Next-generation sequencing in paediatric hepatology

Nearly half of children with chronic liver disorders have a genetic cause, and approximately 20% of paediatric liver transplants are performed in children with monogenic diseases (MDs). In the field of inherited disorders, next-generation sequencing (NGS) has already revolutionized the analysis of human genetic variations, demonstrating to be a great tool to improve the diagnostic yield and offering a highly cost-effective way to diagnose MDs. 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 diagnosis 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 wrong diagnosis. In paediatric hepatology, targeted panels can be very valuable to discriminate neonatal/infantile cholestatic disorders, disclose genetic causes of acute liver failure and 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). The inevitable inclusion of NGS in diagnostic algorithms will soon lead to a new era in medicine, changing completely our approach to the patient as well as our understanding of factors affecting genotype-phenotype match. In this chapter, we discuss the opportunities and the challenges offered nowadays by NGS, which will become a pivotal tool for the diagnosis of liver-based MDs.