martiniano, Hugo F. M. C.; Vicente, Astrid M.Review of the literature on the distribution of pharmacogenetic variants in European populations.. Pharmacogenetics (PGx) is the study of how genetic variants affect drug metabolism, transport and target interactions, impacting efficacy and risk of adverse reactions. PGx variants can affect either pharmacokinetics – the processes of drug absorption, distribution, metabolism and elimination of drugs -or pharmacodynamics - the biochemical and physiological effects of drugs and their mechanisms of action. Pharmacokinetics gene variants often define haplotypes, which are described using the star (*) allele nomenclature for genes such as those in the Cytochrome P450 (CYP450) family. This results in phenotypes of normal, rapid, ultrarapid or poor metabolisers, leading to various drug responses 1. In recognition of the importance of understanding the clinical impact of PGx variants, the Clinical Pharmacogenetics Implementation Consortium (CPIC) has developed guidelines that translate PGx test results into clinical recommendations for drug dosing 2. Reports in the literature of ancestrality differences in drug response highlight the need for a broader investigation of PGx variants, namely in CYP450 genes, across diverse groups.
- From Uncertainty To Diagnosis: Functional Reclassification Of LDLR Variants In Familial HypercholesterolemiaPublication . Chora, Joana Rita; Islam, Mohammad Majharul; Alves, Ana Catarina; Pfisterer, Simon; Bourbon, MafaldaObjectives: Familial hypercholesterolaemia (FH) is a common disorder of lipid metabolism marked by an increased risk of premature atherosclerotic cardiovascular disease. While genetic testing confirms diagnosis, many LDLR variants are classified as variants of uncertain significance (VUS) due to lack of evidence, limiting clinical actionability. Functional assays can support reclassification, but conventional approaches are time-consuming. This study aims to use a high-throughput functional pipeline to evaluate LDLR VUS and improve diagnostic precision in FH. Methods: We analysed 133 LDLR VUS lacking functional evidence using an automated analysis platform based on multiplexed high-content imaging to quantify LDL uptake. Variants were classified based on uptake relative to wild-type: <70% for PS3_Supporting (pathogenic) and >90% for BS3_Supporting (benign), according to LDLR-specific ACMG/AMP guidelines. A subset of 46 “hot VUS” required only one supporting criterion to reach a likely benign or likely pathogenic classification. Results: Of the 133 variants, 53 showed <70% uptake and were assigned PS3_Supporting, while 41 showed >90% uptake and received BS3_Supporting. The remaining 39 variants exhibited intermediate activity (70–90%). Among the 46 hot VUS, 12 were reclassified as likely benign and 11 as likely pathogenic. An additional 43 variants are now one supporting criterion away from potential reclassification. Conclusions: High-throughput functional testing provides robust and rapid evidence for LDLR variant interpretation. By adding evidence about LDLR activity these assays contribute to resolve diagnostic uncertainty and enables earlier and more accurate diagnosis, optimizes cascade screening, and enables better risk stratification to inform treatment options. These findings support a shift toward personalised genomic medicine in lipid disorders, with direct implications for patient care and cardiovascular risk reduction.
- MODY em Contexto Clínico: Impacto do Diagnóstico Genético na Tomada de Decisão TerapêuticaPublication . Vaz, Margarida; Gaspar, Gisela; Dario, Paulo; Bourbon, MafaldaA diabetes monogénica representa 1–5% dos casos de diabetes, destacando-se o subtipo MODY, causado por variantes em 14 genes, dos quais GCK, HNF1A, HNF1B e HNF4A são os mais comuns. Este estudo teve como objetivo identificar casos de diabetes tipo MODY, apoiar a decisão clínica e detetar familiares em risco. Foram analisados 79 casos índex de várias regiões de Portugal e 45 familiares, através de sequenciação por PCR dos quatro genes principais e pesquisa de grandes rearranjos por MLPA. Variantes patogénicas ou provavelmente patogénicas foram encontradas em 48% dos casos índex, e 29 familiares receberam também o diagnóstico de MODY, sendo o gene GCK o mais frequentemente afetado. Até agora, 67 indivíduos foram identificados com variantes causadoras de MODY. A ausência de variantes em metade dos casos índex pode dever-se à não análise de todos os genes associados ou a etiologia poligénica. O diagnóstico molecular revelou-se essencial para orientar a terapêutica personalizada nestes doentes.