title: Whole exome sequencing identifies a homozygous POLG2 missense variant in an infant with fulminant hepatic failure and mitochondrial DNA depletion.
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.
authors: Department of Pathology and Cell Biology, Columbia University, 630 W, 168th Street, New York, NY 10032, USA; Division of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University Medical Center, USA.
authors: Hemant
authors: H
authors: Varma
authors: Department of Pathology and Cell Biology, Columbia University, 630 W, 168th Street, New York, NY 10032, USA.
authors: Phyllis L
authors: PL
authors: Faust
authors: Division of Medical Genetics, Columbia University, New York Presbyterian Hospital, USA.
authors: Alejandro D
authors: AD
authors: Iglesias
authors: Department of Pathology and Cell Biology, Columbia University, 630 W, 168th Street, New York, NY 10032, USA.
authors: Stephen M
authors: SM
authors: Lagana
authors: Division of Genetics, New York Presbyterian Hospital, USA.
authors: Karen
authors: K
authors: Wou
authors: Department of Neurology, Columbia University Medical Center, USA.
authors: Michio
authors: M
authors: Hirano
authors: Department of Neurology, Columbia University Medical Center, USA.
authors: Salvatore
authors: S
authors: DiMauro
authors: Department of Pathology and Cell Biology, Columbia University, 630 W, 168th Street, New York, NY 10032, USA; Division of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University Medical Center, USA.
authors: Mahesh M
authors: MM
authors: Mansukani
authors: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
authors: Kirsten E
authors: KE
authors: Hoff
authors: Department of Pathology and Cell Biology, Columbia University, 630 W, 168th Street, New York, NY 10032, USA; Division of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University Medical Center, USA.
authors: Peter L
authors: PL
authors: Nagy
authors: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA. Electronic address: copelan1@niehs.nih.gov.
authors: William C
authors: WC
authors: Copeland
authors: Department of Pathology and Cell Biology, Columbia University, 630 W, 168th Street, New York, NY 10032, USA; Division of Personalized Genomic Medicine, Department of Pathology and Cell Biology, Columbia University Medical Center, USA. Electronic address: abn2@cumc.columbia.edu.
authors: Ali B
authors: AB
authors: Naini
mesh_terms: D001483:Base Sequence; D004272:DNA, Mitochondrial / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D059472:Exome / Q000235:genetics; D006801:Humans; D007223:Infant; D007418:Intestinal Pseudo-Obstruction / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D017114:Liver Failure, Acute / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D017237:Mitochondrial Encephalomyopathies / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D039141:Muscular Dystrophy, Oculopharyngeal; D020125:Mutation, Missense; D009886:Ophthalmoplegia / Q000151:congenital; D028361:Mitochondrial Diseases
chemical_list: D004272:DNA, Mitochondrial; D004259:DNA-Directed DNA Polymerase; C544932:POLG2 protein, human
keywords: Hepatic failure; Mitochondrial DNA depletion; POLG; POLG2; Whole-exome sequencing