Decipher Mitochondrial Disorders using Exome Sequencing. R. Kopajtich1,2, T. Haack1,2, L. Kremer1,2, C. Biagosch1,2, B. Haberberger1,2, T. Wieland1,2, T. Schwarzmayr1,2, P. Freisinger3, T. Klopstock4, J. Mayr5, W. Sperl5, M. Minczuk6, T. M. Strom1,2, T. Meitinger1,2, H. Prokisch1,2 1) Institute of Human Genetics, Helmholtz Zentrum München, Munich / Neuherberg, Germany; 2) Institute of Human Genetics, Technische Universität München, Munich, Germany; 3) Department of Pediatrics, Community Hospital Reutlingen, Germany; 4) Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germany; 5) Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria; 6) MRC Mitochondrial Biology Unit, Cambridge, United Kingdom.

   Mitochondrial disorders are a genetically and clinically highly heterogeneous group of diseases characterized by defective oxidative phosphorylation. Despite good progress in the field, most disease causing mutations still have to be identified. During the course of three years, we applied whole exome sequencing to investigate more than 400 unrelated individuals with a suspected mitochondrial disorder and provided molecular diagnoses to 200 patients with mutations affecting almost 100 distinct genes. In a quarter of patients, we identified mutations in known disease genes. In another quarter of patients, we identified mutations in genes previously not associated with mitochondrial disorders. Mutations in the majority of genes are rare and could be identified due to loss-of-function alleles in evolutionary conserved genes such as MGME1, an exonuclease involved in mitochondrial replication. Mutations in other genes are more frequent, with ACAD9 being the most common finding with more than 15 cases, providing statistical evidence for the association with isolated respiratory chain complex I deficiency. Diagnostic challenges are patients with recessive mutations in more than one gene resulting in a compound clinical phenotype. Evolving topics are tRNA modifying enzymes (ELAC2, MTO1 and GTPBP3) and tRNA synthetases, both involved in the translation of mitochondrial proteins as well as cofactor metabolism defects. For more than 30 patients (out of 200), the molecular diagnosis offered rational therapeutic options. In summary, the genetically heterogeneous group of mitochondrial disorders is an example par excellence for the application of genome wide sequencing which is underway to be implemented at an early stage in the routine diagnostic work-up of pediatric patients suffering from genetically unclear metabolic conditions.

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