The Australian Genomic Health Alliance (AGHA) Mitochondrial Flagship:delivering mitochondrial disease diagnoses nationally

Abstract

Background: The application of multi-omic technologies has transformed the diagnosis of mitochondrial respiratory chain disorders (RCD). The AGHA Mitochondrial Flagship was a nationally funded research project examining the clinical utility of genomic sequencing for the effective diagnosis of RCD. Materials and Methods: 140 paediatric-or adult-onset disease individuals were recruited and randomised to have either genome sequencing (GS) or exome sequencing (ES) and subsequent mtDNA genomic sequencing (mtDNASeq) as needed. Transcriptomic, proteomic and/or cell-based functional studies were undertaken to functionally validate variants as needed. Results: A genetic diagnosis was obtained in 77 (55%) of individuals in 77 different genes. The aetiology was nuclear in origin in 77% of cases, with the diagnostic rate being 71% in paediatric onset cases and 31% in adult-onset cases. The diagnostic yield from GS was not significantly different to ES/ mtDNASeq. Twenty-two individuals (29%) had diagnoses in nonmitochondrial disease genes (so-called phenocopies). A health economic analysis in paediatric-onset cases showed that genomic sequencing was less costly than the “traditional” diagnostic approach (saving $2000-$9000AUD per diagnosis), with an 11-14% higher diagnostic yield. Based on the estimated incidence of childhood-onset RCD, implementation of genomic sequencing early in the diagnostic odyssey could translate to an annual cost saving of up to $700,000AUD. Conclusion: We show that a national networked approach with consistent selection of individuals for testing, and with subsequent implementation of “multi-omic” technologies, is a powerful method for efficiently delivering genetic diagnoses for this complex group of disorders, preventing the need for invasive testing for many.