The Australian Genomics Mitochondrial Flagship: A National Program Delivering Mitochondrial Diagnoses
- Author(s)
- Rius, R; Compton, AG; Baker, NL; Balasubramaniam, S; Best, S; Bhattacharya, K; Boggs, K; Boughtwood, T; Braithwaite, J; Bratkovic, D; Bray, A; Brion, MJ; Burke, J; Casauria, S; Chong, B; Coman, D; Cowie, S; Cowley, M; de Silva, MG; Delatycki, MB; Edwards, S; Ellaway, C; Fahey, MC; Finlay, K; Fletcher, J; Frajman, LE; Frazier, AE; Gayevskiy, V; Ghaoui, R; Goel, H; Goranitis, I; Haas, M; Hock, DH; Howting, D; Jackson, MR; Kava, MP; Kemp, M; King-Smith, S; Lake, NJ; Lamont, PJ; Lee, J; Long, JC; MacShane, M; Madelli, EO; Martin, EM; Marum, JE; Mattiske, T; McGill, J; Metke, A; Murray, S; Panetta, J; Phillips, LK; Quinn, MCJ; Ryan, MT; Schenscher, S; Simons, C; Smith, N; Stroud, DA; Tchan, MC; Tom, M; Wallis, M; Ware, TL; Welch, AE; Wools, C; Wu, Y; Christodoulou, J; Thorburn, DR;
- Journal Title
- Genetics in Medicine
- Publication Type
- Online publication before print
- Abstract
- 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.
- Keywords
- Genomics; Mitochondrial Disease; diagnosis; proteomics
- Department(s)
- Health Services Research; Pathology
- Publisher's Version
- https://doi.org/10.1016/j.gim.2024.101271
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-10-01 07:30:52
Last Modified: 2024-10-01 07:37:32