Genomics in the era of personalised precision medicine

Б  том ХXXI, 2025, № 2 ДРУЖЕСТВО НА КАРДИОЛОЗИТЕ В БЪЛГАРИЯ РЕДАКЦИОНЕН КОМЕНТАР EDITORIAL doi: 10.3897/bgcardio.31.e173631 Introduction to personalised genomics Genomics is among the fastest-evolving scientifi c disciplines. At the beginning of this century the fi rst draft of the human genome was published – a milestone that ranks among the greatest scientifi c achievements of our time. Rapid technological advances since then have made sequencing much faster, more precise and far more aff ordable, culminating in the complete, gapless, telomere-to-telomere assembly of the human genome (reported in 2021) that revealed previously inaccessible DNA regions. Over the past two decades precision genomics has dramatically expanded our understanding of genome architecture and gene function, which in turn has powered the rise of personalised medicine: an approach that tailors diagnostic and therapeutic strategies to the unique characteristics of each patient, including their genetic makeup and other biomarkers. Moving beyond the traditional “one-size-fi ts-all” model, personalised medicine stratifi es patients into subgroups using genomic data, molecular profi ling and computational tools to diagnose conditions earlier, predict disease risk more accurately, and select therapies that are more likely to work for a given individual. When combined with advances in artifi cial intelligence and high-throughput molecular assays, genomics promises more precise, eff ective and patient-centred healthcare – and the fi eld of cardiology stands to benefi t particularly. Genetic information now enables defi nitive diagnosis of inherited heart disease, refi nes population-level risk stratifi cation, and helps select safer, more eff ective therapies. As whole-genome approaches, polygenic modelling and high-fi delity longread sequencing move from “promising” to practical tools, clinicians can increasingly personalise prevention, diagnosis and treatment across the spectrum of cardiovascular disease. Monogenic diagnosis: clarity where it matters most A clear clinical implication of precision genomics in cardiology is the diagnosis of monogenic disorders. Pathogenic variants in single genes underlie many inherited channelopathies and arrhythmias (for example long-QT and short-QT syndromes, Brugada syndrome), cardiomyopathies (hypertrophic, dilated, arrhythmogenic and metabolic forms), aortopathies, familial dyslipidaemias, and certain thrombophilias and clotting disorders. Establishing a genetic diagnosis provides immediate clinical value: it confi rms aetiology, enables cascade (family) testing, informs prognosis (some genotypes predict rapid progression or high arrhythmic risk) and guides management decisions such as device implantation, targeted therapies or personalised prophylaxis. In some cases, pathogenic variants across two or more genes jointly cause cardiac disease, refl ecting digenic or oligogenic inheritance. Such complex mechanisms of pathogenesis underline the need to test multiple genes to identify the exact causative variants. As the catalogue of disease-associated genes has continued to expand over recent decades, clinical testing progressed from targeted gene panels to whole-exome sequencing (WES), which captures all protein-coding genes, and now to whole-genome sequencing (WGS). WGS interrogates the entire genome and increases diagnostic yield beyond panels and WES by detecting deep-intronic or other non-coding (regulatory) variants as well as structural variants (deletions, duplications, inversions and complex rearrangements) that were previously missed, improving diagnostic rates in selected patients with unexplained cardiovascular disease. Rapid WGS has demonstrated clinical utility in acute settings (for example critically ill neonates and selected cardiac presentations), shortening the diagnostic odyssey and informing urgent management. Genome-wide analysis often generates a large number of variants of uncertain signifi cance (VUS), which often require family testing to determine inheritance patterns and aid in reclassifying them as likely pathogenic or likely benign. Polygenic risk: stratifying common disease earlier Although most rare cardiac diseases are monogenic (or occasionally digenic), many common cardiovascular complications such as stroke or myocardial infarction are polygenic, arising from the combined infl uence of numerous genetic variants together with lifestyle and environmental factors. Each individual carries a unique balance of protective genetic variants and risk alleles, each contributing to overall liability. Biostatistical approaches such as polygenic risk scores (PRS) estimate this inherited risk and support population-level GENOMICS IN THE ERA OF PERSONALISED PRECISION MEDICINE GENOMICS IN THE ERA OF PERSONALISED PRECISION MEDICINE ГЕНОМИКА В ЕРАТА НА ПЕРСОНАЛИЗИРАНАТА ПРЕЦИЗНА МЕДИЦИНА ГЕНОМИКА В ЕРАТА НА ПЕРСОНАЛИЗИРАНАТА ПРЕЦИЗНА МЕДИЦИНА L. Balabanski. Genomics in the era of personalised precision medicine 6 stratifi cation. PRS aggregate the small eff ects of many common variants into a single numeric measure of genetic susceptibility compared to the common population. For conditions like coronary artery disease and atrial fi brillation, polygenic scores can identify individuals with substantially elevated risk. In some studies, those in the highest PRS percentiles face several-fold greater risk than the average person. Such individuals may benefi t from earlier lifestyle optimisation, personalised prophylaxis, imaging surveillance, or pharmacoprevention. A limitation is that most early PRS algorithms were derived from European cohorts, and their predictive accuracy declines when applied to other non-European ancestries. Recent multi-ancestry models have improved transferability, but performance still varies across populations, making local validation essential before clinical use. Pharmacogenomics: safer, more eff ective prescribing Genetics is already changing how we prescribe cardiovascular drugs. Well-validated gene–drug pairs (for example CYP2C19 genotype and clopidogrel effi cacy, or SLCO1B1 and statin-associated myopathy risk) have evidence-based implementation guidelines from pharmacogenomics consortia. Genotype-guided antiplatelet selection after percutaneous coronary intervention (PCI), and genotype-informed statin choice or dosing, are practical examples of precision prescribing that reduce adverse events and improve outcomes for individual patients. Incorporating pharmacogenetic testing into routine clinical workfl ows – either ahead of treatment or at the point of prescribing – is a sensible and pragmatic next step for cardiology. Long-read sequencing: providing new insights about the genome Genome-wide clinical testing approaches (WES/ WGS) in the last 20 years have relied mostly on shortread next-generation sequencing technologies. While highly accurate and cost-eff ective, short reads typically span only ~100-150 base pairs at a time, which makes it diffi cult to resolve repetitive regions, detect large structural variants, or identify other complex chromosomal rearrangements. These limitations leave gaps in our ability to fully characterise the genome, particularly in regions that are clinically relevant but diffi cult to sequence. Long-read sequencing technologies – exemplifi ed by Oxford Nanopore and Pacifi c Biosciences (PacBio) HiFi platforms – have recently started to overcome many of these challenges. Long reads can span repeats and structural variants, enable phasing of alleles, and directly reveal epigenetic methylation patterns as well, substantially increasing diagnostic yield. PacBio’s HiFi reads combine long read length with very high per-base accuracy, while Oxford Nanopore provides native DNA sequencing in real-time, and portable sequencing capabilities. Together, these approaches enhance detection of pathogenic structural variants and allow characterisation of genomic regions that were previously intractable. As costs decline and analysis pipelines mature, hybrid strategies that combine shortand long-read data are poised to become a standard component of clinical genomics, off ering more comprehensive and accurate diagnostics for cardiovascular and other genetic diseases. These techniques will be particularly valuable in patients who remain undiagnosed after conventional testing. Barriers, responsibilities and the path to routine use Despite its great promise, integrating genomics into routine cardiology requires careful attention to several challenges. Variant interpretation sometimes yields results of uncertain signifi cance that require additional testing or reanalysis. Polygenic risk scores for common diseases must be interpreted cautiously and are strongly infl uenced by ancestry. Many aspects of clinical genomics still need standardisation, including bioinformatic pipelines, data storage, informed consent, and the reporting of incidental fi ndings. Clinicians also require training to interpret and communicate genetic results eff ectively to patients. Finally, cost-eff ectiveness and reimbursement policies will infl uence adoption and accessibility. Addressing these issues demands multidisciplinary collaboration among cardiologists, clinical geneticists, bioinformaticians, ethicists, and healthcare policymakers. Conclusion: a pragmatic optimism Personalised genomics has laid the foundation for precision medicine. Over the past decade, genetics and clinical care have converged in remarkable ways: what once belonged primarily to research laboratories is now increasingly reshaping patient management in everyday cardiology. Genomics is neither a panacea nor a replacement for clinical judgement. Rather, it off ers a powerful perspective for understanding the molecular aetiology of cardiovascular disease, enhancing diagnostic accuracy, personalising risk assessment, and refi ning therapy. As genomic technologies become faster, cheaper, and more accurate, and as polygenic and pharmacogenomic tools are rigorously validated, genomic analyses will progressively move from specialty clinics into mainstream cardiology. The future of cardiovascular care is increasingly predictive, preventive, and personalised – our challenge is to translate this genomic promise into equitable benefi t for every patient. Lubomir Balabanski, PhD Еditor in charge of issue 2/2025 of Bulgarian Cardiology Journal