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Correlation of mitochondrial DNA content in muscle with genetic diagnosis

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction:
Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a group of genetically heterogenous disorders characterized by significant reduction in mtDNA within cells, leading to impaired energy production. Pathogenic variants in nuclear genes involving in mtDNA biosynthesis and maintenance can cause MDS. Reduced mtDNA content has also been observed in individuals with neurodegenerative disorders, associated with aging. In this study, we correlated genetic testing results with mtDNA content and characterized the clinical features of each category of mtDNA content result.

Methods:
We reviewed the medical records of individuals who underwent muscle mtDNA content analysis (via droplet digital PCR based assay) in the Division of Genomic Diagnostics at the Children’s Hospital of Philadelphia. For each case, we collected results from mtDNA content analysis and genetic testing. The genetic diagnoses were evaluated based on genotype-phenotype correlation. The mtDNA content results were calculated by comparing with age- and tissue- matched controls. MtDNA values between -1 and +1 standard deviation (SD) from the mean were considered as normal. Values < -2 SD were classified as depleted, and values between -1 and -2 SD as reduced. Similarly, values between +1 and +2 SD were classified as increased, and values > +2 SD as proliferated. Genetic diagnostic yield was assessed for each category based on mtDNA sequencing, exome sequencing (ES), and/or genome sequencing (GS).

Results:
A total of 90 muscle samples underwent mtDNA content analysis. Patient ages (at sample collection) ranged from 10 months to 71 years, with 11 (12.2%) under 3 years and 79 (87.8%) older than 3 years, which are the two age groups for mtDNA content evaluation. The distribution of mtDNA content results was as follows: depleted (8.9%, 8/90), reduced (18.9%, 17/90), proliferated (13.3%, 12/90), increased (16.7%, 15/90), and normal (42.2%, 38/90). Among the 27 individuals with mtDNA content in depleted or reduced categories, 5 (out of 27) had diagnostic or likely diagnostic WS or GS results, and two individuals also had multiple large-scale mtDNA deletions (>15% heteroplasmy).

 

The percentage of individuals with diagnostic ES or GS in each category is 50% (4/8, depleted), 5.9% (1/17, reduced), 10.5% (4/38, normal), 26.7% (4/15, increased), and 16.7% (2/12, proliferated) respectively. Diagnoses associated with depleted mtDNA content included two cases of autosomal recessive POLG-related MDS, one case of MECR-related neurological disorder. Additionally, one case with confirmed SMC3-related Cornelia de Lange syndrome was also had mtDNA depletion, but this condition is not known for MDS. The reduced mtDNA category included one case with HCCS-related primary mitochondrial disorder.

Conclusion:
Both the depleted and reduced mtDNA content categories contained diagnoses of primary mtDNA disorder, while the depleted mtDNA category having the highest diagnosis yield, although sample size (n=8) was small. Diagnoses in the normal mtDNA content category were generally unrelated to primary mtDNA disorders. MtDNA content analysis is a valuable tool for screening MDS and has proven effective in identifying cases for further genetic work-up.

 

Besides the individuals with confirmed genetic diagnoses, a considerable number were found to have variants of uncertain significance (VOUS) in mitochondrial genes or candidate genes. As variant classification may evolve over time, further review of these data is warranted and may enhance our standing of these conditions.

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