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Improved detection of mitochondrial DNA instability in mitochondrial genome maintenance disorders.

Authors :
Bris C
Goudenège D
Desquiret-Dumas V
Gueguen N
Bannwarth S
Gaignard P
Rucheton B
Trimouille A
Allouche S
Rouzier C
Saadi S
Jardel C
Slama A
Barth M
Verny C
Spinazzi M
Cassereau J
Colin E
Armelle M
Pereon Y
Martin-Negrier ML
Paquis-Flucklinger V
Letournel F
Lenaers G
Bonneau D
Reynier P
Amati-Bonneau P
Procaccio V
Source :
Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2021 Sep; Vol. 23 (9), pp. 1769-1778. Date of Electronic Publication: 2021 May 26.
Publication Year :
2021

Abstract

Purpose: Diseases caused by defects in mitochondrial DNA (mtDNA) maintenance machinery, leading to mtDNA deletions, form a specific group of disorders. However, mtDNA deletions also appear during aging, interfering with those resulting from mitochondrial disorders.<br />Methods: Here, using next-generation sequencing (NGS) data processed by eKLIPse and data mining, we established criteria distinguishing age-related mtDNA rearrangements from those due to mtDNA maintenance defects. MtDNA deletion profiles from muscle and urine patient samples carrying pathogenic variants in nuclear genes involved in mtDNA maintenance (n = 40) were compared with age-matched controls (n = 90). Seventeen additional patient samples were used to validate the data mining model.<br />Results: Overall, deletion number, heteroplasmy level, deletion locations, and the presence of repeats at deletion breakpoints were significantly different between patients and controls, especially in muscle samples. The deletion number was significantly relevant in adults, while breakpoint repeat lengths surrounding deletions were discriminant in young subjects.<br />Conclusion: Altogether, eKLIPse analysis is a powerful tool for measuring the accumulation of mtDNA deletions between patients of different ages, as well as in prioritizing novel variants in genes involved in mtDNA stability.<br /> (© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.)

Details

Language :
English
ISSN :
1530-0366
Volume :
23
Issue :
9
Database :
MEDLINE
Journal :
Genetics in medicine : official journal of the American College of Medical Genetics
Publication Type :
Academic Journal
Accession number :
34040194
Full Text :
https://doi.org/10.1038/s41436-021-01206-w