The Australian Genomics Mitochondrial Flagship: A national program delivering mitochondrial diagnoses

Area of Science:

• Genomics and Bioinformatics
• Rare Diseases
• Clinical Diagnostics

Background:

• Mitochondrial diseases (MD) present diagnostic challenges, often involving lengthy and invasive procedures.
• Many patients with suspected MD remain undiagnosed, highlighting the need for improved diagnostic strategies.
• The Australian Genomics Mitochondrial Flagship aimed to enhance diagnostic yield in MD.

Purpose of the Study:

• To evaluate the diagnostic utility of singleton genomic sequencing in individuals with suspected mitochondrial diseases.
• To compare exome + mitochondrial DNA (mtDNA) sequencing with whole genome sequencing for MD diagnosis.
• To assess the impact of patient characteristics, such as onset age and ancestry, on diagnostic yield.

Main Methods:

• 140 children and adults with suspected MD were recruited based on modified Nijmegen criteria (MNC).
• Participants were randomized to either exome + mtDNA sequencing or whole genome sequencing.
• Analysis included variants in nuclear and mtDNA genes, as well as phenocopy genes.

Main Results:

• A diagnostic yield of 55% was achieved, identifying variants in nuclear MD genes (37), mtDNA genes (18), and phenocopy genes (22).
• Nuclear gene etiology was found in 77% of diagnoses, with higher rates in pediatric-onset (71%) versus adult-onset (31%) cases.
• Higher MNC scores correlated with increased diagnostic yield in children; 3 adult cases identified mtDNA deletions in muscle tissue not found in blood.

Conclusions:

• Singleton genomic sequencing from blood offers a streamlined diagnostic pathway for suspected mitochondrial diseases.
• The method is especially beneficial for individuals with childhood-onset MD and high MNC scores.
• Genomic sequencing significantly improves diagnostic rates compared to traditional methods.