Chetta Massimiliano, Tarsitano Marina, Bukvic Nenad, Fontana Laura, Miozzo Monica Rosa
A.O.R.N. A. Cardarelli Hospital's Laboratory of Medical Genetics and Genomics, 80131 Naples, Italy.
U.O.C Genetica Medica, Azienda Ospedaliero Universitaria Consorziale Policlinico di Bari, 70124 Bari, Italy.
J Pers Med. 2025 Aug 20;15(8):390. doi: 10.3390/jpm15080390.
The genomic era has transformed not only the tools of medicine but the very logic by which we understand health and disease. Whole Exome Sequencing (WES), Clinical Exome Sequencing (CES), and Whole Genome Sequencing (WGS) have catalyzed a shift from Mendelian simplicity to polygenic complexity, from genetic determinism to probabilistic interpretation. This epistemological evolution calls into question long-standing notions of causality, certainty, and identity in clinical genomics. Yet, as the promise of precision medicine grows, so too do the tensions it generates: fragmented data, interpretative opacity, and the ethical puzzles of Variants of Uncertain Significance (VUSs) and unsolicited secondary findings. Despite technological refinement, the diagnostic yield of Next-Generation Sequencing (NGS) remains inconsistent, hindered by the inherent intricacy of gene-environment interactions and constrained by rigid classificatory systems like OMIM and HPO. VUSs (neither definitively benign nor pathogenic) occupy a liminal space that resists closure, burdening both patients and clinicians with uncertainty. Meanwhile, secondary findings, though potentially life-altering, challenge the boundaries of consent, privacy, and responsibility. In both adult and pediatric contexts, genomic knowledge reshapes notions of autonomy, risk, and even personhood. Genomic medicine has to develop into a flexible, morally sensitive paradigm that neither celebrates certainty nor ignores ambiguity. Open infrastructures, dynamic variant reclassification, and a renewed focus on interdisciplinary and humanistic approaches are essential. Only by embracing the uncertainty intrinsic to our biology can precision medicine fulfill its promise, not as a deterministic science, but as a nuanced dialogue between genes, environments, and lived experience.
基因组时代不仅改变了医学工具，还改变了我们理解健康与疾病的逻辑。全外显子组测序（WES）、临床外显子组测序（CES）和全基因组测序（WGS）促使医学从孟德尔式的简单模式转向多基因复杂性模式，从基因决定论转向概率性解释。这种认识论的演变对临床基因组学中因果关系、确定性和身份的长期概念提出了质疑。然而，随着精准医学前景的不断拓展，它所引发的矛盾也日益凸显：数据碎片化、解释不透明，以及意义未明变异（VUS）和意外次要发现带来的伦理难题。尽管技术不断完善，但由于基因与环境相互作用的内在复杂性以及诸如《在线人类孟德尔遗传》（OMIM）和人类表型本体（HPO）等严格分类系统的限制，新一代测序（NGS）的诊断效率仍不稳定。VUS（既非明确良性也非致病性）处于一种难以界定的模糊状态，给患者和临床医生都带来了不确定性。与此同时，次要发现虽然可能改变人生，但却对同意、隐私和责任的界限构成了挑战。在成人和儿科领域，基因组知识都重塑了自主性、风险乃至人格的概念。基因组医学必须发展成为一种灵活且具有道德敏感性的范式，既不盲目追求确定性，也不忽视模糊性。开放的基础设施、动态的变异重新分类，以及对跨学科和人文方法的重新关注至关重要。只有接受我们生物学中固有的不确定性，精准医学才能实现其承诺，它并非一门确定性科学，而是基因、环境和生活经历之间细致入微的对话。
