Rare Disease Discovery
The Rare Disease Discovery group at Murdoch Children’s Research Institute (MCRI), led by Professors Tiong Tan and Sue White, brings together more than 35 years of clinical genetics expertise to improve the lives of children with undiagnosed rare diseases.
Our group aims to provide precise diagnoses and optimal care, plus access to the latest research and therapies for all individuals with rare diseases. Collaboration with various groups is central to our mission of transforming the rare disease care system.
A precise diagnosis is crucial for rare disease care, ending the diagnostic journey for families and enabling us to make informed management decisions while avoiding unnecessary investigations.
Although genomic technologies have transformed diagnosis, challenges remain.
Advanced 'multi-omics' technologies, like long-read genome sequencing and proteomics, have the potential to enhance rare disease diagnoses. Our group is dedicated to integrating these tools into care and assessing their impact on improving outcomes.
Our objectives
- Innovate: Use new technologies to find diagnoses in undiagnosed children.
- Collaborate: Engage with health professionals for skill development and connect with global researchers.
- Transform: Implement a whole-of-system approach to accelerate rare disease care.
Group Leaders
Rare Diseases Now (RDNow)
RDNow is a campus-wide initiative addressing barriers to rare disease care. Using advanced methods, the team analyses data to find answers for undiagnosed families and collaborates with campus experts to improve health systems and access to clinical trials.
A National Long-Read Genome Sequencing Program
This project is a collaboration with researchers around Australia to use a new form of DNA sequencing called long-read sequencing to try to help make diagnoses in children with undiagnosed rare disease. Long-read sequencing can read longer segments of DNA, which can help our team detect certain types of DNA rearrangements not visible on short-read testing, which is the main form of sequencing currently in use.
RD-MassSpec: A functional genomics platform for solving rare genetic disorders
The RDMassSpec project aims to show the benefit of using mass spectrometry to increase diagnostic rates in patients with undiagnosed rare monogenic disorders (disorders caused by the inheritance of single gene mutations). Looking at the proteins (proteomic testing) or metabolites (metabolomic testing) can help to understand the cause of their rare disease.
UDN-Aus: An internationally networked national approach for transforming diagnosis for individuals living with rare disease
UDN-Aus is a national program offering innovative, interdisciplinary approaches to families who remain undiagnosed after initial clinical genomic sequencing.
PERSYST: Pathogenic Evaluation of Recalcitrant Variants by Systematic Transactivation
More than 1,000 rare disease genes are not expressed in tissue that is easily accessible from a patient. The PERSYST study uses specialised cell technologies to make skin or blood cells ‘turn on’ the message coded by these genes to help understand if the gene is causing the rare disease.
Funding
- The Royal Children’s Hospital Foundation
- Genomics Health Futures Mission, Medical Research Future Fund
- Pierce Armstrong Foundation
- Centre for Population Genomics
- The Andrew and Geraldine Buxton Foundation Donation
- Murdoch Children’s Research Institute
Collaborations
- Victorian Clinical Genetics Services
- Centre for Population Genomics
- The Garvan Institute of Medical Research
- Bio21 Institute, The University of Melbourne
- Centre for Human Genetics, Keio University School of Medicine
- The Royal Children’s Hospital
- The University of Adelaide
- Broad Institute Center for Mendelian Genomics
- International Precision Child Health Partnership (IPCHiP)
Cloney T, Gallacher L, Pais LS, Tan NB, Yeung A, Stark Z, Brown NJ, McGillivray G, Delatycki MB, de Silva MG, Downie L, Stutterd CA, Elliott J, Compton AG, Lovgren A, Oertel R, Francis D, Bell KM, Sadedin S, Lim SC, Helman G, Simons C, Macarthur DG, Thorburn DR, O'Donnell-Luria AH, Christodoulou J, White SM, Tan TY. Lessons learned from multifaceted diagnostic approaches to the first 150 families in Victoria’s Undiagnosed Diseases Program. J Med Genet. 2021 Nov 5:jmedgenet-2021-107902. doi: 10.1136/jmedgenet-2021-107902.
Stephenson SEM, Costain G, Blok LER, Silk MA, Nguyen TB, Dong X, Alhuzaimi DE, Dowling JJ, Walker S, Amburgey K, Hayeems RZ, Rodan LH, Schwartz MA, Picker J, Lynch SA, Gupta A, Rasmussen KJ, Schimmenti LA, Klee EW, Niu Z, Agre KE, Chilton I, Chung WK, Revah-Politi A, Au PYB, Griffith C, Racobaldo M, et al. Germline variants in tumour suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome. Am J Hum Genet. 2022 Apr 7;109(4):601-617. doi: 10.1016/j.ajhg.2022.03.002.
Dong X, Tan NB, Howell KB, Barresi S, Freeman JL, Vecchio D, Piccione M, Radio FC, Calame D, Zong S, Eggers S, Scheffer IE, Tan TY, Van Bergen NJ, Tartaglia M, Christodoulou J, White SM. (2020) Biallelic loss-of-function NRROS variants impairing active TGF-β1 delivery cause a severe infantile onset neurodegenerative condition with intracranial calcification. Am J Hum Genet. doi: 10.1016/j.ajhg.2020.02.014
White SM, Bhoj E, Nellåker C, Lachmeijer AMA, Marshall AE, Boycott KM, Li D, Smith W, Hartley T, McBride A, Ernst ME, May AS, Wieczorek D, Abou Jamra R, Koch-Hogrebe M, Õunap K, Pajusalu S, van Gassen KLI, Sadedin S, Ellingwood S, Tan TY, Christodoulou J, Barea J, Lockhart PJ; Care4Rare Canada Consortium, Nezarati MM, Kernohan KD. A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome. Am J Hum Genet. 2021 Apr 1;108(4):749-756. doi: 10.1016/j.ajhg.2021.03.007.
Tan NB, Pagnamenta AT, Ferla MP, Gadian J, Chung BH, Chan MC, Fung JL, Cook E, Guter S, Boschann F, Heinen A, Schallner J, Mignot C, Keren B, Whalen S, Sarret C, Mittag D, Demmer L, Stapleton R, Saida K, Matsumoto N, Miyake N, Sheffer R, Mor-Shaked H, Barnett CP, Byrne AB, Scott HS, Kraus A, Cappuccio G, Brunetti-Pierri N, Iorio R, Di Dato F, Pais LS, Yeung A, Tan TY, Taylor JC, Christodoulou J, White SM. Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability. J Med Genet. 2021 Jun 28:jmedgenet-2020-107462. doi: 10.1136/jmedgenet-2020-107462.