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 (>100 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 10 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) and IQSEC2 (Nature Genetics 2010 and 2 other articles).

Most recently Prof Gecz’s pioneering research has delved into the role of non-coding regulatory mutations causing ID. He identified a mutation in HCFC1 in a large Australian family with non-syndromic ID, which had eluded 3 generations of scientists and clinicians for more than 40 years (Am J Human Genet 2012).  While initially regarded as a somewhat separate field to epilepsy genetics, discoveries in intellectual disability by Prof Gecz and others, are showing increasing overlap with epilepsy, explaining their not infrequent co-occurrence.

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, where the first epilepsy genes were discovered. 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 and GOSR2 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 also co-morbid with epilepsy. Prof Gecz has recently engaged in gene discovery in CP, a disorder thought to be primarily due to perinatal trauma. In addition to the CP-involved genes he has already published (NKX2.1, Eur J Med Genet 2013; ZC4H2, Am J Human Genet 2013) he recently directed a large whole exome sequencing study of 183 CP patients and their parents (500 exomes, under review). This study (Mol Psych 2015 shows that 1 in 6 CP patients may have a genetic etiology, potentially a major paradigm shift in the field with broad implications for medicine.

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: Over the last 5 years, 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).

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 Wellcome 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). He is a member of the ASID (Autism Spectrum/Intellectual Disability network) established in 2014 and led by Prof E Eichler (Uni Washington, Seattle, USA).

Prof Gecz’s research laboratory is strategically located within the Adelaide Women’s and Children’s Hospital, in immediate proximity to the Diagnostic Molecular Genetics, Diagnostic Cytogenetics, Clinical Genetics (SA Pathology), Neurology and Paediatric 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 (1-2 local, national & international enquiries weekly), or technology transfer from the research domain to use in clinical care (e.g. arrayCGH in 2007 and more recently massively parallel sequencing for targeted and whole exome or genome sequencing).

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.