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PURPOSE: Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples. METHODS: 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized 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 etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases, and comparable in children with non-European (78%) versus European (67%) ancestry. 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 identified 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.
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Background: Newborn bloodspot screening (NBS) programs have improved neonatal healthcare since the 1960s. Genomic sequencing now offers potential to generate polygenic risk score (PRS) that could be incorporated into NBS programs, shifting the focus from treatment to prevention of future noncommunicable disease (NCD). However, Australian parents' knowledge and attitudes regarding PRS for NBS is currently unknown. Methods: Parents with at least one Australian-born child under 18 years were invited via social media platforms to complete an online questionnaire aimed at examining parents' knowledge of NCDs, PRS, and precision medicine, their opinions on receiving PRS for their child, and considerations of early-intervention strategies to prevent the onset of disease. Results: Of 126 participants, 90.5% had heard the term "non-communicable disease or chronic condition," but only 31.8% and 34.4% were aware of the terms "polygenic risk score" and "precision medicine" respectively. A large proportion of participants said they would consider screening their newborn to receive a PRS for allergies (77.9%), asthma (81.0%), cancer (64.8%), cardiovascular disease (65.7%), mental illness (56.7%), obesity (49.5%), and type 2 diabetes (66.7%). Additionally, participants would primarily consider diet and exercise as interventions for specific NCDs. Discussion: The results from this study will inform future policy for genomic NBS, including expected rate of uptake and interventions that parents would consider employing to prevent the onset of disease.