Identifying Genetic Causes of Primary Congenital Glaucoma in Australia

New gene discoveries indicate that primary congenital glaucoma may be inherited in a dominant pattern, as well as recessive. In Australia, around 20% of cases are caused by mutations, however the cause of the other 80% is unknown.

Our research project is part of the Australian and New Zealand Registry for Advanced Glaucoma (ANZRAG) which aims to uncover the genetic causes of glaucoma in Australia. As part of this overall goal, we are investigating primary congenital glaucoma (PCG). This form of glaucoma affects children, often from birth, and leads to lifelong visual problems including blindness. In Australia, around 20% of cases are caused by mutations in the CYP1B1 gene, however the cause of the other 80% is unknown. We have recently made progress in understanding some of the other genetic causes for this disease.

Recently, our collaborators in the USA reported mutations in the TEK gene in PCG patients from the USA. To help find out if this gene is a new cause of PCG, we have screened this gene in Australian PCG patients. We identified five mutations. Two of these mutations altered a single position in the TEK protein and three result in a short protein. Such mutations are hardly ever seen in people without PCG. Although mutations in this gene are rare overall, we see a mutation rate of 9% in PCG patients and our findings mirror those seen in the USA study indicating that this gene is highly likely to be involved in PCG.

Typically in PCG, we see patients carry two mutations in the causative gene (one from each parent). This is called ‘recessive inheritance’ and has been thought to be the main inheritance pattern for PCG. In this study we see PCG patients that have only one mutation in TEK (received from one parent, but not the other). This is called ‘dominant inheritance’ and has not previously been demonstrated in PCG.

We have also found mutations in PCG patients in a range of other genes that cause other types of glaucoma. One patient in our study has two mutations in TMEM98 which is a gene we previously identified that causes small eyes, which can lead to glaucoma. This result opens up a new mechanisms for the cause of PCG which requires further investigation. Two patients have mutations in FOXC1. This gene is typically associated with anterior segment dysgenesis where the front of the eye doesn’t develop correctly which leads to glaucoma. This result suggests that PCG might be part of the spectrum of anterior segment dysgenesis. One patient has a mutation in MYOC, which is a gene that causes around 3% of primary open angle glaucoma in adults. This means there may be some overlap between the causes of PCG and adult glaucoma. Interestingly, both FOXC1 and MYOC seem to lead to dominant inheritance, not recessive, just like TEK. So dominant PCG is probably much more common that we realise.

Our research helped reveal that a patient in our cohort was misdiagnosed with PCG. The sequencing results identified a mutation in the CHRDL1 gene, which causes X-linked Megalocornea. Megalocornea can lead to childhood glaucoma but is different to PCG. The correct diagnosis was made by the patient’s doctors at the same time as we found the genetic results. This highlights how genetic screening can be used to verify or alter clinical diagnoses and how important it is that we learn which genes can lead to which diseases.

This pie chart shows the types of glaucoma in ANZRAG excluding the common Primary Open Angle Glaucoma. Primary Congenital Glaucoma is a developmental glaucoma. PCG accounts for around 6% of participants with secondary glaucoma in our study. We can now explain the genetic cause of around 30% of PCG cases. (Figure adapted from Souzeau et al. Clinical and Experimental Ophthalmology 2012; 40: 569–575).

Overall, the findings from this project so far indicate that PCG is not necessarily always a recessive disease and that dominant mutations may account for more cases than previously recognised. It seems likely that PCG is part of a cluster of diseases with overlapping genetic causes. Clinical diagnoses are often unable to separate patients with similar genetic causes of disease such as TMEM98, FOXC1 and MYOC identified. This has implications for diagnosis and genetic counselling in the modern genomics era and supports the idea of genome sequencing as a front line diagnostic tool for congenital diseases.