POLG-Related Mitochondrial Disorders via the POLG Gene

The POLG-related disorders are a continuous series of overlapping phenotypes that can be clinically classified into six subgroups, involve multiple organs, and have variable severity and age of onset (Tang et al. J Med Genet 48(10):669-681, 2011; Cohen et al. GeneReviews, 2010). Onset of the POLG-related disorders ranges from infancy to late adulthood. Resulting in mitochondrial DNA (mtDNA) depletion and/or multiple deletions, POLG deficiency has been recognized as one of the most common causes of inherited mitochondrial disorders (Tang et al., 2011). Due to the highly heterogeneous manifestations, clinical description of each POLG-related disease and the extent of overlapping between diseases remain largely inconclusive. The diagnosis of a POLG-related disorder relies on identification of pathogenic POLG mutations (Cohen et al., 2010). Six subgroups of POLG-related disorders are briefly listed as follows.

1. Alpers-Huttenlocher syndrome (AHS) (OMIM #203700) is characterized by severe encephalopathy with intractable epilepsy and hepatic failure. This childhood-onset progressive disease is one of the most severe POLG-related phenotypes.

2. Childhood myocerebrohepatopathy spectrum (MCHS) is characterized by developmental delay or dementia, myopathy with failure to thrive, and lactic acidosis. Other clinical features include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. The age onset of MCHS ranges between the first few months after birth up to about age three years.

3. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) is characterized by a spectrum of clinical presentations including epilepsy, myopathy, and ataxia without ophthalmoplegia. It also covers a disorder that was previously described as spinocerebellar ataxia with epilepsy (SCAE) (OMIM #607459).

4. The ataxia neuropathy spectrum (ANS) mainly includes two previously described diseases: mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) (OMIM #607459). As key features, ataxia and neuropathy have been found in about 90% of ANS patients. Other main features include seizures and ophthalmoplegia, but clinical myopathy is rare.

5. Autosomal dominant progressive external ophthalmoplegia (adPEO) (OMIM #157640) is characterized by ptosis and ophthalmoparesis with a generalized myopathy. Other clinical phenotypes include proximal muscle weakness, peripheral neuropathy, ataxia, cataracts, cardiomyopathy, and depression. The disease previously called chronic progressive external ophthalmoplegia plus (CPEO+) has been merged into this group.

6. Autosomal recessive progressive external ophthalmoplegia (arPEO) (OMIM #258450) is also characterized by ptosis and ophthalmoparesis but with more severe features compared with adPEO.

The POLG gene has 22 coding exons that encode the catalytic subunit of human DNA polymerase gamma, the DNA polymerase essential for mtDNA replication and repair. The mature POLG protein can be divided into four functional domains: (1) the N-terminal domain; (2) the exonuclease domain; (3) the spacer region; and (4) the polymerase domain. More than 200 pathogenic variants have been documented across all domains of the POLG gene. The majority (approximately 94%) of the POLG mutations are missense changes. Null mutations (nonsense, frameshift, splice site) account for 6% of the mutated alleles; in-frame deletions, duplications and large deletions/duplications appear to be rare. In a summarized analysis across multiple published studies, c.1399G>A (p.A467T) is the most common mutation, accounting for approximately 31% of all mutant alleles, followed by c.2542G>A (p.G848S) (~10%) and c.2243G>C (p.W748S) (~8%) (Tang et al., 2011).

Except for adPEO, which is an autosomal dominant disorder, all of other POLG-related disorders are inherited in an autosomal recessive manner. Patients with two pathogenic alleles presented a broad spectrum of disease. Therefore, there are no established genotype-phenotype correlations. A few autosomal dominant POLG mutations are located within the polymerase catalytic domain in adPEO.

In the most comprehensive study by far, POLG mutations were identified in 136 out of 2,697 unrelated individuals (5%) with clinical presentations suggestive of POLG deficiency (Tang et al. J Med Genet 48(10):669-681, 2011).

This test provides full coverage of all coding exons of the POLG gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.