Abstract / Summary
Genomic advances have transformed the landscape of genetic kidney diseases, enabling a shift from traditional phenotype-based diagnostics to molecularly precise classification. Large-scale genetic testing has revealed that approximately 10% of chronic kidney diseases are monogenic, greatly improving disease recognition and refining epidemiological prevalence—most notably for autosomal dominant polycystic kidney disease, Alport syndrome, podocytopathies, and autosomal dominant tubulointerstitial kidney disease. Importantly, genetic diagnostics have clarified previously uncertain etiologies in both pediatric and adult populations, enhancing diagnosis, prognosis, and clinical management. Integration of molecular genetics into nephrology has also exposed key limitations of phenotype-driven classification: genotype-phenotype discordance, single-gene variants causing diverse clinical syndromes, and similar phenotypes arising from distinct genetic etiologies. This complexity underscores the risks of relying solely on clinical observation, including inappropriate treatments or missed diagnoses that compromise patient outcomes. For instance, multiple renal cysts can result from various genetic disorders, and misclassification as autosomal dominant polycystic kidney disease may lead to inappropriate tolvaptan use. Molecular diagnostics now enable precision medicine by guiding therapy, optimizing transplantation decisions, and facilitating genetic counseling. Meanwhile, innovative therapies targeting the DNA-RNA-protein-epigenetic axis are advancing toward mechanism-driven treatments that deliver genuine patient benefits. Nonetheless, critical gaps remain in variant interpretation, equitable access to testing, and translation of genetic discoveries to clinical practice. The ongoing evolution of multi-omics integration, robust variant curation, and targeted delivery platforms holds promise for further breakthroughs, transforming outcomes and care standards for patients with genetic kidney diseases and ushering in an era of true precision nephrology.