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

• Published in: Journal of cellular and molecular medicine 2024-06, Vol.28 (11), p.e18485-n/a
• Main Authors: Lülecioğlu, Aysima Atılgan, Yazıcı, Yılmaz Yücehan, Baran, Alperen, Warasnhe, Khaled, Beyaz, Şengül, Aytekin, Caner, Özçay, Figen, Aydemir, Yusuf, Barış, Zeren, Belkaya, Serkan
• Format: Article
• Language: English
• Subjects: acute liver failure; Adolescent; Algorithms; Child; Child, Preschool; children; Diagnosis; Enzymes; Etiology; Exome Sequencing; Female; Genes; Genetic Predisposition to Disease; Genetic screening; Genomes; Genomics; Humans; idiopathic hepatic injury; Infant; Liver; Liver diseases; Liver Diseases - diagnosis; Liver Diseases - genetics; Liver Failure, Acute - diagnosis; Liver Failure, Acute - genetics; Male; Mutation; Original; Patients; Pediatrics; recurrent elevated transaminases; Transaminases - genetics; Whole genome sequencing; whole‐exome sequencing
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.18485

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.