Information for genetic management of mtDNA disease: sampling pathogenic mtDNA mutants in the human germline and in placenta

Marchington, David R.; Malik, Sajida; Banerjee, Anita; Turner, K; Samuels, David C.; Macaulay, Vincent; Oakeshott, Pippa; Fratter, Carl; Kennedy, Stephen; Poulton, Joanna

doi:10.1136/jmg.2009.072900

Cited by 34 publications

(20 citation statements)

References 43 publications

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“…A previous study on a placental fragment carrying m.3243A>G showed that a 60% mutant load was associated with a fivefold variation of the mtDNA copy number, but failed to establish a clear correlation between mutant load and mtDNA 11. In the current study, plotting the mutant load against the relative mtDNA amount for each of the five mtDNA mutations failed to detect any correlation, apart from m.3243A>G where the correlation was extremely strong (figure 2).…”

Section: Discussioncontrasting

confidence: 87%

Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders

et al. 2017

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Section: Discussioncontrasting

confidence: 87%

Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders

et al. 2017

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“…However, in most asymptomatic siblings of an index patient (a low) mtDNA mutation load could not be excluded as they were not tested for the mutation on ethical grounds. Recurrence risk is increased in the case of gonadal mosaicism, which was shown for one of the de novo cases in the literature (case 9, table 2/case 58, online supplementary table S2 34 ). The single case where the mutation was present in subsequent pregnancies of the mother (case 12, table 2/case 59, online supplementary table S2 18 ) without being detectable in her blood or urine is presumably also an example of gonadal mosaicism.…”

Section: Recurrence Risk Of De Novo Mtdna Mutation or Diseasementioning

confidence: 53%

De novo mtDNA point mutations are common and have a low recurrence risk

et al. 2016

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BackgroundSevere, disease-causing germline mitochondrial (mt)DNA mutations are maternally inherited or arise de novo. Strategies to prevent transmission are generally available, but depend on recurrence risks, ranging from high/unpredictable for many familial mtDNA point mutations to very low for sporadic, large-scale single mtDNA deletions. Comprehensive data are lacking for de novo mtDNA point mutations, often leading to misconceptions and incorrect counselling regarding recurrence risk and reproductive options. We aim to study the relevance and recurrence risk of apparently de novo mtDNA point mutations.MethodsSystematic study of prenatal diagnosis (PND) and recurrence of mtDNA point mutations in families with de novo cases, including new and published data. ‘De novo’ based on the absence of the mutation in multiple (postmitotic) maternal tissues is preferred, but mutations absent in maternal blood only were also included.ResultsIn our series of 105 index patients (33 children and 72 adults) with (likely) pathogenic mtDNA point mutations, the de novo frequency was 24.6%, the majority being paediatric. PND was performed in subsequent pregnancies of mothers of four de novo cases. A fifth mother opted for preimplantation genetic diagnosis because of a coexisting Mendelian genetic disorder. The mtDNA mutation was absent in all four prenatal samples and all 11 oocytes/embryos tested. A literature survey revealed 137 de novo cases, but PND was only performed for 9 (including 1 unpublished) mothers. In one, recurrence occurred in two subsequent pregnancies, presumably due to germline mosaicism.ConclusionsDe novo mtDNA point mutations are a common cause of mtDNA disease. Recurrence risk is low. This is relevant for genetic counselling, particularly for reproductive options. PND can be offered for reassurance.

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“…Statistical analysis of oocytes shows that in some cases the distribution of mutant mtDNA is consistent with random drift, but does not exclude the possibility of selection in the germline at an earlier stage [66]. On the other hand, a de novo mutation in a child and in oocytes appeared to be absent from the mother's other tissues [83], suggesting that it arose within the development of her germ cells. Comparison of human and mouse data suggests potentially important differences in both the type of rearrangement that is typical [59], [60] and in the bottleneck size [55].…”

Section: Mitochondrial Dna Bottlenecks In Human Germ Cell Developmentmentioning

confidence: 86%

“…The main drawback of CVS for mtDNA disorders is that it is not entirely certain that the level of mutant mtDNA detectable in a single CVS sample will accurately reflect that of the foetus [10]. Indeed, such data that exist suggest that there is a degree of variation of perhaps ±10% in the level of neutral [88] and pathogenic variants in placenta [83]. Moreover, certain centers are now offering PGD [5], [6], [23].…”

Section: Implications Of Heteroplasmy For Genetic Management Of Humanmentioning

confidence: 99%

Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them

et al. 2010

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Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy—the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk (i.e., those having low mutant mtDNA load) can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders.

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Information for genetic management of mtDNA disease: sampling pathogenic mtDNA mutants in the human germline and in placenta

Cited by 34 publications

References 43 publications

Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders

Segregation of mitochondrial DNA mutations in the human placenta: implication for prenatal diagnosis of mtDNA disorders

De novo mtDNA point mutations are common and have a low recurrence risk

Transmission of Mitochondrial DNA Diseases and Ways to Prevent Them

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