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

Abstract

Genome-wide approaches, such as whole-exome sequencing (WES), are widely used to decipher the genetic mechanisms underlying inter-individual variability in disease susceptibility. We aimed to dissect inborn monogenic determinants of idiopathic liver injury in otherwise healthy children. We thus performed WES for 20 patients presented with paediatric-onset recurrent elevated transaminases (rELT) or acute liver failure (ALF) of unknown aetiology. A stringent variant screening was undertaken on a manually-curated panel of 380 genes predisposing to inherited human diseases with hepatobiliary involvement in the OMIM database. We identified rare nonsynonymous variants in nine genes in six patients (five rELT and one ALF). We next performed a case-level evaluation to assess the causal concordance between the gene mutated and clinical symptoms of the affected patient. A genetic diagnosis was confirmed in four rELT patients (40%), among whom two carried novel mutations in ACOX2 or PYGL, and two had previously-reported morbid variants in ABCB4 or PHKA2. We also detected rare variants with uncertain clinical significance in CDAN1, JAG1, PCK2, SLC27A5 or VPS33B in rELT or ALF patients. In conclusion, implementation of WES improves diagnostic yield and enables precision management in paediatric cases of liver injury with unknown aetiology, in particular recurrent hypertransaminasemia.

Keywords: acute liver failure; children; idiopathic hepatic injury; recurrent elevated transaminases; whole‐exome sequencing.

FIGURE 1

Familial pedigrees. Pedigrees of the six families affected by idiopathic liver injury with nonsynonymous variants in the liver panel genes are shown. Patients (P1–P6) are shown in black, whereas healthy individuals are shown in white. Familial segregation of the variants with the disease was confirmed by Sanger sequencing. Mutation status is indicated, where possible. WT, wild type, M, mutation.

FIGURE 2

Variant effect predictions. (A) Schemas show conservation of mutated amino acid residues across various species. Asterisk (*), colon (:), and period (.) indicate fully conserved, strongly similar, and weakly similar sites, respectively. Source: Clustal Omega (B) The predicted impact of variants using four algorithms, CADD, MutationTaster, PolyPhen‐2 and SIFT, is shown. Red colour indicates damaging, whereas green colour is benign. N/A, Not applicable.