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Advanced approach for comprehensive mtDNA genome testing in mitochondrial disease. | LitMetric

Advanced approach for comprehensive mtDNA genome testing in mitochondrial disease.

Mol Genet Metab

Mitochondrial Medicine Frontier Program, Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

Published: January 2022

AI Article Synopsis

  • Diagnosis of mitochondrial disease involves analyzing both nuclear and mitochondrial genomes for variants, often requiring samples from relatives and correlating with patient symptoms.
  • The developed 'MitoGenome' test uses long-range PCR and next generation sequencing to identify single-nucleotide variants and large-scale mtDNA deletions, alongside droplet digital PCR for quantifying heteroplasmy levels.
  • Out of 394 patients tested, 11% had positive results for mitochondrial disease, with various pathogenic variants detected, emphasizing the accuracy and comprehensiveness of this new diagnostic method.

Article Abstract

Mitochondrial disease diagnosis requires interrogation of both nuclear and mitochondrial (mtDNA) genomes for single-nucleotide variants (SNVs) and copy number alterations, both in the proband and often maternal relatives, together with careful phenotype correlation. We developed a comprehensive mtDNA sequencing test ('MitoGenome') using long-range PCR (LR-PCR) to amplify the full length of the mtDNA genome followed by next generation sequencing (NGS) to accurately detect SNVs and large-scale mtDNA deletions (LSMD), combined with droplet digital PCR (ddPCR) for LSMD heteroplasmy quantification. Overall, MitoGenome tests were performed on 428 samples from 394 patients with suspected or confirmed mitochondrial disease. The positive yield was 11% (43/394), including 34 patients with pathogenic or likely pathogenic SNVs (the most common being m.3243A > G in 8/34 (24%) patients), 8 patients with single LSMD, and 3 patients with multiple LSMD exceeding 10% heteroplasmy levels. Two patients with both LSMD and pathogenic SNV were detected. Overall, this LR-PCR/NGS assay provides a highly accurate and comprehensive diagnostic method for simultaneous mtDNA SNV detection at heteroplasmy levels as low as 1% and LSMD detection at heteroplasmy levels below 10%. Inclusion of maternal samples for variant classification and ddPCR to quantify LSMD heteroplasmy levels further enables accurate pathogenicity assessment and clinical correlation interpretation of mtDNA genome sequence variants and copy number alterations.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8877466PMC
http://dx.doi.org/10.1016/j.ymgme.2021.12.006DOI Listing

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