International Research Team Develops Consensus Variant Classification Guidelines for Genomic Variants in Mitochondrial DNA

Published on in CHOP News

A team of researchers in the Mitochondrial Medicine Frontier Program at Children’s Hospital of Philadelphia (CHOP) led an international effort to standardize how variants in mitochondrial DNA (mtDNA) are interpreted, detailing the unique aspects of the mtDNA genome and outlining when specific variants may cause medical problems when detected in a patient. Their work was published this month in the journal Human Mutation.

Marni Falk, MD Marni Falk, MD “This work represents the culmination of several years of collaboration by global leaders in mtDNA genomics and disease, all aimed at improving the ability of labs and clinicians around the world to more accurately diagnose patients with mtDNA-based mitochondrial disease,” said Marni Falk, MD, Professor and Executive Director of the Mitochondrial Medicine Frontier Program at CHOP and senior author of this study.

Mitochondrial disease refers to a heterogeneous group of energy disorders that may be caused by genetic mutations in either the body’s nuclear DNA, which is found in the nucleus of our cells, or by genetic mutations or deletions in our mtDNA, a separate chromosome with many repeating copies that is found specifically in the mitochondria. Given the unique features of the mtDNA genome, evaluating variants requires special considerations. However, there are currently insufficient standardized criteria to assess the potential impact of mtDNA variants, which leads to inconsistencies in interpreting their likelihood to be the cause of disease when they are encountered by diagnostic laboratories and clinicians.

To address this ongoing issue, an international working group of mtDNA experts was assembled within the Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium. The research team obtained Expert Panel status from ClinGen, a central resource funded by the National Institutes of Health (NIH) to define the clinical relevance of genes and variants reported in the literature and in the centralized NIH ClinVar database, and clarify their applications in precision medicine and research.

Working from the 2015 American College of Medical Genetics (ACMG) and Association of Molecular Pathology (AMP) standards and guidelines that are widely used for clinical interpretation of DNA sequence variants, the mtDNA Expert Panel working group determined consensus specifications to provide additional guidance for mtDNA variant classification. Unique aspects of mtDNA were addressed to properly classify its variants, including addressing mtDNA genome composition and structure, maternal inheritance, heteroplasmy, functional analyses unique to mtDNA, and the heterogeneous presentations of mitochondrial disease.

Elizabeth McCormick, MS Elizabeth McCormick, MS “Being able to agree whether a specific variant that may be identified in a given patient is known to cause disease or is a benign finding is essential knowledge to guide counseling for their own medical prognosis, recurrence risk for their family members, and whether they may qualify for emerging therapies that target specific causes of mitochondrial disease,” said Elizabeth McCormick, MS, licensed certified genetic counselor at CHOP and first author of the study.

McCormick et al, “Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation.” Hum Mutat, online September 9, 2020. DOI: 10.1002/humu.24107.

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