Next Generation Sequencing (NGS) has revolutionized the analysis of human genetic variations, offering a highly cost-effective way to diagnose monogenic diseases (MDs). Since nearly half of children with chronic liver disorders have a genetic cause and approximately 20% of pediatric liver transplants are performed in children with MDs, NGS offers the opportunity to significantly improve the diagnostic yield in this field. Among the NGS strategies, the use of targeted gene panels has proven useful to rapidly and reliably confirm a clinical suspicion, whereas the whole exome sequencing (WES) with variants filtering has been adopted to assist the diagnostic work up in unclear clinical scenarios. WES is powerful but challenging, since it detects a great number of variants of unknown significance, that can be misinterpreted and lead to an incorrect diagnosis. In pediatric hepatology targeted NGS can be very valuable to discriminate neonatal/infantile cholestatic disorders, disclose genetic causes of acute liver failure, diagnose the subtype of inborn errors of metabolism presenting with a similar phenotype (such as glycogen storage disorders, mitochondrial cytopathies or non-alcoholic fatty liver disease). The inclusion of NGS in diagnostic processes will lead to a paradigm shift in medicine, changing our approach to the patient as well as our understanding of factors affecting genotype-phenotype match. In this review we discuss the opportunities and the challenges offered nowadays by NGS, and we propose a novel algorithm for cholestasis of infancy adopted in our center, including targeted NGS as a pivotal tool for the diagnosis of liver based MDs. This article is protected by copyright. All rights reserved.
© 2017 by the American Association for the Study of Liver Diseases.