Emine Begüm GENCER ÖNCÜL, Duygu DUMAN, Süleyman AKTUNA, Mustafa Türker DUMAN, Fatma Tuba EMİNOĞLU

Whole Mitochondrial Genome Analysis in Turkish Patients with Mitochondrial Diseases

Background: Mitochondrial diseases are a clinically heterogeneous group of rare hereditary disorders that are defined by a genetic defect predominantly affecting mitochondrial oxidative phosphorylation. Mitochondrial diseases are caused by mutations of genes encoded by either nuclear DNA or mitochondrial DNA. Hundreds of different mitochondrial DNA point mutations and large-scale mitochondrial DNA rearrangements have been shown to cause mitochondrial diseases including Kearns–Sayre syndrome, Leber’s hereditary optic neuropathy, Leigh syndrome, myoclonic epilepsy with ragged-red fibers, mitochondrial encephalopathy lactic acidosis stroke. Aims: To investigate new variants that could be associated with mitochondrial diseases and to determine the effect of mitochondrial DNA mutations on the clinical spectrum. Study Design: Cross-sectional study. Methods: We screened whole mitochondrial DNA genome using next-generation sequencing in 16 patients who are considered to have mitochondrial disease. CentoGene and Mikrogen Genetic Diseases Diagnostic Center’s database were used to investigate sequence variants. Detected variants were evaluated in bioinformatic databases to determine pathogenicity and were classified as class 1 (pathogenic), class 2 (likely pathogenic), and class 3 (variant of uncertain significance) according to CentoGene-ACMG database. Results: As a result of the study, 2 patients were diagnosed with Leigh syndrome as previously reported class 1 mutations in MT-ATP6 and MT-ND5 genes. Four variants were identified for the first time in literature and 2 variants, previously reported but with uncertain pathogenic effect, are thought to be associated with mitochondrial disease. Conclusion: Mitochondrial DNA screening should be among the primary clinical tests in patients with suspected mitochondrial disease to rule out DNA-associated mutations.

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1. Anderson S, Bankier AT, Barrell BG, et al. Sequence and organization of the human mitochondrial genome. Nature.1981;290:457-465. [CrossRef]
2. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17:689-701. [CrossRef]
3. Gorman GS, Chinnery PF, DiMauro S, et al. Mitochondrial diseases. Nat Rev Dis Primers. 2016;2:16080. [CrossRef]
4. El-Hattab AW, Scaglia F. Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics. 2013;10(2):186-198. [CrossRef]
5. Alston CL, Rocha MC, Lax NZ, Turnbull DM, Taylor RW. The genetics and pathology of mitochondrial disease. J Pathol. 2017;241:236-250. [CrossRef]
6. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-424. [CrossRef]
7. Coelho MP, Martins E, Vilarinho L. Diagnosis, management, and follow-up of mitochondrial disorders in childhood: a personalized medicine in the new era of genome sequence. Eur J Pediatr. 2019;178:21-32. [CrossRef]
8. Barker. Phenol-chloroform isoamyl alcohol (PCI) DNA extraction. Tampa, Florida: University of South Florida; 1998. Available at: http: //cco on.my web.u sf.ed u/eco immun ology .org/ PCI_e xtrac tion_ files /PCI extraction.pdf. [CrossRef]
9. Pütz J, Dupuis B, Sissler M, Florentz C. Mamit-tRNA, a database of mammalian mitochondrial tRNA primary and secondary structures. Rna. 2007;13:1184-1190. [CrossRef]
10. Yarham JW, Al-Dosary M, Blakely EL, et al. A comparative analysis approach to determining the pathogenicity of mitochondrial tRNA mutations. Hum Mutat. 2011;32:1319-1325. [CrossRef]
11. Sonney S, Leipzig J, Lott MT, et al. Predicting the pathogenicity of novel variants in mitochondrial tRNA with MitoTIP. PLoS Comput Biol. 2017;13:e1005867. [CrossRef]
12. Parikh S, Karaa A, Goldstein A, et al. Diagnosis of ‘possible’ mitochondrial disease: an existential crisis. J Med Genet. 2019;56:123-130. [CrossRef]
13. Bannwarth S, Procaccio V, Lebre AS, et al. Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders. J Med Genet. 2013;50:704-714. [CrossRef]
14. Buermans HPJ, den Dunnen JT. Next generation sequencing technology: advances and applications. Biochim Biophys Acta. 2014;1842:1932-1941. [CrossRef]
15. Duan M, Tu J, Lu Z. Recent advances in detecting mitochondrial DNA heteroplasmic variations. Molecules. 2018;23:1-18. [CrossRef]
16. Ganetzky RD, Stendel C, Mccormick EM, et al. MT-ATP6 mitochondrial disease variants: phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases. Hum Mutat. 2020;40:499-515. [CrossRef]
17. Jackson CB, Hahn D, Schröter B, et al. A novel mitochondrial ATP6 frameshift mutation causing isolated complex V deficiency, ataxia and encephalomyopathy. Eur J Med Genet. 2017;60:345-351. [CrossRef]
18. Brautbar A, Wang J, Abdenur JE, et al. The mitochondrial 13513G>A mutation is associated with Leigh disease phenotypes independent of complex I deficiency in muscle. Mol Genet Metab. 2008;94:485-490. [CrossRef]
19. Danhelovska T, Kolarova H, Zeman J, et al. Multisystem mitochondrial diseases due to mutations in mtDNA-encoded subunits of complex I. BMC Pediatr. 2020;20:41. [CrossRef]
20. Dai Y, Wang C, Nie Z, et al. Mutation analysis of Leber’s hereditary optic neuropathy using a multi-gene panel. Biomed Rep. 2018;8:51-58. [CrossRef]
21. Qu J, Zhou X, Zhao F, et al. Low penetrance of Leber’s hereditary optic neuropathy in ten Han Chinese families carrying the ND6 T11484C mutation. Biochim Biophys Acta. 2010;1800:305-312. [CrossRef]
22. Lam CW, Yang T, Tsang MW, Pang CP. Homoplasmic 3316G-->A in the ND1 gene of the mitochondrial genome: a pathogenic mutation or a neutral polymorphism? J Med Genet. 2001;38:E10. [CrossRef]
23. Ji Y, Liang M, Zhang J, et al. Mitochondrial ND1 variants in 1281 Chinese subjects with Leber’s hereditary optic neuropathy. Invest Ophthalmol Vis Sci. 2016;57:2377- 2389. [CrossRef]
24. Opdal SH, Vege A, Egeland T, Musse MA, Rognum TO. Possible role of mtDNA mutations in sudden infant death. Pediatr Neurol. 2002;27:23-29. [CrossRef]
25. Sakuta R, Honzawa S, Murakami N, Goto Y, Nagai T. Atypical MELAS associated with mitochondrial tRNA(Lys) gene A8296G mutation. Pediatr Neurol. 2002;27:397- 400. [CrossRef]
26. Akita Y, Koga Y, Iwanaga R, et al. Fatal hypertrophic cardiomyopathy associated with an A8296G mutation in the mitochondrial tRNA(Lys) gene. Hum Mutat. 2000;15:382. [CrossRef]
27. Arenas J, Campos Y, Bornstein B, et al. A double mutation (A8296G and G8363A) in the mitochondrial DNA tRNA(Lys) gene associated with myoclonus epilepsy with ragged-red fibers. Neurology. 1999;52:377-382. [CrossRef]
28. Bornstein B, Mas JA, Patrono C, et al. Comparative analysis of the pathogenic mechanisms associated with the G8363A and A8296G mutations in the mitochondrial tRNA(Lys) gene. Biochem J. 2005;387:773-778. [CrossRef]
29. Seneca S, Vancampenhout K, Van Coster R, et al. Analysis of the whole mitochondrial genome: translation of the ion torrent personal genome machine system to the diagnostic bench? Eur J Hum Genet. 2015;23:41-48. [CrossRef]
30. Dogulu CF, Kansu T, Seyrantepe V, et al. Mitochondrial DNA analysis in the Turkish Leber’s hereditary optic neuropathy population. Eye. 2001;15:183-188. [CrossRef]
31. Johns DR, Neufeld MJ, Hedges TR. Mitochondrial dna mutations in Cuban optic and peripheral neuropathy. J Neuroophthalmol. 1994;14:135-140. [CrossRef]
32. Naue J, Hörer S, Sänger T, et al. Evidence for frequent and tissue-specific sequence heteroplasmy in human mitochondrial DNA. Mitochondrion. 2015;20:82-94. [CrossRef]
33. Wallace DC, Chalkia D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb Perspect Biol. 2013;5:a021220. [CrossRef]
34. Abaci N, Arıkan M, Tansel T, et al. Mitochondrial mutations in patients with congenital heart defects by next generation sequencing technology. Cardiol Young. 2015;25:705-711. [CrossRef]