The Australian Genomics Mitochondrial Flagship: A National Program Delivering Mitochondrial Diagnoses

Abstract

Purpose. Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. Through a national team of clinicians, diagnostic, and research scientists, the Australian Genomics Mitochondrial disease flagship conducted a prospective study to identify the diagnostic utility of singleton genomic sequencing using blood samples as a first step to diagnose MD. Methods. 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomised to either exome + mtDNA sequencing (ES+mtDNAseq) or genome sequencing (GS). Results. Diagnostic yield was 55% (n=77) with variants in nuclear (n=37) and mtDNA (n=18) MD genes, as well as phenocopy genes (n=22). A nuclear gene aetiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rate was higher in paediatric-onset (71%) than adult-onset (31%) cases. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, three adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially detected in blood. Conclusion. Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.