Abstract
Objective: To evaluate the clinical utility of panel-based NGS in the diagnostic approach of monogenic cholestatic liver diseases.Study design: Patients with diagnosis of chronic cholestatic liver disease of an unknown etiology underwent NGS of targeted genes panel. Group 1 included five patients (prospectively recruited) hospitalized from January to December 2017 while group 2 included seventeen patients (retrospectively recruited) hospitalized from 2010 to 2017 presenting with low-GGT PFIC phenotype (group 2a, 11 patients) or indeterminant cholestatic liver cirrhosis (group 2b, 6 patients).Results: Among 22 patients enrolled into the study, 21 various pathogenic variants (including 11 novel) in 5 different genes (including ABCB11, ABCB4, TJP2, DGUOK, CYP27A1) were identified. The molecular confirmation was obtained in 15 out of 22 patients (68%). In group 1, two out of five patients presented with low-GGT cholestasis, and were diagnosed with BSEP deficiency. Out of three patients presenting with high-GGT cholestasis, one patient was diagnosed with PFIC-3, and the remaining two were not molecularly diagnosed. In group 2a, seven out of eleven patients, were diagnosed with BSEP deficiency and two with TJP-2 deficiency. In group 2b, three out of six patients were molecularly diagnosed; one with PFIC-3, one with CYP27A1 deficiency, and one with DGUOK deficiency.Conclusions: Panel-based NGS appears to be a very useful tool in diagnosis of monogenic cholestatic liver disorders in cases when extrahepatic causes have been primarily excluded. NGS presented the highest diagnosis rate to identify the molecular background of cholestatic liver diseases presenting with a low-GGT PFIC phenotype.
Highlights
Next-generation sequencing (NGS) technology including targeted gene panels, whole-exome sequencing (WES), or even whole-genome sequencing (WGS), have opened promising possibilities to identify the molecular background of rare diseases, in the field of pediatric hepatology and liver transplantation [1,2,3]
The reference ranges for gamma-glutamyl transferase (GGT) in the 1st year of life were in accordance with Cabrera-Abreu and Green [9]
Among 22 patients enrolled into the study, 21 various pathogenic variants in five different genes were identified
Summary
Next-generation sequencing (NGS) technology including targeted gene panels, whole-exome sequencing (WES), or even whole-genome sequencing (WGS), have opened promising possibilities to identify the molecular background of rare diseases, in the field of pediatric hepatology and liver transplantation [1,2,3]. It is estimated that nearly 20% of liver transplantation (LTx) procedures in children are performed due to monogenic, mostly cholestatic, liver disorders [4, 5]. The latest guidelines from the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) have recommended the use of modern, broad-based NGS sequencing in the proper clinical context [7]. The aim of this study was to evaluate the clinical utility of panel-based NGS in the diagnostic approach of monogenic cholestatic liver diseases
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