Interference of nuclear mitochondrial DNA segments in mitochondrial DNA testing resembles biparental transmission of mitochondrial DNA in humans |
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| Affiliation: | 1. GeneDx Inc, Gaithersburg, MD, USA.;2. Cooper Medical School of Rowan University/Cooper University Health Care, Camden, NJ, USA.;3. Department of Genetics, Cook Children’s Health Care System, Fort Worth, TX, USA.;4. Walter Reed National Military Medical Center, Bethesda, MD, USA.;5. Uniformed Services University of the Health Sciences, Bethesda, MD, USA.;6. Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.;7. Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.;8. UCSF/ZSFG Cancer Genetics and Prevention Program, San Francisco, CA, USA.;9. Helen Diller family Comprehensive Cancer Center, San Francisco, CA, USA.;10. National Human Genome Research Institute, NIH, Bethesda, MD, USA.;1. GeneDx Inc, Gaithersburg, MD, USA.;2. Cooper Medical School of Rowan University/Cooper University Health Care, Camden, NJ, USA.;3. Department of Genetics, Cook Children’s Health Care System, Fort Worth, TX, USA.;4. Walter Reed National Military Medical Center, Bethesda, MD, USA.;5. Uniformed Services University of the Health Sciences, Bethesda, MD, USA.;6. Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.;7. Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.;8. UCSF/ZSFG Cancer Genetics and Prevention Program, San Francisco, CA, USA.;9. Helen Diller family Comprehensive Cancer Center, San Francisco, CA, USA.;10. National Human Genome Research Institute, NIH, Bethesda, MD, USA. |
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| Abstract: | ![]()
PurposeReports have questioned the dogma of exclusive maternal transmission of human mitochondrial DNA (mtDNA), including the recent report of an admixture of two mtDNA haplogroups in individuals from three multigeneration families. This was interpreted as being consistent with biparental transmission of mtDNA in an autosomal dominant–like mode. The authenticity and frequency of these findings are debated.MethodsWe retrospectively analyzed individuals with two mtDNA haplogroups from 2017 to 2019 and selected four families for further study.ResultsWe identified this phenomenon in 104/27,388 (approximately 1/263) unrelated individuals. Further study revealed (1) a male with two mitochondrial haplogroups transmits only one haplogroup to some of his offspring, consistent with nuclear transmission; (2) the heteroplasmy level of paternally transmitted variants is highest in blood, lower in buccal, and absent in muscle or urine of the same individual, indicating it is inversely correlated with mtDNA content; and (3) paternally transmitted apparent large-scale mtDNA deletions/duplications are not associated with a disease phenotype.ConclusionThese findings strongly suggest that the observed mitochondrial haplogroup of paternal origin resulted from coamplification of rare, concatenated nuclear mtDNA segments with genuine mtDNA during testing. Evaluation of additional specimen types can help clarify the clinical significance of the observed results. |
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