Application of multi-omic approaches to identify the genetic bases of disorders of mitochondrial oxidative phosphorylation.

Summary A combination of state-of-the-art technologies will be employed to identify candidate disease genes, including where appropriate whole genome sequencing, transcriptomic and quantitative proteomic studies, followed by a range of cell and/or tissue-based functional studies to validate their pathogenic significance. This combination of approaches will allow us to reach a definitive diagnosis for a significant proportion of patients who are currently missed by initial genomic sequencing approaches.

Project Details

Although individually rare, as a group, the disorders of mitochondrial oxidative phosphorylation (OXPHOS) are the most common inherited metabolic disorders, with more than 300 distinct monogenic disorders now identified.  Whilst genomic sequencing technologies have greatly improved the genetic diagnosis of this complex group of disorders, many cases remain unsolved, as exemplified by the Australian Genomics Health Alliance Mitochondrial Flagship patient cohort.  In this group of patients, analysis of known mitochondrial disease genes has resulted in a diagnostic yield of ~ 45% so far.  For some of those unsolved cases, candidate disease genes have been identified that need to be functionally validated, whereas in other cases genomic sequencing has failed to identify plausible targets.      These unsolved cases will be tackled in this project.  A combination of state-of-the-art technologies will be employed to identify candidate disease genes, including where appropriate whole genome sequencing, transcriptomic and quantitative proteomic studies, followed by a range of cell and/or tissue-based functional studies to validate their pathogenic significance.    This combination of approaches will allow us to reach a definitive diagnosis for a significant proportion of patients who are currently missed by initial genomic sequencing approaches. For some, this may point to a targeted therapy and for all will restore reproductive confidence in their parents.