The utility of hierarchical genetic testing in paediatric liver disease

Abstract

Background & Aims Genetic factors underlie a substantial proportion of paediatric liver diseases. Hereditary liver diseases have considerable genetic heterogeneity and variable clinical manifestations, which bring great challenges to clinical and molecular diagnoses. In this study, we investigated a group of paediatric patients with varying degrees of liver dysfunction using a hierarchical genetic testing strategy. Methods We first applied a panel encompassing 166 known causal genes of liver disease. We then used exome sequencing (ES) in those patients whose cases remained undiagnosed to identify the genetic aetiology of their symptoms. Results In total, we enrolled 131 unrelated paediatric patients with liver disease of Chinese Han ethnicity. We first applied targeted gene sequencing of 166 genes to all patients and yielded a diagnostic rate of 35.9% (47 of 131). Eighty‐four patients who remained undiagnosed after target gene sequencing were subjected to ES. As a result, eight (8/84, 9.5%) of them obtained molecular diagnoses, including four patients suspected of abnormal bilirubin metabolism and four idiopathic cases. Non‐typical genetic findings, including digenic inheritance and dual molecular diagnosis, were also identified. Through a comprehensive assessment of novel candidate variants of uncertain disease association, 11 patients of the remaining undiagnosed patients were able to obtain likely molecular diagnoses. Conclusions Our study presents evidence for the diagnostic utility of sequential genetic testing in a cohort of patients with paediatric liver disease. Our findings expand the understanding of the phenotypic and mutational spectrum underlying this heterogeneous group of diseases.

Whole‐exome sequencing for genetic diagnosis of idiopathic liver injury in children

“…Of note, six of these 36 genes, MRPS5 , SUCLG1 , AP4M1 , CACNA1E , NSD1 and STAT3 were not present among our panel of 380 genes curated from the OMIM based on an associated hepatobiliary phenotype, yet we did not find any candidate disease‐causing variation in those six genes in ALF patients in this report. Consistently, previous studies on the genetics of indeterminate paediatric ALF did not reveal an underlying monogenic cause in majority of the cases, whereas some were diagnosed with hitherto unrecognized inherited metabolic diseases 18–23 . It is also possible that nongenetic factors may account for ALF in some children.…”

“…In particular, WES has been instrumental in the genetic diagnosis of idiopathic liver diseases. 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 Herein, we investigated a total of 20 paediatric cases with rELT or ALF of unknown aetiology using WES. While there was no candidate morbid variation found in ALF patients, we established a genetic diagnosis in four out of 10 rELT patients (40%) using a liver gene panel.…”

“…Consistently, previous studies on the genetics of indeterminate paediatric ALF did not reveal an underlying monogenic cause in majority of the cases, whereas some were diagnosed with hitherto unrecognized inherited metabolic diseases. 18 , 19 , 20 , 21 , 22 , 23 It is also possible that nongenetic factors may account for ALF in some children. Nonetheless, WES and/or whole‐genome sequencing (WGS) should be included in the diagnostic workup of idiopathic liver injury, including ALF and persistent/recurrent ELT, in children for earlier identification of the underlying disease aetiology, proper medical management and referral for liver transplantation when necessary.…”

“… 9 , 10 , 11 Recent studies have highlighted the utility of whole‐exome sequencing (WES) in the identification of genetic causes underlying liver diseases of unknown aetiology in both paediatric and adult patients. 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 However, genetic studies focusing on children and, in particular, patients with different ethnic backgrounds are still limited. The identification of inborn monogenic causes of indeterminate liver diseases holds significant clinical importance, as it may facilitate familial testing for earlier diagnosis, prognosis prediction and more precise management in high‐risk family members.…”

“…Next‐generation sequencing technologies, such as whole‐exome and ‐genome sequencing, are now widely used in clinics as powerful genome‐wide scanning tools in the search for genetic variants responsible for phenotypes of interest 9–11 . Recent studies have highlighted the utility of whole‐exome sequencing (WES) in the identification of genetic causes underlying liver diseases of unknown aetiology in both paediatric and adult patients 12–23 . However, genetic studies focusing on children and, in particular, patients with different ethnic backgrounds are still limited.…”