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Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders
  1. Pauline Vachin1,
  2. Elodie Adda-Herzog1,
  3. Gihad Chalouhi2,
  4. Caroline Elie3,
  5. Marlène Rio4,
  6. Sophie Rondeau1,4,
  7. Nadine Gigarel4,
  8. Fabienne Jabot Hanin5,
  9. Sophie Monnot1,4,
  10. Roxana Borghese4,
  11. Joana Bengoa4,
  12. Yves Ville2,
  13. Agnes Rotig1,
  14. Arnold Munnich1,4,
  15. Jean-Paul Bonnefont1,4,
  16. Julie Steffann1,4
  1. 1Université Paris Descartes – Sorbonne Paris Cité, Institut Imagine, INSERM UMR1163, Laboratoire des Maladies Mitochondriales, Paris, France
  2. 2Maternité, Groupe Hospitalier Necker Enfants Malades, Assistance Publique -Hôpitaux de Paris, Paris, France
  3. 3Unité de Recherche Clinique, Groupe Hospitalier Necker-Enfants Malades, Paris, France
  4. 4Unité de génétique moléculaire, Groupe hospitalier Necker Enfants malades, Assistance Publique -Hôpitaux de Paris, Paris, France
  5. 5Université Paris Descartes - Sorbonne Paris Cité, Institut Imagine, Plateforme de Bioinformatique, Paris, France
  1. Correspondence to Julie Steffann; julie.steffann{at}


Background Mitochondrial DNA (mtDNA) disorders have a high clinical variability, mainly explained by variation of the mutant load across tissues. The high recurrence risk of these serious diseases commonly results in requests from at-risk couples for prenatal diagnosis (PND), based on determination of the mutant load on a chorionic villous sample (CVS). Such procedures are hampered by the lack of data regarding mtDNA segregation in the placenta.

The objectives of this report were to determine whether mutant loads (1) are homogeneously distributed across the whole placentas, (2) correlate with those in amniocytes and cord blood cells and (3) correlate with the mtDNA copy number.

Methods We collected 11 whole placentas carrying various mtDNA mutations (m.3243A>G, m.8344A>G, m.8993T>G, m.9185T>C and m.10197G>A) and, when possible, corresponding amniotic fluid samples (AFSs) and cord blood samples. We measured mutant loads in multiple samples from each placenta (n= 637), amniocytes and cord blood cells, as well as total mtDNA content in placenta samples.

Results Load distribution was homogeneous at the sample level when average mutant load was low (<20%) or high (>80%) at the whole placenta level. By contrast, a marked heterogeneity was observed (up to 43%) in the intermediate range (20%80%), the closer it was to 40%50% the mutant load, the wider the distribution. Mutant loads were found to be similar in amniocytes and cord blood cells, at variance with placenta samples. mtDNA content correlated to mutant load in m.3243A>G placentas only.

Conclusion These data indicate that (1) mutant load determined from CVS has to be interpreted with caution for PND of some mtDNA disorders and should be associated with/substituted by a mutant load measurement on amniocytes; (2) the m.3243A>G mutation behaves differently from other mtDNA mutations with respect to the impact on mtDNA copy number, as previously shown in human preimplantation embryogenesis.

  • mitochondria
  • mitochondrial DNA
  • mtDNA mutations
  • placenta
  • prenatal diagnosis

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  • Contributors JS and JPB planned and supervised the study, and wrote the manuscript. GC, SR and YV collected the placentas. MR (clinical geneticist) diagnosed a mtDNA disorder in all families included in the manuscript, RB and JB (genetics counsellors) collected the consent forms. PV, EAH, NG and SM performed the experiments. CE and FJH performed statistical analyses. AR and AM provided part of funding as reagents and consumables.

  • Funding This work was supported by the Association Française contre les Myopathies (AFM no 16515/R13112KK) and the Agence de la Biomédecine (ABM, project 061 2013 115).

  • Competing interests None declared.

  • Patient consent Detail has been removed from these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

  • Ethics approval Review Board of l'Agence de Biomedecine (France).

  • Provenance and peer review Not commissioned; externally peer reviewed.