Project Lead

Professor David Thorburn

Full bio


MACH Omics

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Lead partner

Murdoch Children’s Research Institute (MCRI)


University of Melbourne, Bio21 Institute, Royal Children’s Hospital (RCH), Victorian Clinical Genetics Services (VCGS)

Other partners: Australian Genomics, Centre for Population Genomics (CPG)

We will generate matched omic datasets (genomics, RNAseq, proteomics) on undiagnosed patients from two well characterised cohorts of patients with rare diseases. This will enable integrated patient-specific analysis across DNA, RNA and protein.

Cohort 1 is drawn from ~400 patients with mitochondrial diseases recruited clinically or via Australian Genomics in which ~100 remain unsolved after genomic sequencing.

Cohort 2 will be drawn from the “RDNow” cohort of ~300 unsolved cases with genomic sequencing, representing a wide range of rare diseases. Approximately 60% will be selected for multi-omic studies based on lack of leads or the likelihood that additional omics will resolve the diagnosis.

Patients will have either cell lines or lymphocyte pellets (PBMC) available for RNAseq and proteomics. We have collected PBMCs from ~40 healthy children aged 3 months to 17 years from the RCH HappiKids project for use as controls.

Data from genomic & RNAseq analysis (via MCRI/VCGS) and proteomic analyses (via Bio21) will be ingested into “PSIkick” to enable multi-omic analyses and visualisation of all three datasets side by side. In partnership with the Centre for Population Genomics, we will develop new approaches for deepening the computational integration of multi-omic data for gene discovery and understanding pathomechanisms.

  • We will demonstrate the feasibility and utility of integrating multiple Omic technologies into a single pipeline suitable for translation into mainstream laboratory diagnostics.
  • Improved diagnostic rates and earlier diagnoses will enable precision care and provision of reproductive options to affected families. This has been a huge challenge for inherited rare disease as more than 6000 different rare diseases are known, each affecting fewer than 1 in 2000 individuals but collectively affecting at least 1 in 20 individuals, corresponding to over 15,000 births per year in Australia. The majority of these patients undergo a lengthy diagnostic odyssey that has significant health and economic implications to both the individuals and society more broadly.
  • Identification of biomarkers and pathomechanisms will guide the use of existing treatments, participation in clinical trials (with small molecule or genetic therapies) and preclinical studies.

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  5. Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., Cummings, B. B., Tukiainen, T., Birnbaum, D. P., Kosmicki, J. A., Duncan, L. E., Estrada, K., Zhao, F., Zou, J., Pierce-Hoffman, E., Berghout, J., Cooper, D. N., Deflaux, N., DePristo, M., Do, R., Flannick, J., Fromer, M., Gauthier, L., Goldstein, J., Gupta, N., Howrigan, D., Kiezun, A., Kurki, M. I., Moonshine, A. L., Natarajan, P., Orozco, L., Peloso, G. M., Poplin, R., Rivas, M. A., Ruano-Rubio, V., Rose, S. A., Ruderfer, D. M., Shakir, K., Stenson, P. D., Stevens, C., Thomas, B. P., Tiao, G., Tusie-Luna, M. T., Weisburd, B., Won, H. H., Yu, D., Altshuler, D. M., Ardissino, D., Boehnke, M., Danesh, J., Donnelly, S., Elosua, R., Florez, J. C., Gabriel, S. B., Getz, G., Glatt, S. J., Hultman, C. M., Kathiresan, S., Laakso, M., McCarroll, S., McCarthy, M. I., McGovern, D., McPherson, R., Neale, B. M., Palotie, A., Purcell, S. M., Saleheen, D., Scharf, J. M., Sklar, P., Sullivan, P. F., Tuomilehto, J., Tsuang, M. T., Watkins, H. C., Wilson, J. G., Daly, M. J., and MacArthur, D. G. (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285-291
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  7. Kang, Y., Stroud, D. A., Baker, M. J., De Souza, D. P., Frazier, A. E., Liem, M., Tull, D., Mathivanan, S., McConville, M. J., Thorburn, D. R., Ryan, M. T., and Stojanovski, D. (2017) Sengers Syndrome-Associated Mitochondrial Acylglycerol Kinase Is a Subunit of the Human TIM22 Protein Import Complex. Molecular Cell 67, 457-470
  8. Lake, N. J., Webb, B. D., Stroud, D. A., Richman, T. R., Ruzzenente, B., Compton, A. G., Mountford, H. S., Pulman, J., Zangarelli, C., Rio, M., Bodaert, N., Assouline, Z., Sherpa, M., Schadt, E. E., Houten, S. M., Byrnes, J., McCormick, E. M., Zolkipli-Cunningham, Z., Haude, K., Zhang, Z., Retterer, K., Bai, R., Calvo, S. E., Mootha, V. K., Christodoulou, J., Rotig, A., Filipovska, A., Cristian, I., Falk, M. J., Metodiev, M. D., and Thorburn, D. R. (2017) Biallelic mutations in MRPS34 lead to instability of the small mitoribosomal subunit and Leigh syndrome. American Journal of Human Genetics 101, 239-254
  9. Desai, R., Frazier, A. E., Durigon, R., Patel, H., Jones, A. W., Dalla Rosa, I., Lake, N. J., Compton, A. G., Mountford, H. S., Tucker, E. J., Mitchell, A. L. R., Jackson, D., Sesay, A., Di Re, M., van den Heuvel, L. P., Burke, D., Francis, D., Lunke, S., McGillivray, G., Mandelstam, S., Mochel, F., Keren, B., Jardel, C., Turner, A. M., Andrews, I. A., Smeitink, J., Spelbrink, J. N., Heales, S. J., Kohda, M., Ohtake, A., Murayama, K., Okazaki, Y., Lombes, A., Holt, I. J., Thorburn, D. R., and Spinazzola, A. (2017) ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. Brain 140, 1595-1610
  10. Forbes, T. A., Howden, S. E., Lawlor, K., Phipson, B., Maksimovic, J., Hale, L., Wilson, S., Quinlan, C., Ho, G., Holman, K., Bennetts, B., Crawford, J., Trnka, P., Oshlack, A., Patel, C., Mallett, A., Simons, C., and Little, M. H. (2018) Patient-iPSC-derived kidney organoids show functional validation of a ciliopathic renal phenotype and reveal underlying pathogenetic mechanisms. American Journal of Human Genetics 102:816-831
  11. Kang, Y., Anderson, A. J., Jackson, T. D., Palmer, C. S., De Souza, D. P., Fujihara, K. M., Stait, T., Frazier, A. E., Clemons, N. J., Tull, D., Thorburn, D. R., McConville, M. J., Ryan, M. T., Stroud, D. A., and Stojanovski, D. (2019) Function of hTim8a in complex IV assembly in neuronal cells provides insight into pathomechanism underlying Mohr-Tranebjaerg syndrome. eLife 8, e48828
  12. Van Bergen, N. J., Guo, Y., Rankin, J., Paczia, N., Becker-Kettern, J., Kremer, L. S., Pyle, A., Conrotte, J. F., Ellaway, C., Procopis, P., Prelog, K., Homfray, T., Baptista, J., Baple, E., Wakeling, M., Massey, S., Kay, D. P., Shukla, A., Girisha, K. M., Lewis, L. E. S., Santra, S., Power, R., Daubeney, P., Montoya, J., Ruiz-Pesini, E., Kovacs-Nagy, R., Pritsch, M., Ahting, U., Thorburn, D. R., Prokisch, H., Taylor, R. W., Christodoulou, J., Linster, C. L., Ellard, S., and Hakonarson, H. (2019) NAD(P)HX dehydratase (NAXD) deficiency: a novel neurodegenerative disorder exacerbated by febrile illnesses. Brain 142, 50-58
  13. Riley, L. G., Cowley, M. J., Gayevskiy, V., Minoche, A. E., Puttick, C., Thorburn, D. R., Rius, R., Compton, A. G., Menezes, M. J., Bhattacharya, K., Coman, D., Ellaway, C., Alexander, I. E., Adams, L., Kava, M., Robinson, J., Sue, C. M., Balasubramaniam, S., and Christodoulou, J. (2020) The diagnostic utility of genome sequencing in a pediatric cohort with suspected mitochondrial disease. Genetics in Medicine 22, 1254-1261
  14. Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., Gauthier, L. D., Brand, H., Solomonson, M., Watts, N. A., Rhodes, D., Singer-Berk, M., England, E. M., Seaby, E. G., Kosmicki, J. A., Walters, R. K., Tashman, K., Farjoun, Y., Banks, E., Poterba, T., Wang, A., Seed, C., Whiffin, N., Chong, J. X., Samocha, K. E., Pierce-Hoffman, E., Zappala, Z., O’Donnell-Luria, A. H., Minikel, E. V., Weisburd, B., Lek, M., Ware, J. S., Vittal, C., Armean, I. M., Bergelson, L., Cibulskis, K., Connolly, K. M., Covarrubias, M., Donnelly, S., Ferriera, S., Gabriel, S., Gentry, J., Gupta, N., Jeandet, T., Kaplan, D., Llanwarne, C., Munshi, R., Novod, S., Petrillo, N., Roazen, D., Ruano-Rubio, V., Saltzman, A., Schleicher, M., Soto, J., Tibbetts, K., Tolonen, C., Wade, G., Talkowski, M. E., Neale, B. M., Daly, M. J., and MacArthur, D. G. (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434-443
  15. Collins, R. L., Brand, H., Karczewski, K. J., Zhao, X., Alföldi, J., Francioli, L. C., Khera, A. V., Lowther, C., Gauthier, L. D., Wang, H., Watts, N. A., Solomonson, M., O’Donnell-Luria, A., Baumann, A., Munshi, R., Walker, M., Whelan, C. W., Huang, Y., Brookings, T., Sharpe, T., Stone, M. R., Valkanas, E., Fu, J., Tiao, G., Laricchia, K. M., Ruano-Rubio, V., Stevens, C., Gupta, N., Cusick, C., Margolin, L., Taylor, K. D., Lin, H. J., Rich, S. S., Post, W. S., Chen, Y. I., Rotter, J. I., Nusbaum, C., Philippakis, A., Lander, E., Gabriel, S., Neale, B. M., Kathiresan, S., Daly, M. J., Banks, E., MacArthur, D. G., and Talkowski, M. E. (2020) A structural variation reference for medical and population genetics. Nature 581, 444-451
  16. Lunke, S., Eggers, S., Wilson, M., Patel, C., Barnett, C. P., Pinner, J., Sandaradura, S. A., Buckley, M. F., Krzesinski, E. I., de Silva, M. G., Brett, G. R., Boggs, K., Mowat, D., Kirk, E. P., Adès, L. C., Akesson, L. S., Amor, D. J., Ayres, S., Baxendale, A., Borrie, S., Bray, A., Brown, N. J., Chan, C. Y., Chong, B., Cliffe, C., Delatycki, M. B., Edwards, M., Elakis, G., Fahey, M. C., Fennell, A., Fowles, L., Gallacher, L., Higgins, M., Howell, K. B., Hunt, L., Hunter, M. F., Jones, K. J., King, S., Kumble, S., Lang, S., Le Moing, M., Ma, A., Phelan, D., Quinn, M. C. J., Richards, A., Richmond, C. M., Riseley, J., Rodgers, J., Sachdev, R., Sadedin, S., Schlapbach, L. J., Smith, J., Springer, A., Tan, N. B., Tan, T. Y., Temple, S. L., Theda, C., Vasudevan, A., White, S. M., Yeung, A., Zhu, Y., Martyn, M., Best, S., Roscioli, T., Christodoulou, J., and Stark, Z. (2020) Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System. JAMA 323, 2503-2511
  17. Vanderver, A., Bernard, G., Helman, G., Sherbini, O., Boeck, R., Cohn, J., Collins, A., Demarest, S., Dobbins, K., Emrick, L., Fraser, J. L., Masser-Frye, D., Hayward, J., Karmarkar, S., Keller, S., Mirrop, S., Mitchell, W., Pathak, S., Sherr, E., van Haren, K., Waters, E., Wilson, J. L., Zhorne, L., Schiffmann, R., van der Knaap, M. S., Pizzino, A., Dubbs, H., Shults, J., Simons, C., and Taft, R. J. (2020) Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders. Annals of Neurology 88, 264-273
  18. Van Bergen, N. J., Ahmed, S. M., Collins, F., Cowley, M., Vetro, A., Dale, R. C., Hock, D. H., de Caestecker, C., Menezes, M., Massey, S., Ho, G., Pisano, T., Glover, S., Gusman, J., Stroud, D. A., Dinger, M., Guerrini, R., Macara, I. G., and Christodoulou, J. (2020) Mutations in the exocyst component EXOC2 cause severe defects in human brain development. Journal of Experimental Medicine 217, e20192040
  19. Helman, G., Compton, A. G., Hock, D. H., Walkiewicz, M., Brett, G. R., Pais, L., Tan, T. Y., De Paoli-Iseppi, R., Clark, M. B., Christodoulou, J., White, S. M., Thorburn, D. R., Stroud, D. A., Stark, Z., and Simons, C. (2020) Multiomic analysis elucidates Complex I deficiency caused by a deep intronic variant in NDUFB10. Human Mutation 42, 19-24
  20. Hardee, J. P., Martins, K. J. B., Miotto, P. M., Ryall, J. G., Gehrig, S. M., Reljic, B., Naim, T., Chung, J. D., Trieu, J., Swiderski, K., Philp, A. M., Philp, A., Watt, M. J., Stroud, D. A., Koopman, R., Steinberg, G. R., and Lynch, G. S. (2020) Metabolic remodeling of dystrophic skeletal muscle reveals biological roles for dystrophin and utrophin in adaptation and plasticity. Molecular Metabolism 45, 101157
  21. Cummings, B. B., Karczewski, K. J., Kosmicki, J. A., Seaby, E. G., Watts, N. A., Singer-Berk, M., Mudge, J. M., Karjalainen, J., Satterstrom, F. K., O’Donnell-Luria, A. H., Poterba, T., Seed, C., Solomonson, M., Alföldi, J., Daly, M. J., and MacArthur, D. G. (2020) Transcript expression-aware annotation improves rare variant interpretation. Nature 581, 452-458
  22. Frazier, A. E., Compton, A. G., Kishita, Y., Hock, D. H., Welch, A. E., Amarasekera, S. S. C., Rius, R., Formosa, L. E., Imai-Okazaki, A., Francis, D., Wang, M., Lake, N. J., Tregoning, S., Jabbari, J. S., Lucattini, A., Nitta, K. R., Ohtake, A., Murayama, K., Amor, D. J., McGillivray, G., Wong, F. Y., van der Knaap, M. S., Jeroen Vermeulen, R., Wiltshire, E. J., Fletcher, J. M., Lewis, B., Baynam, G., Ellaway, C., Balasubramaniam, S., Bhattacharya, K., Freckmann, M. L., Arbuckle, S., Rodriguez, M., Taft, R. J., Sadedin, S., Cowley, M. J., Minoche, A. E., Calvo, S. E., Mootha, V. K., Ryan, M. T., Okazaki, Y., Stroud, D. A., Simons, C., Christodoulou, J., and Thorburn, D. R. (2021) Fatal perinatal mitochondrial cardiac failure caused by recurrent de novo duplications in the ATAD3 locus. Med 2, 49-73
  23. Jackson, T. D., Hock, D. H., Fujihara, K. M., Palmer, C. S., Frazier, A. E., Low, Y. C., Kang, Y., Ang, C. S., Clemons, N. J., Thorburn, D. R., Stroud, D. A., and Stojanovski, D. (2021) The TIM22 complex mediates the import of Sideroflexins and is required for efficient mitochondrial one-carbon metabolism. Molecular Biology of the Cell 32, 475-491
  24. Van Bergen, N. J., Massey, S., Stait, T., Ellery, M., Reljić, B., Formosa, L. E., Quigley, A., Dottori, M., Thorburn, D., Stroud, D. A., and Christodoulou, J. (2021) Abnormalities of mitochondrial dynamics and bioenergetics in neuronal cells from CDKL5 deficiency disorder. Neurobiology of Disease 155, 105370
  25. Granata, C., Caruana, N. K., Botella, J., Jamnick, N. A., Huynh, K., Kuang, J., Janssen, H. A., Reljic, B., Mellett, N. A., Laskowski, A., Stait, T. L., Frazier, A. E., Coughlan, M. E., Meikle, P. J., Thorburn, D. R., Stroud, D. A., and Bishop, D. J. (2021) Training-induced bioenergetic improvement in human skeletal muscle is associated with non-stoichiometric changes in the mitochondrial proteome without reorganization of respiratory chain content. Nat Commun 12:7056
  26. Wong, G., Weir, J. M., Mishra, P., Huynh, K., Nijagal, B., Gupta, V., Broekman, B. F. P., Chong, M. F., Chan, S. Y., Tan, K. H., Tull, D., McConville, M., Calder, P. C., Godfrey, K. M., Chong, Y. S., Gluckman, P. D., Meaney, M. J., Meikle, P. J., and Karnani, N. (2021) The placental lipidome of maternal antenatal depression predicts socio-emotional problems in the offspring. Translational Psychiatry 11, 107
  27. Wu, Y., Balasubramaniam, S., Rius, R., Thorburn, D. R., Christodoulou, J., and Goranitis, I. (2021) Genomic sequencing for the diagnosis of childhood mitochondrial disorders: a health economic evaluation. European Journal of Human Genetics (in press, online June 8, 2021, doi: 10.1038/s41431-021-00916-8)
  28. Van Bergen, N. J., Hock, D. H., Spencer, L., Massey, S., Stait, T., Stark, Z., Lunke, S., Roesley, A., Peters, H., Lee, J. Y., Fevre, A. L., Heath, O., Mignone, C.,  Yuan-Mou, Y., Ryan, M. M., D’Arcy, C., Nash, M., Smith, S., Caruana, N., Thorburn, D. R., Stroud, D. A., White, S. M., Christodoulou, J., Brown, N. J. (2022) Biallelic Variants in PYROXD2 Cause a Severe Infantile Metabolic Disorder Affecting Mitochondrial Function. International Journal of Molecular Sciences 23, 986.
  29. Kumar, R., Corbett, M. A., Smith, N. J. C., Hock, D. H., Kikhtyak, Z., Semcesen, L. N., Morimoto, A., Lee, S., Stroud, D. A., Gleeson, J. G., Haan, E. A., Gecz, J. (2022) Splice-Switching Oligonucleotide-mediated Correction of a Deep Intronic Splice-variant in TIMMDC1 in Cells of Patients with Severe Early Onset Neurodegenerative Disorder. NPJ Genomic Medicine 7, 1-12.

Clinical and Australian Genomics cohort

  • Thorburn, Christodoulou (MCRI, Australian Genomics)

RDNow cohort

  • White, Thorburn, Christodoulou (RCH, VCGS, MCRI)

Genomics and Transcriptomics facility and expertise

  • Lunke, Sadedin (VCGS), MacArthur, Simons (CPG)

Proteomics facility and expertise

  • Stroud (Bio21)

Metabolomics facility and expertise

  • McConville (Metabolomics Australia, Bio21), Stojanovski (Bio21)

Computational Integration

  • Simons, MacArthur (CPG), Stroud (Bio21)