The Australian Genomics Health Alliance Mitochondrial Flagship: Searching for what Lies Beneath

Abstract

Background: With the advent of genomic technologies, the diagnostic landscape for mitochondrial respiratory chain disorders (RCD), notorious for their complexity, has changed dramatically. The Australian Genomics Health Alliance aims to bring genomic technologies to the clinic, and has established a Mitochondrial Disease Flagship. This focused national network has brought together clinicians, diagnostic and research scientists with specific interest and expertise in RCD to examine the clinical utility of genomic sequencing for the efficient diagnosis of RCD. Research Question: The challenge is how to tackle the cases that remain without a diagnosis, some of which have variants of uncertain significance in known disease genes (VUS), and others which have variants in genes of uncertain significance (GUS). Methods: We are using 'multi-omic' approaches to solve these difficult cases, including enzyme analyses, western blotting, quantitative proteomics, Blue-Native PAGE and RNA analyses. Results: Of the 135 pediatric and adult individuals recruited, based on modified Nijmegen criteria, we currently have a diagnostic yield of ∼37% in known disease genes, mostly known RCD genes, but around a quarter in non-RCD known disease genes. Examples of solved cases will be described, including individuals with novel variants in known genes such as MT-ATP6, MRPS34, PNPT1, ACAD9, COX15 and the ATAD3 gene locus. In addition, we are studying several novel candidate disease genes. Conclusions: Through the Mitochondrial Disease Flagship, we have demonstrated the power of a national networked approach, including functional approaches, to maximize the diagnostic yield for this complex group of disorders.L6351863662021-06-10 <br />