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An inherited mtDNA rearrangement, mimicking a single large-scale deletion, associated with MIDD and a primary
Piervito Lopriore1, Andrea Legati2, Christiane Michaela Neuhofer3
1Neurological Institute, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; Scuola Superiore Sant'Anna Ph.D. School in Translational Medicine, Pisa, Italy.
Insights
Mitochondrial DNA (mtDNA) duplications, not just deletions, can cause inherited heart disease and hearing loss. Long-read sequencing is key to detecting these complex mtDNA rearrangements in familial cases.
Area of Science:
- Genetics
- Molecular Biology
- Cardiology
Background:
- Familial cases of dilated cardiomyopathy, diabetes mellitus, and sensorineural hearing loss often remain genetically unsolved.
- Mitochondrial DNA (mtDNA) disorders are typically associated with single deletions or point mutations.
Purpose of the Study:
- To identify the genetic basis of a rare inherited disorder affecting multiple family members.
- To investigate the role of mitochondrial DNA (mtDNA) rearrangements in complex inherited diseases.
Main Methods:
- Utilized whole exome sequencing (WES) for initial genetic analysis.
- Employed long-read next-generation sequencing (NGS) to detect structural alterations in mtDNA.
- Confirmed findings using long-range PCR.
Main Results:
- Identified a novel, heteroplasmic 12 kb mtDNA deletion in affected individuals.
- Discovered maternally inherited mtDNA duplications, comprising wild-type and deleted mtDNA molecules, in all tested family members.
- Demonstrated that these mtDNA rearrangements were the underlying cause of the observed phenotype.
Conclusions:
- Maternally inherited mtDNA duplications can cause syndromic mitochondrial disease.
- Large mtDNA rearrangements should be considered in the genetic diagnosis of familial mitochondrial disorders with atypical presentations.
- Long-read NGS is a valuable tool for detecting complex mtDNA structural variants like duplications.
Aim:
To identify the genetic cause in a previously unsolved pedigree, with mother and two daughters suffering of dilated cardiomyopathy with prevailing arrhythmic burden associated with diabetes mellitus and sensorineural hearing loss, without clear evidence of progressive external ophthalmoplegia.
Methods:
Several genetic tests were performed over the years including single-gene sequencing, mitochondrial DNA (mtDNA) sequencing, NGS panel for mitochondrial diseases and cardiomyopathies, clinical exome sequencing and whole exome sequencing. Specific amplifications and long-read NGS were used to evaluate mtDNA structural alterations.
Results:
By means of whole exome sequencing we found a novel heteroplasmic 12 kb-long single deletion in the mtDNA in all affected family members, confirmed by long-range PCR. However, a deeper investigation by long-read NGS revealed indeed the presence of rearranged mtDNA species, formed by a wild-type plus a deleted molecule. This mtDNA duplication turned out to be inherited in our pedigree and present in all tested specimens.
Conclusion:
While mtDNA single large-scale deletions are generally considered sporadic, few old reports described maternally inherited mtDNA duplication We suggest that mtDNA large rearrangements should be considered as possible disease causes in familial cases with unusual mitochondrial phenotypes. Long-read sequencing is useful for the detection of these variants, particularly mtDNA duplications.
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