Clinical and genetic spectrum of monogenic liver diseases in children diagnosed using next generation sequencing: a single centre experience from Kerala


  • Prasanth Kunjan Nadar Sobhan Department of Gastroenterology, Government Medical College, Thiruvananthapuram, Kerala, India
  • Bindu Sarojam Department of Paediatrics, Government Medical College, Thiruvananthapuram, Kerala, India
  • Sankar Vaikom Hariharan Department of Paediatrics, Government Medical College, Thiruvananthapuram, Kerala, India



Monogenic, Liver disease, Children


Background: Children presenting with chronic liver disease have a high likelihood of an underlying genetic disorder. There is a delay in establishing a diagnosis of monogenic liver diseases if relied on typical clinical phenotypes and conventional laboratory investigations or imaging studies alone. Early diagnosis improves patient outcome through timely and adequate therapy.

Methods: This study retrospectively analyzed the clinical and genetic spectra of monogenic liver disease in children diagnosed using next-generation sequencing (NGS) in a tertiary care teaching hospital in Kerala. Patients were classified into five groups according to their clinical presentation: neonatal/infantile cholestasis, hepatomegaly/ hepatosplenomegaly, progressive cholestasis (beyond infancy), acute liver failure and decompensated chronic liver disease.

Results: There were 31 children enrolled, 14 (45.16%) males and 17 (54.84%) females. The median age at genetic diagnosis was 25.74 months. NGS identified 20 distinct genes related to varying clinical presentation. Six genes were identified in Group A, nine genes were identified in Group B, three genes were identified in Group C and two genes each in Group D and E. JAG1, ABCB4 and PYL1 (13 % each) were the top three genes related to monogenic liver disease in this study.

Conclusions: Patients with hepatomegaly or hepatosplenomegaly constituted the major clinical presentation of genetic disorders followed by neonatal/infantile cholestasis in our study. Genetic cholestatic disorders and glycogen storage disorders were the most common monogenic liver diseases. NGS has an important role in the diagnosis of monogenic liver disease in children and can facilitate early medical treatment and predict the prognosis.  


Karlsen TH, Lammert F, Thompson RJ. Genetics of liver disease: From pathophysiology to clinical practice. J Hepatol. 2015;62(1):S6-14.

Behjati S, Tarpey PS. What is next generation sequencing? Arch Dis Child Educ Pract Ed. 2013;98(6):236-8.

Wright CF, FitzPatrick DR, Firth HV. Paediatric genomics: diagnosing rare disease in children. Nat Rev Genet. 2018;19(5):253-68.

Strande NT, Berg JS. Defining the clinical value of a genomic diagnosis in the era of next-generation sequencing. Annu Rev Genomics Hum Genet. 2016;17:303-32.

Bacchelli C, Williams HJ. Opportunities and technical challenges in next-generation sequencing for diagnosis of rare pediatric diseases. Expert Rev Mol Diagn. 2016;16(10):1073-82.

Nicastro E, D'Antiga L. Next generation sequencing in pediatric hepatology and liver transplantation. Liver Transpl. 2018;24(2):282-93.

Zabaleta N, Hommel M, Salas D, Gonzalez-Aseguinolaza G. Genetic-Based Approaches to Inherited Metabolic Liver Diseases. Hum Gene Ther. 2019;30(10):1190-203.

Stalke A, Skawran B, Auber B, Illig T, Schlegelberger B, Junge N et al. Diagnosis of monogenic liver diseases in childhood by Next-Generation Sequencing.Clin Genet. 2018;93(3):665-70.

Togawa T, Sugiura T, Ito K, Endo T, Aoyama K, Ohashi K, et al. Molecular genetic dissection and neonatal/infantile intrahepatic cholestasis using targeted next-generation sequencing. J Pediatr. 2016;171:171-7.

Chen HL, Li HY, Wu JF, Wu SH, Chen HL, Yang YH, et al. Panel based next-generation sequencing for the diagnosis of cholestatic genetic liver diseases: clinical utility and challenges. J Pediatr. 2019;205:153-9.

Nicastro E, Di Giorgio A, Marchetti D, Barboni C, Cereda A, Iascone M, et al. Diagnostic yield of an algorithm for neonatal and infantile cholestasis integrating next-generation sequencing. J Pediatr. 2019;211:54-62.e4.

Fang Y, Yu J, Lou J, Peng K, Zhao H, Chen J. Clinical and Genetic Spectra of Inherited Liver Disease in Children in China. Front Pediatr. 2021;9:631620.

Lipiński P, Ciara E, Jurkiewicz D, Pollak A, Wypchło M, Płoski R et al. Targeted Next-Generation Sequencing in Diagnostic Approach to Monogenic Cholestatic Liver Disorders-Single-Center Experience. Front Pediatr. 2020;8:414.

Korula S, Danda S, Paul PG, Mathai S, Simon A. Hepatic Glycogenoses Among Children-Clinical and Biochemical Characterization: Single-Center Study. J Clin Exp Hepatol. 2020;10(3):222-7.






Original Research Articles