1. Deep Sequencing Reveals Novel Genetic Variants in Children with Acute Liver Failure and Tissue Evidence of Impaired Energy Metabolism.
- Author
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Valencia, C Alexander, Wang, Xinjian, Wang, Jin, Peters, Anna, Simmons, Julia R, Moran, Molly C, Mathur, Abhinav, Husami, Ammar, Qian, Yaping, Sheridan, Rachel, Bove, Kevin E, Witte, David, Huang, Taosheng, and Miethke, Alexander G
- Subjects
Liver ,Mitochondria ,Humans ,Liver Failure ,Acute ,DNA ,Mitochondrial ,Retrospective Studies ,Energy Metabolism ,Mutation ,Adolescent ,Child ,Child ,Preschool ,Infant ,Infant ,Newborn ,Female ,Male ,Genetic Variation ,High-Throughput Nucleotide Sequencing ,Pediatric ,Rare Diseases ,Pediatric Research Initiative ,Liver Disease ,Genetics ,Chronic Liver Disease and Cirrhosis ,Digestive Diseases ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,General Science & Technology - Abstract
Background & aimsThe etiology of acute liver failure (ALF) remains elusive in almost half of affected children. We hypothesized that inherited mitochondrial and fatty acid oxidation disorders were occult etiological factors in patients with idiopathic ALF and impaired energy metabolism.MethodsTwelve patients with elevated blood molar lactate/pyruvate ratio and indeterminate etiology were selected from a retrospective cohort of 74 subjects with ALF because their fixed and frozen liver samples were available for histological, ultrastructural, molecular and biochemical analysis.ResultsA customized next-generation sequencing panel for 26 genes associated with mitochondrial and fatty acid oxidation defects revealed mutations and sequence variants in five subjects. Variants involved the genes ACAD9, POLG, POLG2, DGUOK, and RRM2B; the latter not previously reported in subjects with ALF. The explanted livers of the patients with heterozygous, truncating insertion mutations in RRM2B showed patchy micro- and macrovesicular steatosis, decreased mitochondrial DNA (mtDNA) content
- Published
- 2016