The Australian Genomics Mitochondrial Flagship: A National Program Delivering Mitochondrial Diagnoses
Author:
Rius RocioORCID, Compton Alison G.ORCID, Baker Naomi L., Balasubramaniam ShantiORCID, Best StephanieORCID, Bhattacharya Kaustuv, Boggs Kirsten, Boughtwood TiffanyORCID, Braithwaite JeffreyORCID, Bratkovic DragoORCID, Bray Alessandra, Brion Marie-Jo, Burke Jo, Casauria Sarah, Chong BelindaORCID, Coman DavidORCID, Cowie Shannon, Cowley MarkORCID, de Silva Michelle G.ORCID, Delatycki Martin B., Edwards Samantha, Ellaway Carolyn, Fahey Michael C.ORCID, Finlay Keri, Fletcher Janice, Frajman Leah E., Frazier Ann E.ORCID, Gayevskiy Velimir, Ghaoui Roula, Goel Himanshu, Goranitis Ilias, Haas MatildaORCID, Hock Daniella H.ORCID, Howting Denise, Jackson Matilda R.ORCID, Kava Maina P., Kemp Madonna, King-Smith Sarah, Lake Nicole J.ORCID, Lamont Phillipa J., Lee Joy, Long Janet C.ORCID, MacShane Mandi, Madelli Evanthia O., Martin Ellenore M., Marum Justine E., Mattiske Tessa, McGill Jim, Metke Alejandro, Murray Sean, Panetta Julie, Phillips Liza K.ORCID, Quinn Michael C.J., Ryan Michael T., Schenscher Sarah, Simons Cas, Smith Nicholas, Stroud David A.ORCID, Tchan Michel C., Tom Melanie, Wallis MathewORCID, Ware Tyson L., Welch AnneMarie E., Wools Christine, Wu You, Christodoulou JohnORCID, Thorburn David R.ORCID
Abstract
AbstractPurposeFamilies 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.Methods140 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).ResultsDiagnostic 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.ConclusionGenomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.
Publisher
Cold Spring Harbor Laboratory
|
|