Solving Rare Diseases Via The Australian Genomics Mitochondrial Disease Flagship

Project Details

A "rare disease" affects fewer than 1/2000 people but there are over 7000 rare diseases that collectively affect 5% to 10% of the population, many of whom suffer life-threatening diseases or lifelong chronic disease. Rare diseases are thus a major public health problem and affected families have often faced a long diagnostic odyssey in attempting to achieve a diagnosis. Australian Genomics is a collaboration of over 40 Australian centres seeking to translate new genomic technologies into improved outcomes for rare diseases and cancer. Mitochondrial (mito) diseases are one of the first flagship projects. They are the most common group of inherited metabolic disorders and highly complex since they comprise almost 300 different genetic disorders with a wide range of clinical phenotypes and types of inheritance.

In previous studies we have used whole exome sequencing or whole genome sequencing to achieve diagnostic yields of over 60% in retrospective cohorts, identifying over a dozen novel disease genes. This project will focus on a prospective national cohort of paediatric patients who fit entry criteria for having probable mitochondrial disease. Recruitment commenced in early 2017, with half the cohort having whole genome and half whole exome sequencing over a 2-year period. Some patients will have sequence variants identified that have been previously shown to cause disease, which are straightforward to classify. Others will have novel sequence variants identified in known disease genes or in candidate disease genes not previously linked to disease. The project will use a range of bioinformatic, molecular, biochemical, immunochemical and cell biology approaches to investigate causality of novel variants. This will contribute to obtaining definitive diagnoses in previously unsolvable cases, understanding pathogenic mechanisms of disease and developing methods that can be applied to understanding the genetics of a wide range of other rare diseases.