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

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

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;
Details: Publication Year 2025-01,Volume 27,Issue #1,Page 101271
Journal Title: Genetics in Medicine
Publication Type: Research article
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: A total of 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mitochondrial DNA (mtDNA) sequencing or genome sequencing. 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%) vs European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, 3 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.
Publisher: Elsevier
Keywords: Humans; *Mitochondrial Diseases/genetics/diagnosis; Child; Male; Australia; Female; *DNA, Mitochondrial/genetics; Adult; *Genomics/methods; Adolescent; Child, Preschool; Middle Aged; Prospective Studies; Young Adult; Genetic Testing/methods; Mitochondria/genetics; Infant; Genome, Mitochondrial/genetics; Exome/genetics; Diagnosis; Diagnostic Yield; Genomics; Mitochondrial Disease; 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: 2024-11-07 06:54:37

Last Modified: 2025-01-21 06:46:01