In their recently published paper describing mutations in mitochondrial DNA polymerase gamma, Tang et al.(1) propose that the POLG p.G268A (c.803G>C) and p.G517V (c.1550G>T) variants which have previously been reported as pathogenic mutations should be considered as unclassified variants that may represent rare neutral polymorphisms or polymorphic modifiers.

We have also identified these variants in our own cohort of 627 patients that were referred with a suspected disorder of mitochondrial DNA maintenance. We detected p.G268A in 9 individuals (allele frequency 0.72%) of ages from 3 months to 63 years. Symptoms were variable ranging from severe early onset mitochondrial DNA depletion syndrome to milder late onset neuropathy/ataxia/ophthalmoplegia. In all 9 cases the variant occurred as a heterozygous change with no other pathogenic POLG mutation, suggesting that p.G268A is not a recessive mutation. Parental samples were available in 3 cases, and for each of these we found the variant in an unaffected parent, suggesting that p.G268A is very unlikely to be a dominant mutation. Furthermore, one of the 9 index cases was later found to be compound heterozygous for pathogenic mutations in another gene associated with mtDNA maintenance disorders, DGUOK. In another case the proband had a similarly affected sibling who did not have p.G268A.

Similarly, we have identified p.G517V 8 times (allele frequency 0.64%), always as a heterozygous change with no other pathogenic POLG mutation. The age of the individuals ranged from 1-81 yrs and the phenotype varied from infantile epilepsy/failure to thrive to adult onset ophthalmoplegia/ataxia/myopathy. The unaffected parent of 1 of these individuals was also heterozygous for p.G517V. A second affected individual was later found to have pathogenic mutations in RRM2B.

Furthermore, the allele frequencies of p.G268A and p.G517V in our patient cohort are remarkably similar to those found in a large control population of European origin (2700 alleles) by the NHLBI exome sequencing project (2); 0.59% and 0.86% respectively.

Therefore, our data, taken together with that for Tang et al. and the NHLBI exome sequencing project, confirm that POLG p.G268A and p.G517V are not pathogenic and are highly likely to represent neutral polymorphisms.

References. (1) Tang S, Wang J, Lee NC, Milone M, Halberg MC, Schmitt ES, Craigen WJ, Zhang W, Wong LJ. Mitochondrial DNA polymerase gamma mutations: an ever expanding molecular and clinical spectrum. J Med Genet 2011;48:669-681. (2) https://esp.gs.washington.edu/drupal/

Conflict of Interest:

None declared