The Genetics of Childhood Glaucoma

Congenital glaucoma — a severe form of the sight-threatening disease found in children — can be caused by a mutation in the thrombospondin-1 (THBS1) gene, according to ophthalmic researcher Janey Wiggs, MD, PhD. Her team published a study with the Journal of Clinical Investigation showing that a genetic alteration can impair aqueous outflow through the trabecular meshwork, leading to elevated intraocular pressures (IOP) for these individuals.¹

The study relied on findings from 3 ethnically diverse families who have novel THBS1 missense alleles (R1034C, R1034S), as well as mice that demonstrate elevated IOP, impaired fluid outflow, and reduced retinal ganglion cell counts associated with congenital glaucoma. 

The results, the researchers say, open up the possibility of better precision in screening protocols, and ultimately, earlier treatment.

Here, Dr Wiggs explains how the findings could affect ophthalmology in the years to come, where the research could eventually lead, and what ophthalmologists in practice can do with this information today. 

Q: Can you explain what your research accomplishes?

Dr Wiggs: Many childhood glaucomas are genetic, which means they are caused by specific gene mutations and that they can be inherited in families. These disease causing mutations can be identified in people using techniques such as DNA sequencing. 

Identifying disease-causing mutations can be a huge benefit to patients and their families — these results can identify people who are at risk for disease, and also importantly identify people in families who do not carry a disease causing mutation. Identifying people whose families who have mutations allows for development of surveillance and treatment plans that initial therapy at the earliest disease stages. For people without the disease-causing mutation they can be reassured that their risk of disease is low.

This paper describes a new gene for congenital glaucoma which expands our ability to identify disease causing mutations. One of the limitations of current genetic testing for early-onset glaucoma is that, with our current set of genes, we can only identify disease in approximately 20% of people. This result suggests that many people have disease due to genes that have not yet been discovered. The identification of new genes will add to our list of genes used for genetic testing and will therefore increase the percentage of people with mutations that we can detect. 

Q: Can you tell me a little bit about the 3 families that the research was based around — and how the study combined an animal study and a human study?

Dr Wiggs: In this study, a very interesting finding is that the 3 families with THBS1 mutations have varied ethnic backgrounds. In genetic research, for decades, much of the research has been in European Caucasian individuals, which limits the generalizability of the results. Additionally, there may be genetic mutations that are missed because they aren’t common in European Caucasian populations. In fact, earlier this year, we published another paper on a new early-onset glaucoma gene that we found by studying families in the Philippines.² 

In this case, what was so remarkable is that we found the same amino acid change in all 3 families despite varied ethnic backgrounds. This result suggests that the amino acid that is altered is likely to have an important role in the disease process. Creating the mutation in the mouse helped confirm the role of the amino acid change in the disease process.

Q: With this research, what can we now say that we know about the mechanism of childhood glaucoma or at least this particular type? 

Dr Wiggs: Genetics research have suggested several different mechanisms of childhood glaucoma with abnormal development of the eye currently as the most common.

The new childhood glaucoma gene mutations discovered in the thrombospondin gene (THBS1), do not cause abnormal eye development. Instead, we found that these mutations cause the mutant thrombospondin protein to aggregate in the trabecular meshwork extracellular matrix thereby interfering with removal of fluid from the eye. Interestingly, 3 other childhood glaucoma genes also impact the trabecular meshwork extracellular matrix suggesting that this is an important childhood glaucoma disease mechanism. 

Q: How might therapy options target that mutant THBS1?

Dr Wiggs: One option for novel gene-based therapy would be to suppress formation of the protein. An earlier prior study suggested that loss of normal thrombospondin, in a mouse eye may lower intraocular pressure and loss of mutant protein would be expected to have an even greater reduction.

Gene-based therapies for glaucoma are a challenge, especially for those genes that function in the trabecular meshwork because any kind of genetic alteration is temporary because the cells turn over which means treatment would have to be repeated over time. 

Q: How can ophthalmology use this finding to better target treatment?

Genetic testing for childhood glaucoma can identify people with high disease risk who will benefit from therapeutic lowering of intraocular pressure, even conventional therapy, especially if detected early in the disease course.

Q: In what direction would you like to see this kind of research be taken in the future? 

Dr Wiggs: Well, a really important need in this area is to identify more genes. This project and the project I mentioned earlier about the Philippines has been funded by a grant from the National Eye Institute. to use the latest cutting-edge sequencing techniques to identify novel disease-causing genes. 

Q: What’s the value that this research is going to have for ophthalmologists in their day-to-day clinical practice?

Dr Wiggs: The value of this report is that we can now include this gene in our genetic testing panels for childhood glaucoma. We would predict that at least some patients with childhood glaucoma are also going to have mutations in this gene. 

Dr Wiggs is a clinician scientist specializing in the genetics of glaucoma with particular interest in childhood and complex forms of glaucoma, and inherited ocular disorders. She is the Paul Austin Chandler Professor of Ophthalmology, the Vice Chair for Clinical Research in Ophthalmology at Harvard Medical School. She is also the director of the Genetic testing laboratory and a co-director of the Ocular Genomic Institute of Mass Eye and Ear and an Associate Member of the Broad Institute of MIT and Harvard.