Rare Eye Diseases are the leading cause of visual impairment and blindness for children and young adults. There are over 900 rare eye diseases. Many eye diseases are genetic. They include retinitis pigmentosa and developmental eye anomalies. How to use genetic methods for the correct diagnosis of rare eye disease?
Which genetic tests are used? Is there a role for Whole Genome Sequencing?
When should parents ask for genetic testing if a child has a vision problem? It is a very good question about genetic rare eye diseases because there is sometimes very difficult to have a correct diagnosis for this rare disease. Why? Because they are rare genetic eye diseases. There is probably around 1000 rare eye disease. So that's many eye diseases. So it's important to have a good phenotype [description of symptoms and disease signs] before going to genotype [genetic cause]. If you don't have a good symptom description, you will not establish the correct diagnosis. So first of all, we need to described eye disease signs with good imaging. We are an OPHTARA Rare Eye Diseases Center. We are a center of rare eye disease. We developed the largest and the most accurate platform of eye imaging for children. Of course, we have that for adults also. But for children especially. The imaging should be adapted to a child. So we need to have some handpieces. And so we have to have an easy diagnostic system, quicker eye disease diagnostic system, for instance. So we have nice OCD [Optical Coherence Tomography] for children that are hand-held pieces. We also have a very wide field retinal funduscopy with a large, large system. And these diagnostic tools are critical to making a good diagnosis of rare eye disease. We must make a good phenotype diagnosis. And after that, we need genotyping to find a cause of rare eye disease. We need geneticists, clinical geneticists, but also we need good molecular genetics. I am in charge of a platform, which is called Sequoia for whole-genome sequencing. And we also work with Professor Sophie Valleix for Molecular Genetics. And so we are interested in anterior eye segment disorders and anterior segment dysgenesis. We also study a retinal disease, of course. We do first NGS sequencing, which usually has 200 genes affected in rare eye genetic diseases. But if NGS sequencing is not good, so we go to whole-genome sequencing. This genetic testing platform is called Sequoia. it's very, very specific. And so we have multidisciplinary meetings to select the child to be diagnosed. Then we use this NGS platform, and there is whole genome sequencing. It's very interesting because probably around 30% of the retinal disease could be solved by NGS sequencing. Probably some pathology, like aniridia, can be solved in 90%, with probably PAX6 mutations identified by NGS sequencing. But for the other rare eye disease, they must be explored widely. So we can find out new affected genes. We can find new mutations that cause rare eye diseases. And so that's why it's very interesting. If you look at aniridia, we had ITPR1 mutation that is associated with Gillespie syndrome. That's a very recent discovery of the gene for aniridia. So that's very interesting. And so, to summarize, a good phenotype [signs of disease], with specific imaging, is essential to diagnose rare eye disorders in children. After that, if you had a good phenotype, you can go to a good genotyping. You can do whole genome sequencing, and the cost is decreasing all the time. Probably by the time parents with children, pediatric patients, come to your tertiary care specialized eye center know, they've seen several doctors. But the eye disease diagnosis still has not been figured out. Or children with eye problems received a more common diagnosis but perhaps incorrect diagnosis. So how do these pediatric patients eventually find you? Is it the initiative of their parents? Is that an initiative of the ophthalmologist? What happens more commonly? We have a lot of patients who are just referred to us. But it's sometimes not enough. And so we work with Association with rare eye diseases. That's very important to have to work together. And for instance, I'm a President of the Scientific Committee of Aniridia, Europe Association, and also President of the Rare Eye Disease Association of in France. So, when you have associations working with you, you can have the patients coming to the centers. You can diffuse information. Also, it is important that we make clinical guidelines on rare eye diseases. And those clinical guidelines are useful for general practitioners. But clinical guidelines are also useful for the patients. And so this is very important. For instance, in aniridia, you need to have eyedrops preservative-free. But that's not so easy for the general practitioner. But if they just go to the clinical guidelines, they can read that, and so they know it. After that, they can refer to an OPHTARA specialize eye center. But at least they have a knowledge of rare eye disease, which is valuable. So that's important to spread information about rare genetic eye diseases. So that's an important point. This is patient-driven healthcare because it is patients who ultimately are in charge of their health. Even though it's sometimes quite convenient to offload the responsibility for your health to the physician. But a patient even should probably take a look at the clinical guidelines relevant to one's disease or condition. Exactly.