HGG Advances (Jul 2025)
Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases
- Sarah L. Stenton,
- Kristen Laricchia,
- Nicole J. Lake,
- Sushma Chaluvadi,
- Vijay Ganesh,
- Stephanie DiTroia,
- Ikeoluwa Osei-Owusu,
- Lynn Pais,
- Emily O’Heir,
- Christina Austin-Tse,
- Melanie O’Leary,
- Mayada Abu Shanap,
- Chelsea Barrows,
- Seth Berger,
- Carsten G. Bönnemann,
- Kinga M. Bujakowska,
- Dean R. Campagna,
- Alison G. Compton,
- Sandra Donkervoort,
- Mark D. Fleming,
- Lyndon Gallacher,
- Joseph G. Gleeson,
- Goknur Haliloglu,
- Eric A. Pierce,
- Emily M. Place,
- Vijay G. Sankaran,
- Akiko Shimamura,
- Zornitza Stark,
- Tiong Yang Tan,
- David R. Thorburn,
- Susan M. White,
- Maha S. Zaki,
- Eric Vilain,
- Monkol Lek,
- Heidi L. Rehm,
- Anne O’Donnell-Luria
Affiliations
- Sarah L. Stenton
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
- Kristen Laricchia
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Nicole J. Lake
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA
- Sushma Chaluvadi
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Vijay Ganesh
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Stephanie DiTroia
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Ikeoluwa Osei-Owusu
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Lynn Pais
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Emily O’Heir
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Christina Austin-Tse
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Melanie O’Leary
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Mayada Abu Shanap
- Hematology/Oncology, Bone Marrow Transplantation and Cellular Therapy, Pediatric Department, King Hussein Cancer Centre (KHCC), Amman, Jordan
- Chelsea Barrows
- Department of Neurosciences, University of California, San Diego, San Diego, CA, USA; Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA
- Seth Berger
- Children’s National Research Institute, Washington, DC, USA
- Carsten G. Bönnemann
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
- Kinga M. Bujakowska
- Ocular Genomics Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
- Dean R. Campagna
- Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
- Alison G. Compton
- Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Flemington Road, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
- Sandra Donkervoort
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
- Mark D. Fleming
- Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
- Lyndon Gallacher
- Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Flemington Road, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
- Joseph G. Gleeson
- Department of Neurosciences, University of California, San Diego, San Diego, CA, USA; Rady Children’s Institute for Genomic Medicine, San Diego, CA, USA
- Goknur Haliloglu
- Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
- Eric A. Pierce
- Ocular Genomics Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
- Emily M. Place
- Ocular Genomics Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
- Vijay G. Sankaran
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Howard Hughes Medical Institute, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Akiko Shimamura
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
- Zornitza Stark
- Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Flemington Road, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
- Tiong Yang Tan
- Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Flemington Road, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
- David R. Thorburn
- Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Flemington Road, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
- Susan M. White
- Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Flemington Road, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia
- Maha S. Zaki
- Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12311, Egypt
- Eric Vilain
- Institute for Clinical and Translational Science, University of California, Irvine, Irvine, CA, USA
- Monkol Lek
- Department of Genetics, Yale School of Medicine, New Haven, CT, USA
- Heidi L. Rehm
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Anne O’Donnell-Luria
- Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Corresponding author
- Journal volume & issue
-
Vol. 6,
no. 3
p. 100441
Abstract
Summary: Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is not always specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants. Here, we analyzed a cohort of 6,660 rare disease families (5,625 genetically undiagnosed [84%]) from the Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium, as well as other rare disease cohorts. Using dedicated pipelines to address the technical challenges posed by the mtDNA—circular genome, variant heteroplasmy, and nuclear misalignment—we called single nucleotide variants, small insertions/deletions, and large mtDNA deletions from exome and/or genome sequencing data, in addition to RNA sequencing data when available. Diagnostic mtDNA variants were identified in 10 previously genetically undiagnosed families (1 large deletion, 8 reported pathogenic variants, and 1 previously unreported likely pathogenic variant), as well as candidate diagnostic variants in a further 11 undiagnosed families. In one additional undiagnosed proband, detection of >900 heteroplasmic variants provided functional evidence of pathogenicity to a de novo variant in the nuclear gene POLG (DNA polymerase gamma), responsible for mtDNA replication and repair. Overall, mtDNA variant calling from data generated by exome and genome sequencing—primarily for nuclear variant analysis—resulted in a genetic diagnosis for 0.2% of undiagnosed families affected by a broad range of rare diseases, as well as the identification of additional promising candidates in 0.2%.
