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Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing
Published on: February 10, 2023
De novo mtDNA point mutations are common and have a low recurrence risk
Suzanne C E H Sallevelt1, Christine E M de Die-Smulders1,2, Alexandra T M Hendrickx1
1Department of Clinical Genetics, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands.
Background:
Severe, 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.
Methods:
Systematic 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.
Results:
In 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 A literature survey revealed 137 de novo cases, but PND was only performed for 9 (including 1 unpublished) mothers.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.
Conclusions:
De 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.
Insights
De novo mitochondrial DNA (mtDNA) point mutations frequently cause mtDNA disease, but their recurrence risk is low. This information is crucial for genetic counseling and reproductive choices, with prenatal diagnosis (PND) offering reassurance.
Area of Science:
- Genetics
- Mitochondrial Biology
- Reproductive Medicine
Background:
- Severe, disease-causing germline mitochondrial (mt)DNA mutations are maternally inherited or arise de novo.
- Genetic counseling for de novo mtDNA point mutations is often hampered by a lack of comprehensive data on recurrence risks and reproductive options.
- Existing strategies for preventing mtDNA transmission vary in effectiveness based on mutation type and recurrence risk.
Purpose of the Study:
- To systematically investigate the relevance and recurrence risk of apparently de novo mitochondrial DNA (mtDNA) point mutations.
- To provide comprehensive data for accurate genetic counseling regarding recurrence risks and reproductive options for de novo mtDNA mutations.
- To assess the utility of prenatal diagnosis (PND) in managing pregnancies with de novo mtDNA point mutations.
Main Methods:
- Conducted a systematic study of prenatal diagnosis (PND) and recurrence in families with de novo mtDNA point mutations, incorporating new and published data.
- Defined 'de novo' based on the absence of the mutation in multiple postmitotic maternal tissues, with allowances for mutations absent only in maternal blood.
- Analyzed data from 105 index patients and performed a literature survey of 137 de novo cases.
Main Results:
- The de novo frequency of pathogenic mtDNA point mutations was 24.6% in the study cohort, predominantly in pediatric cases.
- Prenatal diagnosis (PND) was performed in four subsequent pregnancies of mothers with de novo cases; the mutation was absent in all prenatal samples.
- Preimplantation genetic diagnosis (PGD) was utilized by one mother, with no mutations detected in tested oocytes/embryos. Literature review identified limited PND use for de novo cases, with one instance of recurrence suggesting germline mosaicism.
Conclusions:
- De novo mitochondrial DNA (mtDNA) point mutations represent a significant cause of inherited mtDNA diseases.
- The recurrence risk associated with de novo mtDNA point mutations is generally low.
- Prenatal diagnosis (PND) can be offered to provide reassurance for expectant mothers concerning de novo mtDNA mutations, aiding in genetic counseling and reproductive decision-making.
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