Summary
Purpose
Prenatal diagnosis of mitochondrial DNA (mtDNA) disorders is challenging due to potential instability of fetal mutant loads and paucity of data connecting prenatal mutant loads to postnatal observations. Retrospective study of our prenatal cohort aims to examine the efficacy of prenatal diagnosis to improve counseling and reproductive options for those with pregnancies at risk of mtDNA disorders.
Methods
We report on a retrospective review of 20 years of prenatal diagnosis of pathogenic mtDNA variants in 80 pregnant women and 120 fetuses.
Results
Patients with undetectable pathogenic variants (n = 29) consistently had fetuses free of variants, while heteroplasmic women (n = 51) were very likely to transmit their variant (57/78 fetuses, 73%). In the latter case, 26 pregnancies were terminated because fetal mutant loads were >40%. Of the 84 children born, 27 were heteroplasmic (mutant load <65%). To date, no medical problems related to mitochondrial dysfunction have been reported.
Conclusion
Placental heterogeneity of mutant loads questioned the reliability of chorionic villous testing. Fetal mutant load stability, however, suggests the reliability of a single analysis of amniotic fluid at any stage of pregnancy for prenatal diagnosis of mtDNA disorders. Mutant loads under 40% reliably predict lack of symptoms in the progeny of heteroplasmic women.
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Data availability
Protocols for quantification of each mtDNA variant and reagents are available on request.
References
- 1.
Thorburn, D. R. Mitochondrial disorders: prevalence, myths and advances. J. Inherit. Metab. Dis. 27, 349–362 (2004).
- 2.
Ciafaloni, E., Ricci, E. & Shanske, S. et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann. Neurol. 31, 391–398 (1992).
- 3.
Mäkelä-Bengs, P., Suomalainen, A. & Majander, A. et al. Correlation between the clinical symptoms and the proportion of mitochondrial DNA carrying the 8993 point mutation in the NARP syndrome. Pediatr. Res. 37, 634–639 (1995).
- 4.
Manouvrier, S., Rötig, A. & Hannebique, G. et al. Point mutation of the mitochondrial tRNA(Leu) gene (A 3243 G) in maternally inherited hypertrophic cardiomyopathy, diabetes mellitus, renal failure, and sensorineural deafness. J. Med. Genet. 32, 654–656 (1995).
- 5.
Chinnery, P. F., Howell, N., Lightowlers, R. N. & Turnbull, D. M. Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes. Brain. 120, 1713–1721 (1997).
- 6.
Carelli, V., Baracca, A. & Barogi, S. et al. Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation. Arch. Neurol. 59, 264–270 (2002).
- 7.
Tuppen, H. A., Blakely, E. L., Turnbull, D. M. & Taylor, R. W. Mitochondrial DNA mutations and human disease. Biochim. Biophys. Acta 1797, 113–128 (2010).
- 8.
Bouchet, C., Steffann, J. & Corcos, J. et al. Prenatal diagnosis of myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome: contribution to understanding mitochondrial DNA segregation during human embryofetal development. J. Med. Genet. 43, 788–792 (2006).
- 9.
Steffann, J., Gigarel, N. & Corcos, J. et al. Stability of the m.8993T->G mtDNA mutation load during human embryofetal development has implications for the feasibility of prenatal diagnosis in NARP syndrome. J. Med. Genet. 44, 664–669 (2007).
- 10.
Monnot, S., Gigarel, N. & Samuels, D. C. et al. Segregation of mtDNA throughout human embryofetal development: m.3243A>G as a model system. Hum Mutat 32, 116–125 (2011).
- 11.
Nesbitt, V., Alston, C. L. & Blakely, E. L. et al. A national perspective on prenatal testing for mitochondrial disease. Eur J Hum Genet 22, 1255–1259 (2014).
- 12.
Sallevelt, S. C., de Die-Smulders, C. E. & Hendrickx, A. T. et al. De novo mtDNA point mutations are common and have a low recurrence risk. J. Med. Genet. 54, 73–83 (2017).
- 13.
Vachin, P., Adda-Herzog, E. & Chalouhi, G. et al. Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders. J. Med. Genet. 55, 131–136 (2018).
- 14.
Marmur, J. A procedure for the isolation of deoxyribonucleic acid from micro-organisms. J. Mol. Biol. 3, 208–218 (1961).
- 15.
Gigarel, N., Ray, P. F. & Burlet, P. et al. Single cell quantification of the 8993T>G NARP mitochondrial DNA mutation by fluorescent PCR. Mol. Genet. Metab. 84, 289–292 (2005).
- 16.
Parfait, B., Rustin, P., Munnich, A. & Rötig, A. Co-amplification of nuclear pseudogenes and assessment of heteroplasmy of mitochondrial DNA mutations. Biochem. Biophys. Res. Commun. 247, 57–59 (1998).
- 17.
Grady, J. P., Pickett, S. J. & Ng, Y. S. et al. mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease. EMBO Mol. Med. 10, e8262 (2018).
- 18.
Sato, A., Nakada, K. & Shitara, H. et al. Deletion-mutant mtDNA increases in somatic tissues but decreases in female germ cells with age. Genetics. 177, 2031–2037 (2007).
- 19.
Fan, W., Waymire, K. G. & Narula, N. et al. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science. 319, 958–962 (2008).
- 20.
Pickett, S. J., Blain, A. & Ng, Y. S. et al. Mitochondrial donation—which women could senefit? N. Engl. J. Med. 380, 1971–1972 (2019).
- 21.
Smeets, H. J., Sallevelt, S. C. & Dreesen, J. C. et al. Preventing the transmission of mitochondrial DNA disorders using prenatal or preimplantation genetic diagnosis. Ann. N Y Acad. Sci. 1350, 29–36 (2015).
- 22.
Blok, R. B., Gook, D. A., Thorburn, D. R. & Dahl, H. H. Skewed segregation of the mtDNA nt 8993 (T->G) mutation in human oocytes. Am. J. Hum. Genet. 60, 1495–1501 (1997).
- 23.
Steffann, J., Monnot, S. & Bonnefont, J. P. mtDNA mutations variously impact mtDNA maintenance throughout the human embryofetal development. Clin. Genet. 88, 416–424 (2015).
- 24.
Wilson, I. J., Carling, P. J. & Alston, C. L. et al. Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck. Hum. Mol. Genet. 25, 1031–1041 (2016).
- 25.
Otten, A. B. C., Sallevelt, S. C. E. H. & Carling, P. J. et al. Mutation-specific effects in germline transmission of pathogenic mtDNA variants. Hum. Reprod. 33, 1331–1341 (2018).
- 26.
Matthews, P. M., Hopkin, J. & Brown, R. M. et al. Comparison of the relative levels of the 3243 (A->G) mtDNA mutation in heteroplasmic adult and fetal tissues. J. Med. Genet. 31, 41–44 (1994).
- 27.
Ferlin, T., Landrieu, P. & Rambaud, C. et al. Segregation of the G8993 mutant mitochondrial DNA through generations and embryonic tissues in a family at risk of Leigh syndrome. J. Pediatr. 131, 447–449 (1997).
- 28.
Cardaioli, E., Fabrizi, G. M. & Grieco, G. S. et al. Heteroplasmy of the A3243G transition of mitochondrial tRNA(Leu(UUR)) in a MELAS case and in a 25-week-old miscarried fetus. J. Neurol. 247, 885–887 (2000).
- 29.
Zhang, J., Liu, H. & Luo, S. et al. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Reprod. Biomed. Online 34, 361–368 (2017).
- 30.
Hyslop, L. A., Blakeley, P. & Craven, L. et al. Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature. 534, 383–386 (2016).
- 31.
Kang, E., Wu, J. & Gutierrez, N. M. et al. Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature. 540, 270–275 (2016).
- 32.
Gorman, G. S., McFarland, R. & Stewart, J. et al. Mitochondrial donation: from test tube to clinic. Lancet. 392, 1191–1192 (2018).
Acknowledgements
We thank participating families for their cooperation and the physicians involved for care provided to couples. Research was supported by grants from the Association Française contre les Myopathies (AFM) and the French Agence de la Biomédecine (ABM). The authors thank Jason Miller, who edited the manuscript for style and grammar.
Funding
The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
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Conceptualization: J.-P.B., A.M., A.R. Data curation: J.B., R.B., S.M., J.S. J.-P.B., A.M. Formal analysis: M.M., Z.A., N.G., G.B. Investigation: Y.V., L.S., B.B., J.M. Methodology: J.S., S.M., A.M., J.-P.B. Writing—original draft: J.S, JP.B, A.M. Writing—review and editing: J.S., A.M.
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The authors declare no competing interests.
Ethics Declaration
This retrospective review has been approved by the Research Ethics Committee of the Necker-Enfants Malades University Hospital (IRB registration 00011928). All experiments were performed in accordance with relevant guidelines and French regulations. The Necker-Enfants Malades University Hospital has a general privacy statement informing patients that their data can be used for scientific research (https://www.aphp.fr/protection-des-donnees-personnelles).
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Steffann, J., Monnot, S., Magen, M. et al. A retrospective study on the efficacy of prenatal diagnosis for pregnancies at risk of mitochondrial DNA disorders. Genet Med (2020). https://doi.org/10.1038/s41436-020-01043-3
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