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AbstractBackground/Aim The nuclear POLG gene encodes the catalytic subunit of DNA polymerase gamma (polγ), the only polymerase involved in the replication
and proofreading of mitochondrial DNA. As a consequence, POLG mutations can cause disease through impaired replication of mitochondrial DNA. To date, over 150 different mutations have been identified, with a growing number of associated phenotypes described. The aim of this study was
to determine the prevalence of POLG mutations in an adult population of Australian patients with mitochondrial disease, displaying symptoms commonly associated with POLG‐related diseases. Methods The clinical presentations of 322 patients from a specialist adult mitochondrial disease clinic were reviewed. Nineteen exhibited a cluster of three or more predefined clinical manifestations suggestive of POLG‐related disease: progressive external ophthalmoplegia, seizures
and/or an abnormal electroencephalogram, neuropathy, ataxia, liver function abnormalities, migraine or dysphagia/dysarthria. Patients were screened for mutations by direct nucleotide sequencing of the coding and exon‐flanking intronic regions of POLG. Results Five of the 19 patients (26%) displaying a phenotype suggestive of POLG‐related disease were found to have informative POLG coding mutations (p.T851A, p.N468D, p.Y831C, p.G517V and novel p.P163S
variant). Literature and analysis of these mutations revealed that two of these patients had pathogenic mutations known to cause POLG‐related disease (patient #1: p.T851A and p.P163S; patient #2: p.T851A and p.N468D). Conclusions We conclude that the prevalence of pathogenic POLG mutations in our selected adult Australian cohort with suggestive clinical manifestations was 10%. A further 16% of patients had POLG variants but are unlikely to be responsible
for causing their disease.