King's College London

Research portal

Study of acute liver failure in children using next generation sequencing technology

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
JournalJournal of Pediatrics
Accepted/In press14 May 2021

King's Authors


To use next generation sequencing (NGS) technology to identify undiagnosed, monogenic diseases in a cohort of children who suffered from acute liver failure (ALF) without an identifiable etiology.

Study design:
We identified 148 under 10 years of age admitted to King’s College Hospital, London, with ALF of indeterminate etiology between 2000 and 2018. A custom NGS panel of 64 candidate genes known to cause ALF and / or metabolic liver disease was constructed. Targeted sequencing was carried out on 41 children in whom DNA samples were available. Trio exome sequencing was performed on 4 children admitted during 2019. A comparison of the clinical characteristics of those identified with biallelic variants against those without biallelic variants was then made.

Homozygous and compound heterozygous variants were identified in 8/41 children (20%) and 4/4 children (100%) in whom targeted and exome sequencing were carried out, respectively. The genes involved were: NBAS (3 children); DLD (2 children); and CPT1A, FAH, LARS1, MPV17, NPC1, POLG, SUCLG1, and TWINK (1 each). The 12 children who were identified with biallelic variants were younger at presentation and more likely to die in comparison to those who did not: median age at presentation of 3 months and 30 months and survival rate 75% and 97%, respectively.

Next generation sequencing was successful in identifying several specific etiologies of ALF. Variants in NBAS and mitochondrial DNA maintenance genes were the most common findings. In the future, a rapid sequencing NGS workflow could help in reaching a timely diagnosis and facilitate clinical decision making in children with ALF.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454