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Impact of Measuring Mitochondrial DNA Heteroplasmy Rates Using Different Tissues in 103 Patients with Mitochondrial Disease

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction:
Whether different heteroplasmy distribution patterns are observed in different tissues in patients with mitochondrial diseases has not been fully elucidated.

Methods:
In 103 mitochondrial disease patients with frequent pathogenic mitochondrial DNA (mtDNA) variants or mtDNA single large deletions, we measured heteroplasmy rates of mtDNA variants or deletions using droplet digital PCR (ddPCR) system in different tissues. We used customized primers and probes of each variant and the wild type used in ddPCR. For the mtDNA single large deletions, we customized the primers and probes, one at a common region shared by all patients with mtDNA deletions (MT: 12572-12671) and the other at a region where none of the patients had a deletion (MT: 1827-1934).

 

Results:
Among 103 patients, 75 patients had m.3243A>G variant in MT-TL1 gene, followed by 8 patients with m.8993T>G in MT-ATP6 gene, 7 patients with deletions, 7 patients with m.13513G>A in MT-ND5 gene and 6 patients with m.14453G>A in MT-ND6 gene. The distribution of m.3243A>G heteroplasmy rates in blood ranged from 4% to 91% and those in urine ranged from 35% to 98%. In patients with m.3243A>G where both urine and blood were available, higher heteroplasmy rates were observed in urine. Different heteroplasmy distribution patterns were also observed for other variants or deletions. In patients with mitochondrial cardiomyopathy and mitochondrial nephropathy, high heteroplasmy rates of more than 70% were observed in heart and kidney, respectively.

Conclusion:
In 103 mitochondrial disease patients with pathogenic mtDNA variants or deletions, different heteroplasmy distribution patterns were observed in different tissues. Higher heteroplasmy rates were identified in urine compared to blood in patients with m.3243A>G, suggesting the clinical utility of using urine for heteroplasmy measurements. High heteroplasmy rates were observed in affected tissues. The association between high heteroplasmy rates in affected tissues, including at the single cell level, and clinical outcome should be evaluated in further studies.

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