Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases

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%.

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Publication Details

Journal
Human Genetics and Genomics Advances
Published
2025-04-15
DOI
https://doi.org/10.1016/j.xhgg.2025.100441
Citations
1
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
1.82
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article

Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases

Kinga M. Bujakowska, Vijay G. Sankaran, Kristen M. Laricchia, Stephanie DiTroia et al.
1 citations
Human Genetics and Genomics Advances
Genomics and Rare Diseases
1.82
article

Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases

Kinga M. Bujakowska, Vijay G. Sankaran, Kristen M. Laricchia, Stephanie DiTroia, Heidi L. Rehm, Joseph G. Gleeson, Maha Saad Zaki, Monkol Lek, Mayada Abu Shanap, Sushma Chaluvadi, Sandra C. Donkervoort, Ikeoluwa Osei‐Owusu, Eric J. N. Vilain, Lynn Pais, David R. Thorburn, Eric A. Pierce, Tiong Yang Tan, Melanie O’Leary, Mark D. Fleming, Vijay Ganesh, Alison G. Compton, Carsten G. Bönnemann, Susan M. White, Zornitza Stark, Lyndon Gallacher, Akiko Shimamura, Nicole J. Lake, Göknur Haliloğlu, Emily Place, Emily O’Heir, Chelsea Barrows, Seth Berger, Christina Austin‐Tse, Sarah L. Stenton, Anne O’Donnell‐Luria, Dean R. Campagna
article en
1 citations

Abstract

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%.

Human Genetics and Genomics AdvancesVol. 6(3)
Broad Institute (US), Massachusetts Eye and Ear Infirmary (US), Boston Children's Hospital (US), National Institutes of Health (US), Children's National (US), Harvard University (US), University of California, Irvine (US), King Hussein Cancer Center (JO), Yale University (US), National Institute of Neurological Disorders and Stroke (US), National Research Institute (US), Agricultural Genetic Engineering Research Institute (EG), National Research Centre (EG)
Zero hunger
Openalex Percentile: Top 17%
Genomics and Rare Diseases
1.82
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