Format

Send to

Choose Destination
Eur J Med Genet. 2016 Oct;59(10):540-5. doi: 10.1016/j.ejmg.2016.08.012. Epub 2016 Aug 31.

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

Author information

1
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.
2
Department of Pathology and Cell Biology, Columbia University, 630 W, 168th Street, New York, NY 10032, USA.
3
Division of Medical Genetics, Columbia University, New York Presbyterian Hospital, USA.
4
Division of Genetics, New York Presbyterian Hospital, USA.
5
Department of Neurology, Columbia University Medical Center, USA.
6
Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
7
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.
8
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.

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.

KEYWORDS:

Hepatic failure; Mitochondrial DNA depletion; POLG; POLG2; Whole-exome sequencing

PMID:
27592148
PMCID:
PMC5045816
DOI:
10.1016/j.ejmg.2016.08.012
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center