The Australian Genomic Health Alliance Mitochondrial Flagship-A national approach to genomic diagnostics

Abstract

Introduction: The Australian Genomics Health Alliance is a nationally funded health services research project focused on bringing genomic technologies to the clinic. The Mitochondrial Disease (MD) Flagship brings together expert clinicians from around Australia, specialist diagnostic laboratories and researchers expert in functional characterization of MD to examine the clinical utility of genomic sequencing for efficient diagnosis of MD. Methods: We recruited 134 paediatric and adult individuals with a probable or definite MD diagnosis, based on modified Nijmegen criteria. Their blood DNA was randomized to either whole genome sequencing or whole exome plus mitochondrial DNA sequencing. Results: Our definitive diagnostic yield is currently ~36% for both whole genome and whole exome/mitochondrial DNA approaches, with most diagnosed cases having a primary defect in the nuclear genome. Not surprisingly, 14% of individuals with confirmed molecular diagnoses had mutations in non-MD genes, reflecting phenotypic overlap. Unsolved patients have been triaged to one or more targeted functional tests, quantitative proteomics, RNAseq or long-read genome sequencing. This enabled re-categorising of numerous class 3 variants and identification of novel disease genes and mechanisms, including a de novo duplication within the ATAD3 locus resulting in a presumably toxic fusion protein (see Frazier et al. abstract). Conclusions: Our collaborative effort has demonstrated that using a consistent national approach for clinically triaging cases for genomic sequencing is both effective and efficient, usually obviates the need for invasive biopsies and in some cases enables targeted therapies.L6340692602021-02-08 <br />