Renkui Bai1, Hong Cui2, Joseph M Devaney2, Katrina M Allis2, Amanda M Balog2, Xinyue Liu2, Rhonda E Schnur2,3, Faye L Shapiro3, Ariel Brautbar4, Juvianee I Estrada-Veras5,6,7, Laurel Hochstetler5,7,8,9, Allyn McConkie-Rosell10, Marie T McDonald10, Benjamin D Solomon2,11, Sean Hofherr2, Gabriele Richard2, Sharon F Suchy2. 1. GeneDx Inc, Gaithersburg, MD, USA. rbai@genedx.com. 2. GeneDx Inc, Gaithersburg, MD, USA. 3. Cooper Medical School of Rowan University/Cooper University Health Care, Camden, NJ, USA. 4. Department of Genetics, Cook Children's Health Care System, Fort Worth, TX, USA. 5. Walter Reed National Military Medical Center, Bethesda, MD, USA. 6. Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 7. Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 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. Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA. 11. National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Abstract
PURPOSE: Reports 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. METHODS: We retrospectively analyzed individuals with two mtDNA haplogroups from 2017 to 2019 and selected four families for further study. RESULTS: We 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. CONCLUSION: These 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.
PURPOSE: Reports 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. METHODS: We retrospectively analyzed individuals with two mtDNA haplogroups from 2017 to 2019 and selected four families for further study. RESULTS: We 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. CONCLUSION: These 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.
Authors: Rauan Kaiyrzhanov; Sami E M Mohammed; Reza Maroofian; Ralf A Husain; Alessia Catania; Alessandra Torraco; Ahmad Alahmad; Marina Dutra-Clarke; Sabine Grønborg; Annapurna Sudarsanam; Julie Vogt; Filippo Arrigoni; Julia Baptista; Shahzad Haider; René G Feichtinger; Paolo Bernardi; Alessandra Zulian; Mirjana Gusic; Stephanie Efthymiou; Renkui Bai; Farah Bibi; Alejandro Horga; Julian A Martinez-Agosto; Amanda Lam; Andreea Manole; Diego-Perez Rodriguez; Romina Durigon; Angela Pyle; Buthaina Albash; Carlo Dionisi-Vici; David Murphy; Diego Martinelli; Enrico Bugiardini; Katrina Allis; Costanza Lamperti; Siegfried Reipert; Lotte Risom; Lucia Laugwitz; Michela Di Nottia; Robert McFarland; Laura Vilarinho; Michael Hanna; Holger Prokisch; Johannes A Mayr; Enrico Silvio Bertini; Daniele Ghezzi; Elsebet Østergaard; Saskia B Wortmann; Rosalba Carrozzo; Tobias B Haack; Robert W Taylor; Antonella Spinazzola; Karin Nowikovsky; Henry Houlden Journal: Am J Hum Genet Date: 2022-09-01 Impact factor: 11.043