Professor Jozef Gecz

Prof Gecz is a basic scientist who has built his career at the interface between fundamental ‘breakthrough’ science and health care delivery, i.e. in medical schools and hospitals. His seminal discoveries are primarily in disease gene discovery (>350 disease genes identified) and understanding of their function with the aim of improved diagnosis and management plus development of mechanism based therapies.

Gene discovery in Intellectual disability (ID): Prof Gecz identified the first gene for non-syndromic ID, the FMR2 (or AFF2) gene in 1996 (Nature Genetics), which he followed with 12 other publications on the role of AFF2. AFF2 is the most frequently mutated gene in mild to borderline ID. Many other major ID gene discoveries followed, including ARX (Nature Genetics, 2002 and 27 other articles), PHF6 (Nature Genetics, 2002 and 8 other articles), UPF3B (Nature Genetics 2007 and 9 other articles), IQSEC2 (Nature Genetics 2010 and 2 other articles), HCFC1 (Am J Human Genet 2012), THOC2 (https://pubmed.ncbi.nlm.nih.gov/26166480/ and 3 other articles), USP9X (https://pubmed.ncbi.nlm.nih.gov/24607389/ 2014 and 7 other publications), or ZSWIM6 (https://pubmed.ncbi.nlm.nih.gov/29198722/ in 2017).  

Gene discovery in Epilepsy: Prof Gecz began working on the genetics of epilepsy per se in 1994 as a postdoc in the laboratory of Profs John Mulley and Grant Sutherland in Adelaide and where the first epilepsy genes were discovered since 1995. His focus has been primarily on the X-chromosome and non-ion channel epilepsy gene identification. Among his seminal epilepsy gene discoveries are CDKL5 (Am J Human Genet 2004 and 6 other publications); PCDH19 (Nature Genetics 2008 and 2 other publications); TBC1D24 (Am J Human Genet 2010 and 3 other publications), which has now also been found in DOORS syndrome (Deafness-sensorineural, Onycho/Osteodystrophy and Seizures) and non-syndromic deafness; GOSR2 (Am J Human Genet 2011) and most recently USP9X, a doublecortin interacting protein (Plos One 2013 and Am J Human Genet 2013). Prof Gecz’s group was the first one to implement massively parallel sequencing to epilepsy gene discovery, which yielded, in addition to TBC1D24 (2010) and GOSR2 (2011) also other major epilepsy genes, i.e. PRRT2 (Am J Human Genet 2012), KCNT1 and DEPDC5 (Am J Human Genet 2012, Nature Genetics, 2013; Annals Neurology 2014).

Gene discovery in Cerebral palsy (CP): CP is co-morbid with epilepsy, intellectual disability and speech and language disorders. Prof Gecz has engaged in gene discovery in CP since 2012. CP is a disorder thought to be primarily due to environmental risk factors including perinatal trauma, prematurity, asphyxia or injury. He directed the first, large whole exome sequencing study of 183 CP patients and their parents (500 exomes) with Prof Alastair MacLennan and colleagues from Baylor COllege of Medicine, Houston USA (Prof Richard Gibbs and his team). This study (Mol Psych 2015 showed that at least 14% of individuals had genetic etiology of their CP. This was a major paradigm shift in the field with broad implications for medicine. More recent studies of Prof Gecz demonstrate the extensive genetic etiology of unselected CP to the extent of 30-33% (Nat Rev Neurol 2023: https://pubmed.ncbi.nlm.nih.gov/37537278/ or Npj Gen Med: https://pubmed.ncbi.nlm.nih.gov/34531397/ ).

Unusual Genetic Mechanisms: Prof Gecz has a major interest in unusual genetic mechanisms of disease, including fragile sites.  He discovered three fragile sites and five fragile site-associated genes (FMR2, FMR3, FRA10AC1, FAM11A or AFF3). He identified the gene for X-linked spondyloepiphyseal disaplasia tarda, SEDL (Nature Genetics 1999), discovery of which was featured in the 2001 International Human Genome Sequencing Consortium Nature paper as an example of how the availability of the human genome sequence would speed up human disease gene discovery (it took 3 months to progress from disease mapping to gene identification).

From gene discovery to gene function and therapy: Prof Gecz’s gene discovery work (and the makeup of his research group) has been increasingly and purposefully complemented with more in depth cellular and molecular biology functional studies and animal models. He has embarked on the application of stem cell technologies (mouse embryonic stem cells; adult neuronal stem cells, human iPS cells) to enhance understanding and modeling of human neurological disease. Successes in this area include expression studies suggesting HCFC1 is a potent regulator of embryonic neuronal development (Hum Mol Genet 2015), investigation of UPF3B-dependent nonsense mediated mRNA decay showing UPF3B regulates neural progenitor cell behaviour and neuronal outgrowth (Human Mol Genet 2013), using a conditional knockout mouse model to show USP9X plays an important role in cortical architecture (Plos One 2013). In collaboratiuon with Prof Paul Thomas they generated and characterised first mouse models of PCDH19 clustering epilepsy (https://pubmed.ncbi.nlm.nih.gov/27240640/ in Scientific Reports 2016 and https://pubmed.ncbi.nlm.nih.gov/29301106/ in Neuron 2018), PHF6 mouse model of BFLS syndrome with Prof Anne Voss and Tim Thomas from WEHI (https://pubmed.ncbi.nlm.nih.gov/30755422/ in Blood 2018 or https://pubmed.ncbi.nlm.nih.gov/32994169/ in Development 2020 or https://pubmed.ncbi.nlm.nih.gov/39405291/ in Plos Genetics 2024), or the first THOC2 animal model (Nat Communications 2024: https://pubmed.ncbi.nlm.nih.gov/38331934/ ).

Armed with this greater understanding of the functionality of disease genes, Prof Gecz is developing pre-clinical novel therapeutic treatments. Gecz’s work on TIMMDC1 has demonstrated that antisense oligonucleotides can restore function in vitro (NpjGenMed 2022 7:9). Other example is deficiency of the neurosteroid allopregnanolone contribution to PCDH19-clustering epilepsy (Hum Mol Genet 2015 24:5250-9, Epilepsia 2017 58:e91-95) and subsequent neurosteroid hormone replacement clinical trial (Mol Psychiatry 2015 20:176-82).

Enabling and External Collaborations: Prof Gecz has been instrumental in establishing and contributing to a number of major international consortia to facilitate research and translation. These include the International Genetics of Learning Disability Consortium (IGOLD, with Prof Sir Michael Stratton, Director Welcome Trust Sanger Institute) and the EURO MRX Consortium to identify X-linked ID genes (with Prof Hilger Ropers). Locally, Prof Gecz established the Neurogenetics Research Program at the Women’s and Children’s Hospital and The University of Adelaide in 2002 and has made significant contributions to the Genetics of Learning Disabilities services in South Australia and NSW. Since 2011 he is a major driver in gene discovery in Cerebral Palsy (CP group in South Australia with Prof. A MacLennan) and internationally (Prof. R Gibbs at Baylor College of Medicine). In 2014, Gecz established (alongside Prof. A MacLennan) the Australian Cerebral Palsy Biobank, which he now co-leads alongside Dr C van Eyk). The Australian Cerebral Palsy Biobank has genomic and clinical metadata from over 650 families and supports multiple national and international collaborations and major research efforts (e.g. MRFF GHFM CP Genomics grant 2024-27). Prof. Gecz is also a member of the ASID (Autism Spectrum/Intellectual Disability network) established in 2014 and led by Prof E Eichler (Uni Washington, Seattle, USA). In 2017 Profs Gecz and MacLennan founded the International Cerebral Palsy Genomics Consortium (ICPGC) in Adelaide (https://icpgc.org/ 2017) which continues to be the major international body advocating for genomiucs of CP for better and precision health.

Prof Gecz’s research laboratory is strategically located within the Adelaide Biomedical Precinct, in immediate proximity to the Royal Adelaide Hospital's and the Women’s and Children’s Hospital's Diagnostic Molecular Genetics, Diagnostic Cytogenetics, Clinical Genetics (SA Pathology), Neurology and Pediatric departments. His research into genetics of human childhood neurological disorders is rapidly translated to improved patient care via provision of diagnostic genetic analysis reports (50-100 reports annually), expert advice regarding cytogenetic and molecular genetics enquiries or technology transfer from the research domain to use in clinical practice (e.g. arrayCGH in 2007 and since 2010 massively parallel sequencing for targeted and whole exome or genome sequencing or long read sequencing since 2018).

Prof Gecz sees the big picture challenges of his research as being i) a deeper understanding of the genetics and biology of neurological disorders (epilepsy, ID, autism and CP) and ii) the efficient and timely translation of research results to facilitate improved outcomes for those affected by these conditions. He is a passionate advocate of medical research and its importance in the future of our society, for our health, education and our economy.