Group Leaders – Professor Robyn Jamieson and Professor John Grigg
This research group has benefited from recent advances in next-generation sequencing (NGS) of DNA, with significant progress made in the identification of known and novel disease genes that cause inherited eye disease, critical information in the development of new treatments to preserve or restore vision.
One NGS technique currently being utilised is exome sequencing, where all of the coding regions of an individual’s 23,000 genes are sequenced in one single test. We have successfully applied this technique to investigate disease genes that cause cataract/microcornea, Peters anomaly and microphthalmia/coloboma. This work was accepted for publication in the European Journal of Human Genetics, and the technique is now being applied to patients with retinal dystrophies.
Another NGS approach utilised by the group is called ‘targeted NGS’. A new capture technique was devised to select the coding regions of more than 50 genes known to be critical in the lens and anterior segment of the eye. We applied this to patients with cataract and microcornea/microphthalmia, and preliminary results show it has a disease identification success rate similar to that of exome sequencing. This finding has potential to reduce the cost of diagnostic testing. We are collaborating with The Children’s Hospital at Westmead to translate findings into new and accessible diagnostic tests for patients with genetic eye disorders.
We have identified a number of novel candidate disease genes from exome sequencing and the investigation of patients with eye diseases and structural genomic variation.
In one case, where we identified a novel congenital cataract gene, collaboration with researchers at the Brain and Mind Research Institute (BMR)) led to functional validation through knockdown in a zebrafish model system. We have also created a knockout mouse model for the gene, with mutant mice showing early-onset cataracts, as in the human patients. We are now able to conduct further experiments to understand the functions of this disease gene and its role in normal lens and anterior segment health.
Collaboration with the Genome Institute of Singapore continues to be fruitful, with a project recently commencing to investigate the value of whole genome sequencing when underlying disease genes are not known. Identification of disease genes in infantile cataract, glaucoma and retinal disorders offer direct benefits to patients and families, including genetic diagnosis, and is required for the development of new treatments.
Associate Professor Jamieson was invited to speak on these findings at the Human Genetics Society of Australasia annual conference in New Zealand in 2013.
Cataract, anterior segment and glaucoma project:
Patients with cataracts and small corneas are particularly prone to the development of glaucoma. We have successfully applied exome sequencing to identify known and novel variants in these disorders. Targeted NGS is also proving to be a useful strategy, and we are optimising this for provision of the first comprehensive diagnostic testing for these disorders in the world. This work was the subject of an invited presentation to be given by Associate Professor Jamieson, at the Australian Ophthalmic and Vision Science Annual Meeting, in Hobart, November 2013.
Recognition of our group’s work in glaucoma led to the invitation to Associate Professors John Grigg and Robyn Jamieson to join the Congenital Glaucoma Research Network (CGRN), and contribute to the World Glaucoma Association 9th consensus statement on the diagnosis and management of paediatric glaucoma. The consensus statement is to be published in November 2013 and Associate Professors John Grigg and Robyn Jamieson were invited to give presentations at the World Glaucoma Congress in Vancouver, Canada, in July 2013.
Anophthalmia and microphthalmia are severe debilitating conditions, and while some disease genes are known, they only contribute to a small number of cases. Our exome sequencing work in patients with this group of disorders suggests that variants in a number of genes may contribute to the disorder in any one particular patient. Our study of a large family has identified a novel contributor disease gene which is important in the Wnt signalling pathway. Study of further patients is underway to examine the wider impact of variation in this gene in other patients and families.
Retinal and macular disorder projects: There are at least 120 genes known to be disease causing in the various types of retinal and macular dystrophies. We have applied exome sequencing to patients with retinitis pigmentosa, and we have successfully identified the underlying disease gene in over half of the patients we have studied to date. This project is being conducted in collaboration with the Retina Australia DNA bank. A targeted NGS strategy is also being explored in patients with this group of diseases, for provision of diagnostic testing for Australian patients with these conditions.
The clinical characterisation of the retinal disorders has benefited from improved electrophysiology assessment, as well as collaboration with Professor Graham Holder, electrophysiologist, Moorfields Eye Hospital, who visited Sydney Eye Hospital again this year.
This work resulted in the publication of a paper demonstrating the value of detailed electrophysiological investigation and identification of complete loss of the KCNV2 gene in a child with poor vision and nystagmus.
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