Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion

• Published in: European journal of medical genetics 2016-10, Vol.59 (10), p.540-545
• Main Authors: Varma, Hemant, Faust, Phyllis L, Iglesias, Alejandro D, Lagana, Stephen M, Wou, Karen, Hirano, Michio, DiMauro, Salvatore, Mansukani, Mahesh M, Hoff, Kirsten E, Nagy, Peter L, Copeland, William C, Naini, Ali B
• Format: Article
• Language: English
• Subjects: Base Sequence; DNA, Mitochondrial - genetics; DNA-Directed DNA Polymerase - genetics; Exome - genetics; Hepatic failure; Humans; Infant; Intestinal Pseudo-Obstruction - complications; Intestinal Pseudo-Obstruction - genetics; Intestinal Pseudo-Obstruction - physiopathology; Liver Failure, Acute - complications; Liver Failure, Acute - genetics; Liver Failure, Acute - physiopathology; Male; Medical Education; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial DNA depletion; Mitochondrial Encephalomyopathies - complications; Mitochondrial Encephalomyopathies - genetics; Mitochondrial Encephalomyopathies - physiopathology; Muscular Dystrophy, Oculopharyngeal; Mutation, Missense; Ophthalmoplegia - congenital; POLG; POLG2; Whole-exome sequencing
• ISSN: 1769-7212; 1878-0849
• DOI: 10.1016/j.ejmg.2016.08.012

Abstract Mitochondrial DNA (mtDNA) depletion syndrome manifests as diverse early-onset diseases that affect skeletal muscle, brain and liver function. Mutations in several nuclear DNA-encoded genes cause mtDNA depletion. We report on a patient, a 3-month-old boy who presented with hepatic failure, and was found to have severe mtDNA depletion in liver and muscle. Whole-exome sequencing identified a homozygous missense variant (c.544C > T, p.R182W) in the accessory subunit of mitochondrial DNA polymerase gamma ( POLG2 ), which is required for mitochondrial DNA replication. This variant is predicted to disrupt a critical region needed for homodimerization of the POLG2 protein and cause loss of processive DNA synthesis. Both parents were phenotypically normal and heterozygous for this variant. Heterozygous mutations in POLG2 were previously associated with progressive external ophthalmoplegia and mtDNA deletions. This is the first report of a patient with a homozygous mutation in POLG2 and with a clinical presentation of severe hepatic failure and mitochondrial depletion.