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Advances in Multi-omics Diagnostics Studies of Mitochondrial Diseases in Japan

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction:
Mitochondrial disorders have the highest incidence among inborn errors of metabolism and are characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000~7,500 births, and has phenotypic and genetic heterogeneity. Mutations in mtDNA and about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial disorder. Over 450 genes that lead to mitochondrial disorder have been reported to date. Exact genetic diagnosis for patients, however, still remains largely unimplemented. We performed over 900 targeted and 700 WES and  300 WGS for patients with childhood-onset mitochondrial disorders. We have so far identified and reported mitochondria-related genes (MRPS23, QRSL1, SLC25A26, C1QBP, IARS, ATAD3 del, COQ4, GTPBP3, ECHS1, TOP3A, PTCD3, NDUFA8, ATAD3 dup, etc) as novel causative genes.

 We targeted those undiagnosed cases of our cohort and tried to apply multi-omics strategy in the aim for identifying the causative genes

 

Methods:
Of the 3,400 patients cohort of mitochondrial diseases, we applied multi-omics approach such as WGS, RNA seq and Proteome, and used bioinformatics tools such as OUTRIDER, FRASER, and SAVNET for the analyses.

 

Results:
By using the multi-omics approach combined with bioinformatics analyses, we identified 2 novel genes (MICOS10 and NDUFA3) linked to the mitochondrial disease for the first time.

We also found that one undiagnosed case of mitochondrial encephalopathy was caused by the repeat expansion of GGGCC in the promoter region of NAXE. This is the first report that the repeat expansion can cause mitochondrial disease.

 

Conclusion:
By systemic multi-omics approach, we identified two novel genes (MICOS10 and NDUFA3) linked to the mitochondrial disease for the first time. We also identified the first case of repeat expansion in mitochondrial disease that is caused by GGGCC expansion in the promoter region of NAXE. Our results further strengthen the importance of multi-omics approach in identifying the causative genes for undiagnostic cases. Newly identified genes could add value to the clinical genetic diagnosis and also for the development of cure for mitochondrial diseases.

 

Agenda

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