Professor John Christodoulou

Biography:

Professor Christodoulou is a medical geneticist, genetic pathologist and clinical scientist, and has had a clinical focus for over 30 years on the diagnosis and management of children with rare monogenic disorders. Christodoulou oversees a gene discovery program for Mendelian disorders and has discovered and functionally characterised over 25 novel disease genes, and co-leads the Undiagnosed Diseases Program-Victoria, which has been remarkably successful in solving over 60 cases that were initially negative after clinical exome testing. As at May 2021, CI Christodoulou has co-authored over >290 research papers, 11 major reviews and 14 book chapters, with a total of >14,000 citations (> 30 papers cited > 100 times).Moreover, as co-lead of the Australian Genomics Health Alliance, Christodoulou has helped drive the introduction of genomic testing into mainstream healthcare in Australia.

Professor Christodoulou has influenced the delivery of genetic services in Australia as Past President of the Human Genetics Society of Australasia and through executive roles with the NSW Genetic Services Advisory Committee, NHMRC Human Genetics Advisory Committee, Royal College of Pathologists of Australasia Molecular Genetics Quality Assurance Program Advisory Committee and the Mito Foundation. Christodoulou led the team that prepared a successful MSAC application for testing of childhood syndromes, the first MBS funded genomic test of its kind. Christodoulou was the Director of the Western Sydney Genetics Program from 1997-2015, one of only two fully integrated clinical and laboratory genetics services in Australia, and in this capacity led the introduction of new molecular cytogenetic, genetic and genomic diagnostic modalities into service delivery.

He has served on a number key state and federal committees of the Human Genetics Society of Australasia (HGSA), the premier organisation representing the interests of clinical and laboratory genetics professionals in Australasia, including serving as its President (2005 – 2007). He has also served on the Royal College of Pathologists of Australasia (RCPA) Genetics Scientific Program Committee since 2010, guiding genetic and genomic educative themes for College members. He was the chair of the HGSA/RCPA Molecular Genetics QAP Advisory Committee between 2009 – 2015, which was responsible for overseeing quality assurance processes for all laboratories in Australasia providing NATA accredited diagnostic testing. He served on the NHMRC Principal Committee, the Human Genetics Advisory Committee (2009 – 2015), which was responsible for advising the federal government on the delivery of clinical genetics services across the country, and served on the Scientific Strategic Committee of the Genomics Health Futures Mission, under the auspices of the Medical Research Futures Fund (2019), which was charged with advising on the strategic directions and road map of the GHFM.

Awards:

National Health and Medical Research Council of Australia Postgraduate Medical Research Fellowship -1987-1990.
American Society of Human Genetics Postdoctoral Clinical Research Student Award, 1992.
Vice-Chancellor's Award for Excellence in Postgraduate Research Higher Degree Supervision, 2004.
Became a Member of the Order of Australia (AM), January 2010. Awarded in recognition of my contributions to genetic practice and research, particularly in the area of genetic metabolic disorders.
Ippokratis Award for outstanding achievement by a medical professional. Awarded by the Australasian Hellenic Educational Progressive Association (AHEPA), March 2010.
Elected as Fellow of the Australian Academy of Health & Medical Sciences – October 2017

Research:

Rett syndrome and related disorders

John Christodoulou is internationally regarded for his clinical and laboratory research into Rett syndrome (RTT), a devastating neurodevelopmental disorder predominantly affecting females, for which there is currently no effective treatment. He has been instrumental in enhancing our understanding of the correlation between the clinical features of RTT and specific mutations in the gene responsible for most cases, namely MECP2. In addition, he established RettBASE (http://mecp2.chw.edu.au), a highly regarded mutation database, which has proved to be very useful for clinicians and researchers. He and his collaborators have used mouse models to gain additional major insights into MeCP2 biology. In addition, his group discovered the second gene associated with RTT, CDKL5, which is now known to be a distinct clinical entity, and which opened a new avenue for research into neurodevelopmental disorders. He is driven to develop a deep understanding of the pathogenesis of RTT and related disorders, and a specific current focus of his work is the identification of potential new effective therapies for CDKL5 Deficiency Disorder.

Mitochondrial disorders:

John Christodoulou's significant contributions to the field of mitochondrial respiratory chain disorders research include contribution to the discovery of over a dozen new disease genes, three of which led to the establishment of specific therapies. As Co-Lead of the Mitochondrial Disorders Rare Disease Flagship of the Australian Genomics Health Alliance, he has a very keen focus on the translation of next generation sequencing technologies for rare diseases into the Australian health system, which is very closely aligned with the theme of this research proposal.

Genomic Medicine:

In the field of genomic medicine his group uses genomic technologies and functional assays for novel disease gene discovery (>25 new disease genes), clinical and functional characterisation of novel variants in known genes (> 50 publications), which in some cases extended the recognised phenotypes associated with those genes (16 publications), and in others directly translated to the implementation of targeted therapies with clinical efficacy or that are currently being trialled (8 publications). Moreover, as co-lead of the Australian Genomics Health Alliance, a five-year health services research project, he has driven the introduction of genomic testing into mainstream healthcare in Australia. In addition, he is part of a national steering team developing a national functional genomics network, aimed at creating a structure to enable those who have identified variants in novel candidate disease genes to partner with research labs that have relevant cell or animal model expertise in a bid to functionally validate those genes. Finally, he co-leads the Undiagnosed Disease Program-Victoria, focussed on identifying the genetic basis in paediatric cases that have been intractable to genetic diagnosis.

Projects:

- The Biology of Rett Syndrome: MECP2 Mutations and Beyond
- The Molecular Pathogenesis of Mitochondrial Respiratory Chain Disorders
- Application of Next Generation Sequencing Technologies for Mendelian Gene Disorder Discoveries
- Genetically Engineered Probiotics for the Treatment of Human Disease: Phenylketonuria as a Model Disease
- Preparing Australia for Genomic Medicine: A Proposal by the Australian Genomics Health Alliance

2021

1. Goranitis I, Best S, Stark Z, Boughtwood T, Christodoulou J. The value of genomic sequencing in complex pediatric neurological disorders: a discrete choice experiment. Genetics in Medicine 2021: 23; 155-162.

2. Greaves RF, Pitt J, McGregor C, Wall M, Christodoulou J. Newborn bloodspot screening in the time of COVID-19. Genetics in Medicine 2021: Jan 13; 1-8.

3. Lenherr N, Christodoulou J, Duley J, Dobritzsch D, Fairbanks L, Datta A, Filges I, Gurtler N, Roelofsen J, van Kuilenburg A, Kemper C, West EE, Szinnai G, Huemer M. Co-therapy with S-adenosylmethionine and nicotinamide riboside improves t-cell survival and function in Arts Syndrome (PRPS1 deficiency) Molec Genet Metab Rep 2021 20;26:100709. doi: 10.1016/j.ymgmr.2021.100709. eCollection 2021 Mar

4. Arthur J, Pickett H, Barbaro P, Kilo T, Vasireddy R, Beilharz T, Powell D, Hackett E, Bennetts B, Curtin J, Jones K, Christodoulou J, Reddel R, Teo J, Bryan T. A novel Cause of DKC1 – related bone marrow failure: partial deletion of he 3' untranslated region. Accepted for publication by eJHaem 7 January, 2021

5. Frazier AE, Compton AG, …, Christodoulou J, Thorburn DR. Fatal perinatal mitochondrial cardiac failure caused by recurrent de novo duplications in ATAD3 locus. MED 15 Jan 2021: 2:1 49-73.

6. Boyle L, Rao L, Kaur S, Fan X, Mebane C, Hamm L, Thornton A, Ahrendsen JT, Anderson M, Christodoulou J, Gennerich A, Shen Y, Chung WK. Genotype and defects in microtubule-based motility correlate with clinical severity in KIF1A associated neurological disorder. Human Genet Genom Adv 22nd2021:2(2); 100026. doi: 10.1016/j.xhgg.2021.100026; PMID: 33880452

7. Goranitis I, Best S, Christodoulou J, Boughtwood T, Stark Z. Preferences and values for rapid genomic testing in critically ill infants and children with suspected genetic condition: a discrete choice experiment. Eur J Hum Genet. 2021 Apr 2. doi: 10.1038/s41431-021-00874-1. Online ahead of print. PMID: 33811253

8. White, S.M., ..., Tan T.Y., Christodoulou J., Barea, J., Lockhart, P.J. Care4Canada Consotium, Nezarati M.M., Kernohan, K.D. A DNA repair disorder caused by de novo monoallelic DDB1 variants is associated with a neurodevelopmental syndrome. Am J Hum Genet. 2021:108; 749-756. doi: 10.1016/j.ajhg.2021.03.007. Online ahead of print. PMID: 33743206

9. Alsharhan H, He M, Edmondson AC, Daniel EJP, Donald T, Bakhtiari S, Amor D, Jones EA, Vassallo G, Vincent M, Cogne B, Deb W, Werners AH, Jin SC, Bilguvar K, Christodoulou J, Webster RI, Freeze HH, Kruer MC, Li D, Raymond KM, Morava-Kozick E, Bhoj EJ, Sobering AK. ALG13 X-Linked intellectual disabiligy: New variants, Glycosylation analysis and expanded phenotypes. J Inher Metab Dis 2021 Mar 18. doi: 10.1002/jimd.12378. Online ahead of print

2021 (contd)

1. Li D, Wang Q, Gong NN, …, Pais L, White SM, Christodoulou J, Tiosano D, Kayser MS, Tan TY, Deardorff MA, Song Y, Hakonarson H. Pathogenic variants in SMARCA5 a chromatin remodeler, cause a range of syndromic neurodevelopmental features. Sci Adv 2021: 7; eabf2066. doi: 10.1126/sciadv.abf2066; PMID: 33980485

2. Gyngell, C., Christodoulou, J., Savulescu, J. Ethically utilising COVID-19 host-genomic data. NPJ Genom Med 2021:6(1); 31. doi: 10.1038/s41525-021-00194-9; PMID: 33972547

3. Rius, R., Compton A.G., Baker N.L., Welch A.E., Coman D., Kava M.P., Minoche A.E., Cowley, M.J., Thorburn, D.R., Christodoulou J. Application of genome sequencing from blood to diagnose mitochondrial diseases. Genes 2021:12(4); 607. doi: 10.3390/genes12040607; …, Christodoulou J, Wolf NI, Venselaar H, Mayr JA, Wevers RA. Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency. Accepted by Genetics in Medicine 15 April, 2021

4. Li D, March ME, Fortugno P, …, Christodoulou J, Cox TC, Zackai EH, Brancati F, Hakonarson H, Bhoj EJ. Pathogenic Variants in CDH11 impair cell adhesion and cause Teebi hypertelorism syndrome. Hum Genet. 2021 Apr 3. doi: 10.1007/s00439-021-02274-3. Online ahead of print. PMID: 33811546.

5. The ICIMD Advisory Group for Non-Mitochondrial Disorders, The ICIMD Advisory Group for Mitochondrial Disorders – including Christodoulou J, The ICIMD Advisory Group from International Societies and Organisations. An International Classification of Inherited Metabolic Disorders (ICIMD). J Inherit Metab Dis. 2021 Jan;44(1):164-177. doi: 10.1002/jimd.12348. PMID: 33340416

6. Novelli G, Liu J, Biancolella M,…, COVID Human Genetic Effort – incl. Christodoulou J, French COVID Cohort Study Group, CoV-Contact Cohort, Notarangelo LD, Su HC, Abel L, Cobat A, Latini A, Sidhu S, Jain S, Davey RA, Casanova J-L, Wei W, Pandolfi PP. Inhibition of HECT E3 ligases as potential therapy for COVID-19. Cell Death Dis. 2021 Mar 24;12(4):310. doi: 10.1038/s41419-021-03513-1. PMID: 33762578

7. Van Bergen, N.J., Massey, S., Stait, T., Ellery, M., Reljic, B., Formosa L.E., Dottori, M., Thorburn, D., Stroud, D.A., Christodoulou, J. Abnormalities of mitochondrial dynamics and bioenergetics in neuronal cells from CDKL5 deficiency disorder. Neurobio Dis 2021 Apr 24;105370. doi: 10.1016/j.nbd.2021.105370; PMID: 33905871

8. Tan NB, …, Pais LS, Yeung A, Tan TY, Taylor JC, Christodoulou J, White SM. Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability. Co-corresponding author Accepted by J Medical Genetics 23rd April 2021

Funding:

International Rett Syndrome Foundation Database Grant #2242 – 2014 – 2018
RettBASE: IRSF MECP2 Variation Database – a Global Resource
J. Christodoulou (CIA)
United Mitochondrial Diseases Foundation Grant – 2015 – 2016
Utility of FGF21 and GDF15 as Diagnostic and Prognostic Biomarkers of Mitochondrial Respiratory Chain Disorders
J. Christodoulou (CIA)
NHMRC Targeted Research Grant APP1113531 – 2016 – 2020
Preparing Australia for Genomic Medicine – A proposal by the Australian Genomics Health Alliance
J Christodoulou (CI)
NHMRC CRE APP1117394 – 2016-2021
Transforming the Diagnosis and Management of Severe Neurocognitive Disorders through Genomics
J Christodoulou (CIH)

RCH Foundation Grant 2018 – 2020

Acute Care Genomics – ultra rapid genomic diagnostics for the sickest children

J Christodoulou (CIC)

NHMRC – MRFF Scheme Research Grant Application APP1146756 2017 - 2020

A randomised placebo-controlled trial of combined mitochondrial agents for the treatment of fatigue and depression in multiple sclerosis with an assessment of the impact on kynurenine pathway metabolomics

J Christodoulou CIJ

US Department of Defense office of the Congressionally Directed Medical Research Programs (CDMRP) PR170396 2017 – 2020

Solving the unsolved. Integrating functional, computational and Omic approaches to enable genomic diagnosis of virtually all patients with mitochondrial disease.

John Christodoulou(CIB)

NHMRC Project Grant APP116447 2019 -2021

Identifying Novel Genes and Novel Mechanisms of Mitochondrial Diseases: a Multi-Omics Approach

John Christodoulou (CIB)

The Financial Markets Foundation for Children 2017 - 2019

Brain cells in a dish: strategies for novel therapeutics in CDKL5 disorder

John Christodoulou (CIB)