FROM THE PEDIATRIC LITERATURE

Determining Genetic Variants in Pediatric Acute Liver Failure

Determining Genetic Variants in Pediatric Acute Liver Failure

A large number of pediatric acute liver failure (ALF) cases occur with no diagnosed etiology, and there is concern that potential genetic mutations affecting outcome may be present in such patients. Techniques such as next generation sequencing (typically defined as fast massively parallel sequencing) can determine a human genome in less than one day, and the authors of this study looked at the capacity of such screening techniques to determine genetic causes of ALF in children. This retrospective study of pediatric patients seen in a tertiary pediatric hospital in London looked at all cases of ALF over an 18year period in which stored blood was available. Included study patients had no evidence of chronic liver disease. Additionally, such patients needed to have laboratory evidence of ALF defined as having an international normalized ration (INR) ≥ 1.5 not corrected by Vitamin K with associated hepatic encephalopathy or having an INR ≥ 2 with or without hepatic encephalopathy. Clinical characteristics were obtained for all patients, and children with ALF were determined to have an indeterminate cause of disease if no known cause of ALF could be found. Additionally, blood samples underwent next generation sequencing to evaluate for 64 mutations causing genetic and metabolic liver disease in children, exome sequencing to evaluate the entire genome of the affected child and unaffected parents, or sequence variant filtration to determine potential disease-causing variants.

Next generation sequencing occurred in 41 patients while 4 patients underwent exome sequencing. Next generation sequencing identified eight children with either heterozygous or homozygous ALF-causing mutations of NBAS, TWINK, CPT1A, MPV17, DLD, POLG, and SUCLG1. Exome sequencing found mutations in all four children including mutations in LARS1, FAH1, NPC1, and DLD. Interestingly, those children with biallelic variants of such mutations presented with ALF at a significantly younger age and were significantly more likely to die from liver failure. Thus, this study shows that using genetic testing to diagnose unknown causes of ALF in children is beneficial in elucidating primary causes of hepatic disease. This aspect is especially important since liver transplantation for mitochondrial DNA mutations is controversial depending on the mutation as other organs besides the liver can be affected. This study shows that sequencing the genome for pediatric ALF is important to determine causality and outcome, and more work is urgently needed to make such testing easily available and affordable.

Hegarty R, Gibson P, Sambrotta M, Strautnieks S, Foskett P, Ellard S, Baptista J, Lillis S, Bansal S, Vara R, Dhawan A, Grammatikopoulos T, Thompson R. Study of acute liver failure in children using next generation sequencing technology. Journal of Pediatrics 2021; 236: 124-130.

John Pohl, M.D., Book Editor, is on the Editorial Board of Practical Gastroenterology

Download Tables, Images & References