Related Experiment Video

Updated: Sep 4, 2025

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

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A new pathogenic POLG variant

S Nicholas Russo1,2, Ekta G Shah1, William C Copeland3

  • 1The University of Texas McGovern Medical School, Department of Pediatrics, Division of Child and Adolescent Neurology, Houston, TX, USA.

Molecular Genetics and Metabolism Reports
|July 21, 2022
PubMed

Insights

Mutations in the POLG gene cause inherited mitochondrial disorders. A novel POLG variant, p.S809R, was identified in a child with severe epilepsy and reduced mitochondrial DNA.

Area of Science:

  • Genetics
  • Molecular Biology
  • Neurology

Background:

  • Mutations in the *POLG* gene are the most frequent cause of inherited mitochondrial disorders, affecting mitochondrial DNA replication and repair.
  • Over 300 pathogenic variants in *POLG* are known, leading to diverse clinical phenotypes with significant overlap and no clear genotype-phenotype correlation.

Observation:

  • A 7-year-old male presented with intractable status epilepticus, leading to death.
  • Genetic analysis revealed compound heterozygosity for the common *POLG* variant p.A467T and a novel variant, p.S809R.

Findings:

  • The novel p.S809R *POLG* variant, found *in trans* with p.A467T, was associated with severely reduced mitochondrial DNA levels in patient tissues.
  • This case highlights a new pathogenic variant in the *POLG* gene contributing to severe mitochondrial disease.

Implications:

  • The discovery of the p.S809R variant expands the known spectrum of *POLG* mutations and their associated phenotypes.
  • Further research into genotype-phenotype correlations in *POLG* disorders is warranted to improve diagnostic and prognostic capabilities.
Keywords:
Alpers-Huttenlocher syndromeDNA polymerase gammaMitochondriaMitochondrial depletionPOLG syndrome

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