Effects of direct tracheostomy on ventilator weaning in patients intubated for Guillain-Barré syndrome.

The expansion of newborn screening and whole-genome sequencing has fundamentally reshaped clinical genetics. Increasingly, novel and rare variants in genes associated with known diseases are identified in individuals who are otherwise healthy and asymptomatic before symptom onset. While this progress has enabled earlier diagnosis and access to disease-modifying therapies, it has also amplified an emerging challenge: the clinical interpretation of variants of uncertain significance (VUS) in situations where decisions cannot be deferred. Importantly, the presence of a rare variant does not necessarily equate to disease, and a substantial proportion of individuals identified through population-level screening may remain asymptomatic throughout life due to incomplete penetrance, variable expressivity, or residual gene function. As a result, clinicians are increasingly confronted with situations in which therapeutic decisions must be made despite considerable uncertainty, raising the risk of implementing costly and potentially harmful interventions in individuals who might otherwise have remained healthy (Fig. ). A complementary role for zebrafish in the era of multi-million-dollar therapies. Graphical summary. Original artwork created by the author using Adobe Photoshop. In two recent studies published in and , we addressed this challenge in the context of spinal muscular atrophy (SMA). We demonstrated that the zebrafish can serve as a rapid, robust and complementary “VUS-resolution” tool for geneticists and clinicians requiring urgent functional evidence to support time-critical therapeutic decisions. While zebrafish have long been used to investigate gene function through transient mRNA and transgenic complementation assays ( > 80% of human disease-associated genes have a zebrafish orthologue), and more recently for the study of patient-derived variants, the presented case studies showcase how the zebrafish and established experimental paradigm can have direct real-world impacts on urgent clinical decision-making and human lives.