Next generation sequencing in pediatric hepatology and liver transplantation

Abstract

Next generation sequencing (NGS) has revolutionized the analysis of human genetic variations, offering a highly cost-effective way to diagnose monogenic diseases (MDs). Because nearly half of the children with chronic liver disorders have a genetic cause and approximately 20% of pediatric liver transplantations 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 workup in unclear clinical scenarios. WES is powerful but challenging because 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, and diagnose the subtype of inborn errors of metabolism presenting with a similar phenotype (such as glycogen storage disorders, mitochondrial cytopathies, or nonalcoholic 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. Liver Transplantation 24 282-293 2018 AASLD.

Pediatric liver transplantation for neonatal‐onset Niemann‐Pick disease type C: Japanese multicenter experience

“…Moreover, Rohanizadegan et al reported the usefulness of rapid whole‐exome sequencing to diagnose a case of neonatal NPC . These next‐generation sequencing techniques have been also developing in recent years, and they will help us to obtain accurate and rapid diagnosis in complex disease like NALF, lysosome disease, or metabolic disorders in the near future …”

“…The glucosylceramide synthase inhibitor miglustat, which was developed for the treatment of lysosome disease, has been shown to delay or improve the neurological symptoms, extend survival, maintain the cellular structure of the cerebellum, and suppress the accumulation of gangliosides in the brain in NPC patients or animal models . Multiple clinical trials, particularly in adults, have demonstrated efficacy of miglustat inhibiting the progression of, or improving neurological symptoms . Furthermore, miglustat has been shown to pass through the blood‐brain barrier.…”

Exome Sequencing in Clinical Hepatology

“…Other independent studies have consistently reported WES diagnostic rates of 20% or higher . Furthermore, we and others have successfully combined WES with deep phenotyping (i.e., detailed characterization of each patient's phenotypic features) to identify the underlying genetic defects in infants and children with idiopathic liver diseases, including children with liver failure of indeterminate etiology . Astute clinical annotation (i.e., comprehensive phenotype description of the patient) is central to harnessing the maximal potential of genomic data .…”

“…Children with chronic liver disease represent an enriched population with single gene disorders; therefore, many of the known genetic causes of liver diseases present during childhood . Thus, genetic liver disorders are traditionally associated with pediatric hepatology practice, in which NGS for timely diagnosis has been progressively embraced over the past years . There is extensive experience of application of WES in nonhepatic pediatric disorders.…”

Pediatric Cholestasis: Epidemiology, Genetics, Diagnosis, and Current Management

“…In distinction, cholangiopathies such as biliary atresia, ABCB4 and DCDC2 deficiencies, as well as ALGS often present with elevated GGT levels. With the increasing worldwide use of modern next generation sequencing, the roles for liver biopsy in the evaluation are becoming less essential …”