Quantitative multiplex PCR of short fluorescent fragments for the detection of large intragenic POLG rearrangements in a large French cohort

Eur J Hum Genet. 2014 Apr;22(4):542-50. doi: 10.1038/ejhg.2013.171. Epub 2013 Aug 7.


Polymerase gamma (POLG) is the gene most commonly involved in mitochondrial disorders with mitochondrial DNA instability and causes a wide range of diseases with recessive or dominant transmission. More than 170 mutations have been reported. Most of them are missense mutations, although nonsense mutations, splice-site mutations, small deletions and insertions have also been identified. However, to date, only one large-scale rearrangement has been described in a child with Alpers syndrome. Below, we report a large cohort of 160 patients with clinical, molecular and/or biochemical presentation suggestive of POLG deficiency. Using sequencing, we identified POLG variants in 22 patients (18 kindreds) including five novel pathogenic mutations. Two patients with novel mutations had unusual clinical presentation: the first exhibited an isolated ataxic neuropathy and the second was a child who presented with endocrine signs. We completed the sequencing step by quantitative multiplex PCR of short fluorescent fragments (QMPSF) analysis in 37 patients with either only one POLG heterozygous variant or a family history suggesting a dominant transmission. We identified a large intragenic deletion encompassing part of intron 21 and exon 22 of POLG in a child with refractory epilepsia partialis continua. In conclusion, we describe the first large French cohort of patients with POLG mutations, expanding the wide clinical and molecular spectrum observed in POLG disease. We confirm that large deletions in the POLG gene are rare events and we highlight the importance of QMPSF in patients with a single heterozygous POLG mutation, particularly in severe infantile phenotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Child
  • Child, Preschool
  • Cohort Studies
  • DNA Polymerase gamma
  • DNA, Mitochondrial / genetics
  • DNA-Directed DNA Polymerase / deficiency*
  • DNA-Directed DNA Polymerase / genetics*
  • Epilepsia Partialis Continua / genetics
  • Exons
  • Female
  • France
  • Gene Rearrangement*
  • Heterozygote
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Mitochondrial Diseases / genetics
  • Multiplex Polymerase Chain Reaction
  • Phenotype
  • Sequence Analysis, DNA
  • Sequence Deletion
  • Whites
  • Young Adult


  • DNA, Mitochondrial
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • POLG protein, human