Mitochondrial dysfunction induced by variation in the non-coding genome - A proposed workflow to improve diagnostics

Mitochondrial disorders are one of the most common inherited metabolic disorders and are caused by variants in nuclear genes or the mitochondrial genome. Additionally, there is a large group of patients displaying clinical symptoms, where the genetic background is unknown. Mitochondrial disorders have a huge variety in their clinical presentation, making diagnostics challenging. Genomes of higher organisms contain around 95% non-protein-coding DNA. Recently, non-protein-coding sequences have been shown to affect gene expression in many cellular processes, including mitochondrial functioning. As these insights are not frequently incorporated in diagnostics we propose a workflow utilizing this knowledge for faster diagnostics of patients lacking a molecular diagnosis.