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Information for genetic management of mtDNA disease: Sampling pathogenic mtDNA mutants in the human germline and in placenta.
  1. David Marchington1,
  2. Sajida Malik1,
  3. Anita Banerjee2,
  4. Karen Turner1,
  5. David Samuels3,
  6. Vincent Macaulay4,
  7. Pippa Oakeshott5,
  8. Carl Fratter6,
  9. Stephen Kennedy1,
  10. Joanna Poulton7,*
  1. 1 NDOG University of Oxford, United Kingdom;
  2. 2 Department of Metabolic Medicine, Hammersmith Hospital NHS Trust, United Kingdom;
  3. 3 Vanderbilt University Medical Center, United States;
  4. 4 University of Glasgow, United Kingdom;
  5. 5 Community Health Sciences, St George’s Hospital Medical School, United Kingdom;
  6. 6 Oxford Medical Genetics Laboratory, Churchill Hospital Oxford, United Kingdom;
  7. 7 University of Oxford, United Kingdom
  1. Correspondence to: Joanna Poulton, NDOG, the Women's Centre, University of Oxford, NDOG, Level 3 The Women's Centre, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, United Kingdom; joanna.poulton{at}


Families with a childwho died of severe, maternally inherited mitochondrial DNA (mtDNA) disease need information on recurrence risk. Estimating this risk is difficult because of a) heteroplasmy -coexistence of mutant and normal mtDNA in the same person and b) the so-called "mitochondrial bottleneck", whereby the small number of mtDNAs which become the founders for the offspring cause variation in dose of mutant mtDNA.

The timing of the bottleneck and of segregation of mtDNA during foetal life determine the management options. We therefore studied mtDNAheteroplasmy in oocytesand placenta of women in affected families.

Results: One mother of a child dying from Leigh syndrome due to the 9176T>CmtDNA mutation transmitted various loads of mutant mtDNA to ≤3 of 20 oocytes. We used this to estimate recurrence to be ≤ 5%. She subsequently conceived a healthy son naturally.

Analysis of placenta showed that some segregation also occurred during placental development, mutant mtDNA load varying by >10% in a placenta carrying 65% 3243 A->G mutant mtDNA.

Discussion: This is the first report of a) oocyte analysis for preconception counselling, specifically, refining recurrence risks of rare mutations b) widely different load of a pathogenic mtDNA mutation in multiple oocytes, apparently confined to the germline, in an asymptomatic carrier of a mtDNA disease. This suggests that a major component of the bottleneck occurs during oogenesis, probably early in the foetal life of the mother. The variable mutant load in placenta implies that estimates based a single sample in prenatal diagnosis of mtDNA disorders have limited accuracy.

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