Yodoshi T. Whole-exome sequencing illuminates unexplained pediatric cholestatic liver disease. World J Hepatol 2026; 18(1): 115037 [DOI: 10.4254/wjh.v18.i1.115037]
Corresponding Author of This Article
Toshifumi Yodoshi, MD, PhD, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, United States. toshifumi.yodoshi@cchmc.org
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Editorial
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Toshifumi Yodoshi, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, United States
Author contributions: Yodoshi T contributed to the concept, design, manuscript writing, and editing, as well as the review of the literature.
Conflict-of-interest statement: Toshifumi Yodoshi has nothing to disclose.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Toshifumi Yodoshi, MD, PhD, Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229, United States. toshifumi.yodoshi@cchmc.org
Received: October 9, 2025 Revised: October 21, 2025 Accepted: November 24, 2025 Published online: January 27, 2026 Processing time: 113 Days and 17.8 Hours
Abstract
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.
Core Tip: The advent of whole-exome sequencing (WES) has transformed diagnosis of unexplained pediatric liver disease. In infants with cholestasis and children with cryptogenic hepatitis, comprehensive genomic testing markedly increases diagnostic yield, often exceeding 50% in recent cohorts, enabling earlier identification and management. Incorporating WES early can spare patients invasive procedures, including diagnostic liver biopsy, and facilitate timely, targeted interventions. Yet, given phenotypic heterogeneity, WES must be integrated with careful clinical assessment, family history, and selective traditional diagnostics. Falling costs and faster turnaround make WES a practical cornerstone of precision hepatology, while validation and multi-omics remain essential to realize its full potential.
