Whole-exome sequencing illuminates unexplained pediatric cholestatic liver disease.

Unexplained liver disease in infants and children remains a significant diagnostic challenge as the spectrum of noninfectious pediatric liver disease expands. Timely, accurate etiologic assignment remains central to optimal care and resource allocation. Advances in next-generation sequencing, particularly whole-exome sequencing (WES), have transformed evaluation by enabling rapid identification of monogenic disorders that previously eluded standard algorithms. In this editorial, we synthesize recent evidence showing that comprehensive genetic testing substantially improves etiologic diagnosis in pediatric hepatology. WES markedly increases diagnostic yield in infants with cholestasis and in children with cryptogenic aminotransferase elevations, directly influencing management and outcomes. We compare yields across international reports from Asia, North America, and Europe, illustrating how WES and broad gene panels uncover heterogeneous genetic contributors to pediatric liver disease. We also address practical issues, including decreasing costs, faster turnaround times, and the importance of integrating conventional investigations with modern genomics. Finally, we emphasize that while WES is a powerful tool to "decode" unexplained disease and guide precision therapies, it must complement, not replace, careful clinical assessment and, in selected cases, liver biopsy. An integrated approach is essential for navigating heterogeneity, avoiding unnecessary procedures, and advancing personalized medicine in pediatric hepatology worldwide to improve outcomes and equity.