A retrospective study on the efficacy of prenatal diagnosis for pregnancies at risk of mitochondrial DNA disorders.
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
01
06
2020
accepted:
11
11
2020
revised:
11
11
2020
pubmed:
12
12
2020
medline:
4
6
2021
entrez:
11
12
2020
Statut:
ppublish
Résumé
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. We report on a retrospective review of 20 years of prenatal diagnosis of pathogenic mtDNA variants in 80 pregnant women and 120 fetuses. 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. 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.
Identifiants
pubmed: 33303968
doi: 10.1038/s41436-020-01043-3
pii: S1098-3600(21)02456-4
doi:
Substances chimiques
DNA, Mitochondrial
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
720-731Références
Thorburn, D. R. Mitochondrial disorders: prevalence, myths and advances. J. Inherit. Metab. Dis. 27, 349–362 (2004).
doi: 10.1023/B:BOLI.0000031098.41409.55
Ciafaloni, E., Ricci, E. & Shanske, S. et al. MELAS: clinical features, biochemistry, and molecular genetics. Ann. Neurol. 31, 391–398 (1992).
doi: 10.1002/ana.410310408
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).
doi: 10.1203/00006450-199505000-00014
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).
doi: 10.1136/jmg.32.8.654
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).
doi: 10.1093/brain/120.10.1713
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).
doi: 10.1001/archneur.59.2.264
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).
doi: 10.1016/j.bbabio.2009.09.005
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).
doi: 10.1136/jmg.2005.034140
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).
doi: 10.1136/jmg.2006.048553
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).
doi: 10.1002/humu.21417
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).
doi: 10.1038/ejhg.2014.35
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).
doi: 10.1136/jmedgenet-2016-103876
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).
doi: 10.1136/jmedgenet-2017-104615
Marmur, J. A procedure for the isolation of deoxyribonucleic acid from micro-organisms. J. Mol. Biol. 3, 208–218 (1961).
doi: 10.1016/S0022-2836(61)80047-8
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).
doi: 10.1016/j.ymgme.2004.10.008
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).
doi: 10.1006/bbrc.1998.8666
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).
doi: 10.15252/emmm.201708262
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).
doi: 10.1534/genetics.107.081026
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).
doi: 10.1126/science.1147786
Pickett, S. J., Blain, A. & Ng, Y. S. et al. Mitochondrial donation—which women could senefit? N. Engl. J. Med. 380, 1971–1972 (2019).
doi: 10.1056/NEJMc1808565
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).
doi: 10.1111/nyas.12866
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).
doi: 10.1086/515453
Steffann, J., Monnot, S. & Bonnefont, J. P. mtDNA mutations variously impact mtDNA maintenance throughout the human embryofetal development. Clin. Genet. 88, 416–424 (2015).
doi: 10.1111/cge.12557
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).
doi: 10.1093/hmg/ddv626
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).
doi: 10.1093/humrep/dey114
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).
doi: 10.1136/jmg.31.1.41
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).
doi: 10.1016/S0022-3476(97)80074-1
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).
doi: 10.1007/s004150070080
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).
doi: 10.1016/j.rbmo.2017.01.013
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).
doi: 10.1038/nature18303
Kang, E., Wu, J. & Gutierrez, N. M. et al. Mitochondrial replacement in human oocytes carrying pathogenic mitochondrial DNA mutations. Nature. 540, 270–275 (2016).
doi: 10.1038/nature20592
Gorman, G. S., McFarland, R. & Stewart, J. et al. Mitochondrial donation: from test tube to clinic. Lancet. 392, 1191–1192 (2018).
doi: 10.1016/S0140-6736(18)31868-3