Lecture: Ocular Genetics: What Every Ophthalmologist Should Know and What Opportunities Exist

Ocular genetics is an emerging subspecialty of ophthalmology that is becoming increasingly necessary as our expanding genetic knowledge leads to reclassification of disease, better understanding of disease pathophysiology, and the availability of gene based testing and treatments. There is a need for expanding the number of ocular geneticists worldwide through fellowship training while all ophthalmologists try to improve their knowledge foundations in genetics.

Lecturer: Alex V. Levin, MD, MHSc, FRCSC, Wills Eye Hospital, Philadelphia, USA


(To translate please select your language to the right of this page)

DR LEVIN: Good morning! I’m hoping folks can hear me out there. And hopefully see my slides. Just give me one second. There you go. So my name is Alex Levin. I’m chief of pediatric ophthalmology and ocular genetics here at Wills Eye Hospital in Philadelphia. We have a tremendous group out there. Over 250 people from around the world, representing all types of settings, from government to private to public. And I thank all of you for being here, and I thank you for the questions that you submitted in advance, all of which we will get to at the end of this brief talk. The questions tell me that part of what you’re gonna hear today may not make your life easier at first. But it will make your life easier in the long run, because what every ophthalmologist needs to know is about what opportunities exist in the world of ocular genetics, but how to access them is one of the challenges we see around the world, for individuals dealing with these cases. We’re gonna start off with some objectives first, and then we’re gonna have some participatory slides. I think after this activity, you will know the role of ocular genetics, you’ll know the importance of genetic counseling, you’ll recognize the difficulties in genetic testing, and you’ll be able to respond to patients who ask questions about gene therapy. So the way these poll questions work is you’ll get the opportunity to answer these questions. I’ll read them to you. We’ll wait about 20 seconds of silence, and then I’ll let you know what your answers were. So the question is: I’ll see patients with ocular genetic disease in my practice one, every day, two, once weekly, three, once monthly, and four, rarely. Let’s get a feel for the audience here how often you see ocular genetic disease. So this is very interesting. 50% of you say that you rarely see ocular genetic disease, 23% once monthly, 19% once weekly, and 12% say every day. Well, I’m gonna challenge you, because the correct answer is every day. And the reason it’s every day is because everything is genetic. Every disorder you see, every day, on every patient has a genetic basis and has a genetic factor that’s really important. Even trauma. The healing of trauma is related to genetics. Cataract, strabismus, amblyopia — all of these things have genetic influence. And therefore ocular genetics permeates our practice every day on every patient. And what we can do for these patients using genetic knowledge and a genetic basis changes for different individuals. We’ll talk a little bit about age-related macular degeneration, for example. It’s different than what we can do for someone who has retinitis pigmentosa, but nonetheless, keep in the back of your mind that every patient you see every day has some relation to the world of genetics. In fact, eye genetics really has led the world in terms of our knowledge and our abilities. The first autosomal dominant disorder ever described, which is piebaldism, has genetic manifestations. The first autosomal recessive disorder, alkaptonuria, has effects on ocular muscles. The first X linked recessive disorder has ocular components. The first X-linked dominant disorder was incontinentia pigmenti. Obviously major ocular manifestations. The first mitochondrial disorder, the first digenic disorder, where you need a mutation in two separate genes, was retinitis pigmentosa. The first triallelic disorder. The first two-hit hypothesis we all know was retinoblastoma, and the first contiguous gene deletion syndrome was Wills tumor. So eye genetics has really been at the forefront of our understanding of genetics, and we might start by just simply asking the question why that is, before we delve a little deeper. And we can consider albinism. We have some questions that came regarding albinism. It is essentially a deficiency of ocular melanin that leads to a developmental defect in the eye. It can be divided into ocular albinism, where your skin is essentially normal, and oculocutaneous albinism, where your skin and eyes are both affected, and your hair. It exists throughout the animal kingdom. In snakes, in lions, in koala bears. Here’s Snowflake, who died at the Barcelona zoo, at a late age for living in the wild, but he died from melanoma, something that afflicts patients with albinism. Originally from Canada — we have moose with albinism. And every corner of the animal kingdom has albinism, but we see it in humans too. And this boy, believe it or not, with his black hair, does have albinism. He has X-linked recessive ocular albinism. If we look at his eyes, we see the iris transillumination here, with his lens visible through the iris. We see that compared to normal, you can hardly tell which eye this is, if it’s a right or a left eye. I happen to know it’s a right eye. There’s no identifiable macula here, blood vessels just coursing through the macula, and a very pale appearance, hypopigmented appearance to the retina. And this X-linked recessive form is characterized by a genetic pattern, X-linked disease, that’s called lyonization. And lyonization is a process by which every woman in the world, every cell in her body, is only using one of her two X chromosomes. And for a woman who is a carrier of this OA1 mutation, in her cells that are expressing her bad X, she’s gonna be hypopigmented. And in the cells where she’s expressing her good X, she’s gonna be making pigment. And in a woman with millions and millions and millions of cells, we don’t notice this. But what would happen if she had a patch of cells where she unfavorably lyonized, as you can see here? This patch of cells would be hypopigmented. And that leads to the most fantastic thing I can show you, the real answer to why ocular genetics is ahead of everyone, and that is this. This is the mud-splattered retina of a carrier of X-linked recessive ocular albinism, and we see areas using her good X, next to areas using her bad X. I’m assuming you can see my pointer. Good X, bad X. Good X, bad X. We can actually see molecular genetic events happening in the eye, and that’s what’s led us to such great advances in ocular genetics, as compared to all other fields of genetics for other parts of the body. Because as you all know, the eye is the only organ we can see inside. Now, in the old days, we didn’t know much about albinism. All we knew was this enzyme called tyrosinase. We knew that was important in the making of pigment from tyrosine. And we would look at people and we would say… Oh, you look like you don’t have any tyrosinase, because you don’t have any pigment, so you must be tyrosinase negative. But we look at another person and say… Oh, you look like you have some pigment, so you must have tyrosinase. And that was it. That was how we did genetic diagnosis. But nowadays, things have changed. In fact, if we just look at the tyrosinase gene and mutations in the tyrosinase gene, we would say this boy makes no tyrosinase at all. He has a null mutation in both copies of his gene, and he has 20/400 vision, nystagmus, and is very hypopigmented. This child, however, also has a mutation in his tyrosinase gene. He’s got more sandy blond hair. You’ll notice white tips on it. He has nystagmus, but he sees better, 20/60, maybe 20/40. He has a form of albinism called the yellow variant form of tyrosinase-related albinism. And this gentleman here, who has white hair, 20/200 vision, you can’t see his iris transillumination, macular hypoplasia, everything else, he clearly has albinism, but here’s the hair on his arms. How could he have black hair on his arms? White hair on his armpits, white hair on his chest, white hair on his pubic area and black here on his legs. Because his form of the tyrosine enzyme only works in cooler areas. In warmer areas, it doesn’t work. It’s called the temperature sensitive form of this disease. And our eyeballs live inside our skull, where it’s warmer, and therefore they’re affected by the fact that the tyrosinase doesn’t work there. So here we have a known single gene, and already I’ve shown you three different diseases as a result of the mutation in that gene. So what’s happened is that the knowledge of genetics is changing the way we make diagnoses and what we call things. Here we see a boy who has bruising and albinism. He has Hermansky-Pudlak syndrome. Ten different genes are known to cause this disease. All different in their manifestations, in terms of their effect, for example, on the lungs. So things are getting more complicated. And as we change the way we name disorders, now we use a gene-based nomenclature. Each type representing a different gene. And some disorders such as Hermansky-Pudlak having more than one gene causing that particular phenotype. And this is happening everywhere in ocular genetics. Just look at this old slide of cataract genetics. We now know over 100 genes that are related to cataract, both age-related and congenital and developmental cataract. And now, as you can imagine, phenotypes overlap. But we know that cataract is a complex genetic disorder, in some individuals, and a single gene disorder in other ones. In glaucoma, here’s our adult juvenile open-angle glaucoma, but our adult primary open-angle glaucomas — we’re starting to suss out the different loci, some of which we know are genes responsible — and others — that tell us different phenotypes. What do we call it? We can’t call it just glaucoma anymore. It gets very complicated. And sometimes we don’t even know what to call something. Here’s a child with aniridia. You can see the absence of iris, and that’s due to mutation in the PAX6 gene. But as it turns out, if you have a PAX6 gene mutation, you can have any of these phenotypes as well. Here we see ectopia lentis from PAX6, here we see almost a colobomatous-like iris. Here we see iris stromal defects with corectopia, and a patient with nystagmus and presenile cataract. These are all PAX6 patients. These patients have a normal iris, yet have PAX6 disease. A nuclear cataract and autosomal dominant keratitis. So it’s even getting hard to call things something. Should we all call this PAX6-opathies? Maybe we should. It’s becoming difficult. Why even bother trying to get a gene diagnosis? Well, if you know your gene, you have a diagnosis, and you’ll just have to believe me that 99.9% of families would rather have a bad gene diagnosis than not know what they have. Uncertainty is much worse than bad news. And once you have a diagnosis, you can get counseling, which leads you to a whole host of benefits. Finding others like you. I have patients who when I made their diagnosis, there was only three people, four people in the world with that diagnosis, but through Facebook, they connected, and now have a community of 20, 30, 50, or 100 patients with that diagnosis. The counseling allows for reproductive counseling, and allows for counseling regarding their prognosis for the future. Because they’re no longer this disease, retinitis pigmentosa. They’re a patient with this specific mutation and this specific gene. And now we can compare that to other patients with that specific mutation in that specific disease. We can also counsel in terms of support groups. And we can counsel in terms of treatments and therapies, which we’ll get to. And the whole idea of therapy comes out of the idea that once you know the gene, then you can also get some clue to the etiology, and thus the pressure points for effecting a cure. The eye is a great place for a cure. It has many, many aspects which make it amenable to gene therapy. It has the immune privilege that it enjoys. And subretinal space, the vitreous, the anterior chamber. It’s very accessible. The target cells can be visualized, we can see what we’re doing, we have the barriers that protect it from going elsewhere in the body, and the RPE has some phagocytic properties. We can put needles in the eye all over the place. Peribulbar, subvitreous, anterior chamber — we can get it to go where we need it to go. But everybody who is listening today is already a gene therapist. If you’re using prostaglandin analogs, you’re doing gene therapy. What happens when you give those drops is you’re changing expression of metalloproteinase genes in the area of the trabecular meshwork, and you’re effecting an answer by manipulating genetic knowledge. That’s gene therapy. Gene therapy means many different things. It could mean replacing the protein that a gene makes. It could be replacing the gene. It could be fixing the gene. All of these things are forms of gene therapy. In 2008, the New England Journal of Medicine report from the University of Pennsylvania and Italy showed the initial effects of treatment of humans using a viral vector which carried a copy of the RPE65 gene into patients who had Leber congenital Amaurosis. Previously in dogs this work had showed remarkable ability to restore vision in dogs. Dogs who used to sit around under a table were now chasing balls in the backyard. What we found was that it wasn’t perfect. There were patients who got macular holes, but the process had started. What was dramatic about these first patients was a boy named Cody. Cody had… I think he was 8 years old at the time. And when you put him in an obstacle course, where he was forced at first just to use the eye, which will be treated, he could barely get through the obstacle course. He had to stop midway through, saying I can’t do this. But with gene therapy, he was able to completely navigate the course easily, stepping over obstacles, ducking beneath obstacles, opening a door at the end, and in his real life was able to ride a bike, play baseball, attend a regular school. Amazing, dramatic achievements. Really, this was going from blindness to sight. And in fact, as you know, in 2018, the FDA in the United States approved this drug, Luxturna for RPE65 disease. And that’s for all patients who have a mutation in each copy of their RPE65 gene. Amazing. Sounds fantastic. There’s many other trials that are — over 20 trials right now, involved with gene therapy for a whole variety of diseases. All on a research basis. At many centers around the world. The UK, Canada, the United States. There’s a report from the choroideremia trial, which was less encouraging. Only one patient out of six got better in that trial. One got dramatically worse. But we’re forging ahead, because the RPE65 trial let us know that we could indeed do gene therapy successfully in the eye. There are other ways to address these retinal dystrophies. People have tried medical treatments. That is the replacement of proteins. This is a synthetic rhodopsin, essentially. There’s stem cell transplantation. So keep in mind, if a patient has no photoreceptors, for example, on their OCT, then there are no cells to take on the gene therapy virus. You can’t do gene therapy. They would need new cells. And you can do that through a stem cell transplantation. Stem cell transplantation is, unfortunately, available many places around the world, but it is a sham. There are places out there offering it that really are not things that we should do. Good scientific retinal transplantation — that is taking stem cells from a skin biopsy, for example, transferring them or changing them into retinal cells, developing those retinal cells in culture, and putting them back in the retina — something that Ed Stone and his group are leading in Iowa and others — are really remarkable, remarkable ways — because they will grow into the retina. They will be oriented properly. And if you think about it, you can take the patient’s cells, use CRISPR Cas9 system, you can fix the gene defect in their cells, and put their own cells back in, so we don’t have to worry about immune problems, and even if the patient — let’s say it was an RP patient who has a gene defect, whose onset was 40 years. It took 40 years for it to show itself — we may not even need to fix that person’s gene defect. We can just culture new, fresh, young retinal cells. That patient is 60 years old. We put it in their retina, those cells are not gonna manifest RP for another 40 years. The patient won’t be alive. So they would at least have the benefit of their healthy, young cells in the mean time. So lots of opportunity in the stem cell range. Lastly, we can have bionic chips. We know the Argus II was also approved by the FDA. This implant, which lives on the retina — you know, you can see light perception. Get a little bit of navigational vision. There’s a new implant in Germany which will be coming to Wills in the future — this year, actually — which sees better. That can allow patients to recognize a letter, approximately 6 inches tall, to differentiate between different utensils on a table, to differentiate between different kinds of fruit. So chip technology is also getting better. But let’s get back to gene therapy. You know, in order to have gene therapy, or even stem cell — if you’re gonna use something like CRISPR to fix the cells, you must know your gene. So knowing you have RP is kind of meaningless. You need to know: What is the gene causing this patient’s disease? And that’s where things get tricky. Well, you might say: Let’s start doing gene tests, right? If that’s what we need to know, if I want to refer my patient, all I’ve got to do is order a gene test. So let’s see this. Let’s do poll question two. Who can order a DNA test? Only geneticists, only an ocular geneticist for an ocular disease, any ophthalmologist or optometrist, or genetic counselors? Take your time and put answers in. We should have a little music in the background. Interesting. So 55% of people said any ophthalmologist or optometrist. About a quarter of you said genetic counselors. 13% said only ocular geneticists. In truth, in North America, anybody can order a genetic test, and that’s a problem, as I want to show you. Because you can’t order a test if you don’t know what to do with the result. In fact, maybe the question should have been reworded. Who should order a DNA test? Well, that’s a more complicated question. And we’re gonna answer that now. But before we go on, poll question number three. A patient has a two base pair deletion in an RP gene just downstream from intron 4 donor site. This means, one, this is the cause of the patient’s RP, two, this is not the cause of the patient’s RP, three, it means the patient doesn’t have RP, or four, I don’t know. Well, 59% of you got the right answer. Which is: I don’t know. 24% said this is the cause of the patient’s RP. But we don’t know that. I don’t know that from this slide. I would need to know many things, as I’ll show you. That it’s not the cause of the RP? I don’t know that either. And I don’t know if the patient doesn’t have RP. I really don’t know, and that’s because there’s many things. When we get a gene test result back, first we look… What gene was abnormal? What’s the phenotype? Is this gene known to cause this particular phenotype? Has this change in the sequence previously been reported by others as being pathogenic? Or is it just a normal variant? Do we believe the report? Was the report in the lab done in a way that we think it’s accurate? What’s the biologic prediction? If we go into the computer and do modeling and proteomics, and say… Do we think that this change in the gene is actually gonna change the protein function? Is there evolutionary conservation? There’s ways to see… Is this gene and this mutation or this change so important that it’s in a place in the gene that withstood evolution from flies to humans? We have computer in silico prediction algorithms that can help us decide. We have to look at segregation. Does the unaffected brother of this patient have the same mutation or change in the gene, that it’s not a mutation? It’s just a polymorphism, a normal variant sequencing? And there’s many things. So as you can see, knowing the change in the gene of the sequence is the tip of the iceberg, and just the beginning of understanding what that means for the patient. I would say for every hour we spend with our patient, we spend almost ten hours behind the scenes trying to figure out the answers to all these questions, to convince ourself whether this change is related to the patient’s disease, and what it means for their family, in terms of all the counseling we’re going to do. In fact, sometimes we don’t have an answer. And the more gene tests you order, the more noise you get. Because we all — everyone on this call, from around the world, we all look different because we have different sequences in our gene, and likewise, our retinas have different sequences in our gene. And the trick is trying to sort out the normal variants from those that are truly disease causing. And you can’t just rely on the lab report. Every time we get a lab report, we check to see if we believe what the lab says. We look for new evidence that the lab may not be aware of. We have to always double check. So the lab may say it’s a mutation, and we say… Nah. We don’t think so. The lab may say it’s a variant of unknown significance. We say… Eh, we think it’s a mutation. Sometimes just the passing of time, a report from five years ago may have said one thing, and five years later, we know more, using public databases. So it’s not so easy. Not so easy. To get to a treatment, you have to have a diagnosis. Some of that comes from pattern recognition. Sometimes a patient comes in, our most common misdiagnosis that we get is retinitis pigmentosa that turns out to be something else. Second most common missed diagnosis we get? Stargardt. Turns out to be something else. Sometimes I can look at the patient and say: I know what gene this is. One gene. And that’s not because I’m smart. It’s because we see this all the time. Over and over, we see the same thing. We can begin to recognize these patterns. Of course, our diagnosis is not just clinical exam. It has to do with diagnostic testing. Multifocal ERG, full fundus autofluorescence, color vision, visual fields and more help us understand the phenotype, and only then can we proceed with the most restrictive DNA plan that we can think of to ensure that we are testing the fewest number of genes, for the most accuracy and the least noise. So it’s not just a gene test, right? You want to do DNA, you’ve got to choose which test am I gonna order. And there’s many different tests that we could order. We could order single gene panels, we could order whole exome sequencing, whole genome sequencing. But each test has a specific role, and it all depends on defining the phenotype and the phenotype subtype. We also want to examine the family members, because certain diseases travel in certain ways in families. We want to figure out if there’s people who may be carrying something. They may have glaucoma and never know it. These are things that help us choose a test. And when it gets down to which test to order, there’s many factors that come into play, from insurance to availability to accuracy to turnaround time. A pregnant woman wants a turnaround much faster than someone else. And payment issues, at least in North America — I should say at least in the United States, less so in Canada — are more important. Then you have to interpret the test result. And as I showed you, that is a really complicated, time-consuming process. In particular, is this variant a mutation causing the disease? Or just a normal polymorphic change in the chromosome? Does it explain the phenotype? I got a question before the session about a patient with macular hypoplasia. Maybe we’ll get to that question later. Who had a panel of tests done, and multiple gene came back, including USH2A, a gene which often has polymorphisms in the retina. But the question: Does that cause — well, that doesn’t cause macular hypoplasia. So that gene is unlikely to match. And of course, we’d have to look at each gene change, and say: Is it really a mutation? Or just a polymorphism? And all of us, by the way, carry mutations that may be unrelated. And then we have to test family members to better understand the patient and the finding of their DNA. Now, you can’t do gene testing without a genetic counselor. Or at least, you shouldn’t. You can certainly order it, but there’s a tremendous amount of work that must happen every time a test is done. Our genetic counselor meets with the families before testing, and talks about: What’s the cost? What are the risks? Risk of testing? It’s just a blood draw. In North America, when you draw blood on a family, 10% to 15% of the time, you will discover undisclosed non-paternity. Daddy is not daddy. That’s a risk! Relationships may unravel! Relationships may be revealed that were formerly not known or not disclosed. Turnaround time — what’s the expectation of the patient? If the expectation is you are gonna find a mutation to my disease and cure me, that’s an unrealistic expectation, because we cannot do that with every disease. We’re able now to make a diagnosis on our patients about 80% of the time. We can get a DNA diagnosis. That’s excellent. It’s really, really excellent. Takes a lot of work, a lot of time, and that means 20% of the time, we can’t get a diagnosis. And then after those results come back, someone has to sit down for an hour, sometimes with the patient. To interpret that test. What does it mean? What are the implications, in terms of family counseling for the future? What’s the next step? How can we get to a treatment? Sometimes we might say: We have one gene we’re working on now, where we found out there was a dog model. Where the dogs have been successfully treated. We contacted the dog researchers on behalf of our patients, and now we have an international gene therapy trial that’s getting started. So there’s a lot of work to be done before and after, and that’s where having a genetic counselor is essential. And let’s not forget the ethical issues. Should we be doing prenatal testing for eye disease? In some countries, abortion is legal. In some countries, a woman can have an abortion for any reason she wants. I’m not arguing whether that’s right or wrong. But when we start to think about… Should we test for a disease of adult onset, with no cure, like RP, at the current time… That has some ethical considerations. Should we test young children before they get the disease? I saw a child the other day who has a mutation in one of the genes, 3640, a mitochondrial mutation, for Lebers hereditary optic neuropathy. We don’t know if he’s gonna get the disease. We just know he’s got the mutation. What good are we doing for that child? Is there a treatment now for that kid? Or do we just sit around and let parents treat him differently? And there was already a tremendous amount of psychosocial stress in that family around this. What about confidentiality? Who owns your gene test results? Can an insurance company deny your insurance because they know that someday you’re destined to get a disease? And of course, there’s the issue of what to disclose. When you do a panel of tests and you get six or seven different gene abnormalities that may be unrelated to what you’re looking for, what do we tell the patient? What things are mandatory? There are mandatory genes for disclosure, whole exome, in the United States. What about if it’s not mandatory? Do you want to know if you’re gonna get Alzheimer’s or not? These are all good questions. And even eugenics comes into play. We live in a world where we can make flowers without stamens and chickens without feathers and unusual animals, and you say this would never happen in humans, right? Well, it was only a generation ago that it did happen in humans. We say that would never happen again. Well, look what did happen. Here’s gene therapy for red-green color deficiency. Is that a disease? My son has it. He seems to be okay. Should we be using resources and energy and scientific brain power to treat what is maybe just a normal variant? 8% of males have this. 1% of females. So we do get into some tricky questions, and those are handled by people familiar with it, and our genetic counselors are helpful as well. And when it comes to gene therapy, there’s also ethical issues. Right? Who’s gonna get it? What, when, and where? For example, if we know that a patient is going to get retinitis pigmentosa, we know we can treat them, and we’ve treated successfully when someone is 20/400. Wouldn’t it be better to treat them when they’re 20/20? But who wants to have a subretinal injection when they’re 20/20? What about those risks? Could you cut off the vision they have now, cutting off your nose to spite your face for later? Should we be treating children who are unable to give their own consent? Who is gonna do the treatment? Should it only be at some centers? So these are very difficult issues that we’re still wrestling with, as gene therapy comes to the forefront. Another question we might ask: Is Luxturna a success? Well, from the paper by Stone, there’s probably only 163 people in the United States who have mutations in both copies of their RPE65 gene and are eligible for this treatment. If we imagine that 80 of those are inaccessible because they live in conditions or whatever that we can’t get to them, or maybe they have other medical contraindications, maybe there’s only 80 people out there who are eligible. Should we be putting these kinds of resources into a disorder with only 80 people? Not everyone improves with this. Some improve more than others. There’s questions about: Does it last over time? These are all things we need to address. But most importantly, it costs $425,000 per eye. Many of you in this call are in countries where the per capita income could never sustain this. And I would argue that the United States can barely sustain this. This is a high price! And if you consider it as a two-eye treatment, you’re up to almost a million dollars. This is just for the drug! Not the procedure. So that’s not gonna work. Right? That’s not a success. We need to have affordable gene therapy that’s accessible to everyone. From the most recent study that came out regarding choroideremia — here this patient only has this tiny bit of retina left. If you’re going to do gene therapy, you’re gonna need to inject under their only remaining tiny bit of retina. That’s tricky! If I was a choroideremia patient seeing 20/20, would I want to take that chance? The initial report that just came out was very discouraging. But obviously we’re gonna try and keep moving forward to help people with this disease. Perhaps treating earlier is the key. So take all of these issues we’ve discussed today, all these many, many issues. The complicated nature of making a diagnosis, of what to call something, how to label these, to find the right gene tests, to interpret the gene tests, to counsel, and then apply that to the myriad of genetic disorders. RP, cataract, coloboma, strabismus, retinoblastoma. Apply it to all the systemic diseases with ocular manifestations. Galactosemia. Marfan’s, tuberous sclerosis, neurofibromatosis, Alpert, and on and on and on, you wind up with a mountain of information that is simply enormous and unmanageable. How are we gonna deal with that? Say help! Who you gonna call? You’re gonna call the people who will manage this exciting explosion and that’s the ocular geneticist. So this is a new specialty in ophthalmology. There are only 70 to 80 ocular geneticists in the world. But this is the route to getting the patient the care they need and answering those questions. A typical program like the one here would have an ocular geneticist, or more than one, genetic counselors, ability to do the research and teaching that’s necessary to create new people doing this, the diagnostic testing we mentioned, and ophthalmologists. At Wills, we have over 225 ophthalmologists who can funnel this rare pathology into our ocular genetics program to help establish pattern recognition that can happen in all of these centers. That can do this kind of work. We do clinical and surgical care of adults and children, who have primary genetic eye disease. And we consult with patients who are sent by geneticists, who have systemic disease with eye complications. We may still do gene therapy on a patient who has a systemic disorder, at least to treat their retina, so they can see. Even if we can’t treat their systemic disorder. We work with support groups from around the world. Pediatric glaucoma and cataract family association is an example. The Sturge-Weber Foundation and others. But really, what does it mean for the patient? What it means is that when we see a patient like this, who’s got RP, we would all say RP, but RP is a word that describes a thousand different disorders. Now we can give them something more than what’s been said for all these years. People say… Oh, I’m not sure what you have. See you later. You’re gonna go blind. Nothing I can do. Sometimes… I don’t know what it is! Some weird retinal dystrophy. And we leave these patients to languish. Now we can give them a diagnosis, and not just a phenotypic diagnosis, but a genotypic diagnosis. We can empower them with knowledge, with the support, they feel more in control of their disorder, with genetic counseling, we can identify family members at risk. Imagine a patient has a mutation in myocilin, causing juvenile open-angle glaucoma. They’re a six-year-old, a ten-year-old. There may be people in the family who never knew they were gonna get glaucoma, or may have it now. We can genetically identify them, screen them early, and do the kind of screening that will prevent future damage before they come in for aggressive disease. And we can say to the patient: Here’s what patients who have your genetic mutation look like 50 years from now. We can give them some idea in the future. We can identify the treatable entities. We know we have dietary treatments for some of these. For some, we’re finding out… Oh, you have a fibrillin mutation causing your ectopia lentis. We need to do an ultrasound of your heart, because you can have signs of Marfan syndrome that aren’t obvious. If you have Alstrom, looking for cardiomyopathy — we can save lives by finding things a patient never even knew they had, because we found their gene mutation. And of course, we can identify clinical trials. Now, you can go to www.clinicaltrials.gov, which is a website hosted by the NIH, that tells you all of the active registered clinical trials. In the United States, you can’t do interventional research without registering to do this. But you’ve got to be careful. Just because a trial is registered doesn’t mean it’s good. Doesn’t mean a lot of things. Doesn’t mean your patient fits the inclusion or exclusion criteria. So you need to research that. They may be based on age or vision. Do they cover the travel expenses for your patient? Are you happy with the center that’s doing the treatment? Do you know their doctors? Are they good to use? This is the kind of knowledge that ocular geneticists get, because we work with these centers all the time. But I think ultimately the change in the message now is you will be cured. 12-year-old boy came to me 25 years ago with RP, I would say… I’ve got nothing for you. That 12-year-old boy comes to me today, I say: You will be cured. There’s no question. In fact, for all of these retinal dystrophies, this is the answer. You will be cured. We can do this now. But how do we get there? In order to say this, we need to get a gene diagnosis. That’s gonna be based on a phenotypic diagnosis. That will happen in a center where they can recognize that and know what tests to order, know how to interpret those tests, know how to counsel the family, and that starts the pathway to a cure. Even if there’s not a gene therapy right at this moment, or a trial for this patient, they kind of move to the front of the line for their DNA test. Can you — let’s dig in on this video conference — do it all by yourself? Maybe you can. If you can, that’s great. But if you can’t, if some of this has left you discouraged, say: Well, here’s what you can do. We need to train ocular geneticists and ocular genetics counselors. There are only 30 or 40 ocular genetics counselors in the world. How do we do it? We do it through fellowships. We have a few spots here at Wills. There are a few others in the United States and a couple in Canada and others in Europe. There are places where you can train, and as we do this training, we start to train people. Here are people just from our institution alone. So if you’re in one of these countries on this call or near these countries, help is at hand. You can refer to these individuals. There are many other — as I said, there are 70 or 80 around the world. In almost every country in Europe, you’ll find one. Several in the UK. There’s another in The Middle East. They’re all over. Finding them and linking with them, getting your patients into those pathways, is gonna help you deliver the best care to your patients. Our world is changing. Our world is changing in a way in which we can now deliver really incredible promise to our patients. What we used to say was the future, was science fiction — the future is here. But to get there, we must get there in a rational, understandable way, in order to test our patients, diagnose our patients, and open up for them that future that will happen during your lifetime. So with that, I’m gonna end my formal remarks. We have a list of questions that is gonna be put up on the board in a second by Lawrence from Orbis, who has done a wonderful job. And what I would like to do is invite you — you can submit other questions online. We’re taking those questions as well. And I’ll respond to all of your questions. But let’s look at these questions that came from people who are listening now. Great question. Are any genetic tests for age-related macular degeneration trustful? So when we say: Is a test trustful, we’re answering two things. One, is the test itself done in a way that we can believe the information that it generates. And the answer is yes. We’ve got lots of good tests that we believe the answers. But what do we do with the information? So for complex genetic disorders like macular degeneration, testing is really not helpful at all today. We’re trying to learn. We’re trying to develop personalized medicine, where certain mutations and certain genes make you a better person for an anti-VEGF or a better person for not an anti-VEGF. We don’t have that yet. There’s a wonderful editorial written by Ed Stone within the last five years, I think. I think it was in JAMA Ophthalmology. Talking about what are the pros and cons of testing, and really, at this point in time, we do not recommend gene testing for age-related macular degeneration. It’s an example of where testing creates a lot of noise, and not a lot of clarity. Are there specific RP genetic tests available in the US that are commercially available? Yes, absolutely. There’s all kinds of tests. Single gene tests, panel tests based on whether it’s RP, whether it’s dominant or recessive, based on the pedigree, panels based on macular dystrophy. There’s whole exome sequencing that’s commercially available. But the trick is, number one, RP is our most missed diagnosis. Our most missed diagnosed disease. Just because there’s pigment in the retina doesn’t mean it’s RP. Heck, you could have a normal ERG and have pseudo-RP. First, look at your phenotype. Do diagnostic testing. Yes, there are commercially available labs. You can look them up online. You can go to clinicalgenetests.org. There are lots of ways to find these tests. But make sure you know how to interpret them. And you know what tests to order, using the smallest amount of test possible. Insurance is complicated, because an insurance company can give you preapproval and then not pay. We spend a lot of times arguing on behalf of our patients, and it can cost thousands of dollars. So be careful about where you send the blood and know that you need to counsel before and counsel after. Can we prevent ocular genetic disease by gene mapping the parents? We can gene test anybody for anything. We can test parents only if we know the mutation in their child. You might want to watch the movie Gattaca, a great movie about the future of gene testing, where parents in the future can pick their kid. What color eye they want, what color hair, how tall, and so on and so forth. We don’t do that yet. We don’t do routine gene testing of individuals, except for known treatable genetic conditions. Sickle cell is something that’s screened for in every baby of African descent. PKU, things like that, thyroid disease. But a full panel of genetic testing? We don’t do that. Now, on the other hand, we could prevent ocular genetic disease. If we knew that the first child had a mutation in the gene, we could test the parents. If the parents were found to be carriers, we could do preimplantation genetic diagnosis, where we could select the in vitro fertilized eggs for those that carry the disease and those that don’t, and only reimplant those that don’t have the gene. That’s a little bit more tricky. You can’t just order that from a laboratory. But once again, it all goes back to the right phenotype and genotype in the child, and then going from there. As far as the basic genetics, in relation to the eye, I think we’ve done that. And how can one apply genetics to clinics we’ve discussed as well. But how can ophthalmologists from developing countries like Nigeria get help? This is really a difficult question. Because even when we take our trained ocular geneticists and put them out in other countries, they may not have access to all the diagnostic tests. They may not have access to DNA testing. Their patients may not be able to afford testing. And in fact, there may be cultural barriers to testing in some places. How do we overcome this for our patients? I personally think that ultimately, other than training ocular geneticists to get fellowship training and come back to those countries, it’s gonna come from philanthropy. And we’re working on a philanthropy model right now with a center in Iowa here at Wills. Because every country has rich people. And I think by starting to find how we can use philanthropy to support the cause of genetic testing, of diagnostic testing, the support and care and training of individuals, it’s really going to change. Because as I told you, every single eye problem is genetic. Getting our donors involved is gonna be really helpful. That’s a long-term solution. In the near term, we have this thing you may have heard of called email. I would encourage you — feel free to reach out to me and other ocular geneticists who may be near you. What should I do? Before forging ahead and ordering a DNA test without counseling, reach out by email, and we’re all happy to help. We talked about genetic testing. I want to go down to number nine. I can’t understand well retinoblastoma possibility in a family have a child with RB. That’s complicated than what we can test for today. We did 10. Number 11 — we talked about epigenetics. If you look at it as a general term, it’s: What else is going on that affects how this one gene is going to manifest itself in the eye? For a perfect example, that might be Leber hereditary optic neuropathy, where we know if somebody smokes, it affects the expression of the gene. We also are learning more about digenics. These are all complicated things we need to explore for the future. 12 we just covered. And 13 I think we covered as well. The answer is yes, for every eye disorder. We talked about the UK. If you contact me privately, I can tell you more about who is there. Some great ocular geneticists in the UK who can help you. Some great work being done there. What ocular disease should we keep in mind when dealing with consanguinity? So there are countries in the world where the rates of consanguinity are 80% in couples. Nothing wrong with that. That’s just the nature of the culture. But it does increase the chance of having autosomal recessive disorders. Of course, there’s a host of autosomal recessive disorders, and finding which one is more common in the community is important. And it gets to the same as what mutations run in families. So sometimes I have a patient with RP who comes from a small community somewhere in the world. I can even use that information — he’s got consanguineous parents — to say he’s most likely autosomal recessive, and I know which gene to test, because that’s the gene profile in that community. So consanguinity helps us, but consanguinity does not give you immunity to dominant or X-linked recessive disease, and we have to keep that in mind. We answered number 16 and we answered number 17. I’m gonna go to the Q and A questions that were submitted. We talked a little bit… Someone sent me a question from Spain, a complex question about a child who has a hypoplastic macula. And it is interesting. I don’t have enough information here, and I would encourage that person to contact me by email. But here’s a patient who comes back, and it says three mutations in the USH2A gene and one mutation in RPE65. And now here we are, left trying to sort this all out. If I knew that the kid had an albinotic fundus with hypoplasia, I wouldn’t have ordered those genes in the first place. I would have done a more specific test relevant to that phenotype. Now we’re stuck with mutations that may or may not be related. It generates some noise. We know about Luxturna, so we see RPE65, and we think… Wow, this is exciting. But it may only be in one copy and it may not be disease causing. So there’s a lot of work that needs to be done on this patient, to backtrack and find out what the cause is. I would be happy to help you offline. What strategies do you have when you are concerned about a systemic diagnosis based on an eye diagnosis, but the family does not follow through? The patient has been treated for four years for high astigmatism, diagnosed two months ago with bilateral ectopia lentis, and the mother has not followed through. This is a great question. Families are unpredictable. They may not want to know where this came from. They may be afraid that there’s a secret in family relations that may be revealed. There may be guilt that I gave this to my kid. There are so many things that keep parents away from a genetic diagnosis. And that’s why we have genetic counselors to help them work through those issues with the family. Of course, if the patient needs surgery, you can not go to surgery without testing the heart for an aortic enlargement, without testing for homocystinuria. But short of a real need like that, you need to have conversations. Collegial, long conversations, sometimes, with families, to help them get to see. And also we need strategies to help them get past the cost issues and the availability issues, which may also be a concern for them. Question three: What are the basic things to start a genetic lab in a developing country? That’s a complicated question. I’m happy to deal with that offline. I’ll give you one sentence: It ain’t easy! It takes a lot of work, a lot of money, a lot of knowledge, and it’s important that we do it in ways that yield good results. Lastly, how good is linkage analysis in identifying the mutated gene? Should it be done on all phenotypic as well as genotypic cases in the family? Just to clarify, linkage analysis is not the same as gene testing. In linkage analysis, what you’re doing is tracking through a family looking at affected and unaffected individuals, to try and isolate the piece of DNA that’s running through that family, segregating with the disease. Then you’re left with the question of: Where is the gene in that piece? And how do I find it? And there’s ways to do that through databases or through laboratory methods, but ultimately, linkage is very much — not completely — a thing of the past. Because now we know the genes more, and we can look for more. If we have a family where we can’t find the gene on regular gene testing, whole exome sequencing or whatever, and please everyone understand — whole exome sequencing isn’t the routine test. Sometimes it’s your first test. Sometimes it’s your last test. Sometimes it’s your never test. We have to do that at the right time with the right people. Linkage is similar. There are rare situations where we still do linkage today, to try and find the gene in a family that we can’t find otherwise. So I see that we’re coming to an end. It’s 10:00. Our questions have gone to the end. I want to thank you all very much for being here. Special thanks to Orbis for hosting this seminar. Orbis is a wonderful organization. I’ll declare my conflict of interest. I do sit on their medical advisory committee. But it’s a great organization, doing great work. Special thanks to Lawrence Sica, who helped coordinate this today, and of course, thanks to all of you for being there. And let’s do the best we can for our patients, going forward. Take care. Thank you very much.

Download Slides


October 3, 2018

Last Updated: October 31, 2022

Leave a Comment