Genetic testing gains traction, opens new horizons in eye care
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Over the past 2 decades, a large body of research has shed light on the molecular determinants of many human disorders, including eye diseases.
Genetic ophthalmology is an evolving field, and molecular approaches and techniques are moving from vision research to clinical practice. Among them, genetic testing is emerging as a promising method to increase the accuracy and specificity of a diagnosis, providing the basis for highly personalized care.
Source: Janey L. Wiggs, MD, PhD
“Genetic testing is becoming increasingly available and clinically relevant. For eye diseases, and particularly for glaucoma, genetic advances are gaining traction in the community. I think genetic testing is going to change the way we treat patients,” Janey L. Wiggs, MD, PhD, an ophthalmologist and medical geneticist who specializes in the genetics of glaucoma, said.
Wiggs is associate director of the Ocular Genomics Institute at Harvard and director of the clinical diagnostic laboratory where patients are tested for gene mutations that can cause glaucoma, inherited retinal disease and primary optic neuropathy. She is the author of numerous genome-wide association studies that provided critical information on the genetic factors underlying the various forms of glaucoma.
“Genome-wide association studies have been incredibly successful in identifying risk factors for common diseases with complex inheritance and have formed the basis of polygenic risk scores, a really important tool that we can use now to stratify populations according to risk for these relatively common diseases,” she said.
For glaucoma, genetic testing and polygenic risk score analysis provide the opportunity to identify people at increased risk for developing the disease, allowing for increased surveillance and treatment at the early stages of disease onset.
“Many people with glaucoma don’t know they have the disease, and certainly most people who are at risk are unaware of it. And yet our treatment for glaucoma is most effective at the earliest stages,” Wiggs said.
New pathway for targeted screening
The damage caused by glaucoma is irreversible and can result in blindness, which is why early diagnosis is crucial, according to Anthony P. Khawaja, MD, PhD, honorary consultant at Moorfields Eye Hospital in London and associate professor at UCL Institute of Ophthalmology. He is also a dedicated researcher on glaucoma genetics and genetic testing for glaucoma.
“The current methods of screening are not predictive enough. Despite reasonable sensitivity and specificity, when applied to the general population, there are high rates of false positives, which result in overburdening ophthalmologists and hospitals,” he said.
Genome-wide association studies have opened a new pathway for a more targeted screening of patients potentially at risk of developing the disease.
“We can look at specific genetic markers and predict with a surprising degree of accuracy whether someone will develop glaucoma. Genetic tests will never be diagnostic because you can’t look at someone’s genetic code and say they have 100% or 0% chance of getting glaucoma. But what we can do is give everybody a risk score. And if we target population screening with our current tests to those at high genetic risk, it may well be cost-effective. To me, it is the most exciting route to reducing blindness from glaucoma by enabling cost-effective early detection,” Khawaja said.
Early-onset glaucoma
Glaucoma can occur at all ages. While adult-onset disease, including the most common form primary open-angle glaucoma (POAG), is inherited as complex traits, the early-onset disease that occurs in children and young adults is usually a severe disease with Mendelian inheritance, caused by individual genetic risk factors.
“In early-onset glaucoma families, genetic testing can be extremely helpful in identifying children who have the mutation and need to be carefully monitored and treated. But it also identifies those who don’t have the mutations, and this can be a great relief for their parents, knowing that the risk of glaucoma is not different from that of the general population,” Wiggs said.
However, not all genes involved in early-onset glaucoma have been discovered.
“With the current knowledge, we can only identify the genetic mutation causing the disease in about 20% of the cases. This means that we have yet to discover important disease-causing genes and genetic interactions,” Wiggs said.
Last year, her group found two new genes involved in early-onset forms of glaucoma. One of these is EFEMP1, and the other is a mutation in the THBS1 gene. And a new NIH-funded project in collaboration with the group of Jamie Craig and Owen Siggs in Australia, aimed at investigating the genetics of early-onset glaucoma using next-generation whole genome sequencing, is currently ongoing.
“Our ultimate future goal is to identify specific treatments for these early-onset glaucoma patients, including gene-based therapies,” Wiggs said.
Testing for POAG
POAG is one of the most heritable of all human conditions. The most recently published genome-wide association study for POAG identified 127 genetic regions associated with the disease, and further discoveries are underway.
“Open-angle glaucoma is what’s called a genetically complex trait, where the cause is not just one single genetic variant but the cumulative effect of hundreds of them,” Khawaja said.
Genetic testing for this type of glaucoma is now made available over the counter by direct-to-consumer genotyping companies, the largest of which is 23andMe.
“You send up a saliva sample in the post, they process it, and they send you a report on your risk of different diseases. I believe that many of our patients will be coming in to see their ophthalmologist with their score. This is going to change our practice quite dramatically because we are going to have a much better idea of how to manage these patients,” Khawaja said.
People at a higher genetic risk for glaucoma may be referred to have regular glaucoma screening once they reach a certain age. They may also lower their risk of developing the disease by reducing potential risk factors such as caffeine and alcohol consumption.
“Genetic testing also tells us about the biology of glaucoma. There are new biological pathways that we didn’t know were so important, such as lymphangiogenesis, which points toward pathology in the Schlemm’s canal and collector channel as being very important in POAG. Traditionally, we’ve always thought that POAG was a disease of the trabecular meshwork, and some of our treatments, such as iStents (Glaukos), trabeculotomy or SLT, only target the trabecular meshwork. But if a patient has a problem mainly in the Schlemm’s canal and collector channels, these treatments are not going to work,” Khawaja said.
“If a kitchen sink is not draining, and the problem is in the pipe and not in the drain opening, you will not solve the problem by just changing the drain opening,” he explained.
Studies are also aiming to clarify which genetic variants may influence treatment response, which may allow clinicians to offer more targeted, personalized treatments.
Whole genome sequencing
Panel testing looks at a specific set of genes known to be associated with a disease. But more and more, there is interest in moving toward techniques that identify all mutations, such as whole exome sequencing, Wiggs said. The American College of Medical Genetics and Genomics (ACMG) has published a list of 59 genes associated with severe, medically actionable conditions. Every genetic testing laboratory has a responsibility to report on variants observed in those genes.
“These are variants that have an impact on medical decision-making,” Wiggs said. “For example, there are variants that affect blood clotting, and it is important for patients and physicians to have this information. There are variants that predispose to side effects from anesthesia, and this is critical information if you are going to have surgery.”
In the United Kingdom, a large health research program called Our Future Health is recruiting 5 million adult volunteers to provide information about their health and lifestyle and to undergo genotype testing.
“That’s over 10% of U.K. adults. I think this study is going to pave the way for a paradigm shift in health care. The genetic data are held centrally, and then different specialists will be able to interrogate them. A general practitioner will be able to know about the risk of cardiovascular disease and decide whether to treat the patient with statins. It will feed into diabetes management and cancer screening programs so that people at the highest risk can get screened more often and earlier. Any time new medications are considered to be prescribed, doctors will know whether someone is likely to be a good or a bad responder or have side effects. It will feed into all aspects of patient care. We just need to be ready to make the most of this information in ophthalmology,” Khawaja said.
Inherited retinal diseases
Inherited retinal diseases (IRDs) are a broad group of genetic eye conditions that may present at different stages of life. Several hundred genes are associated with IRDs, and each gene may have a broad spectrum, Robert B. Hufnagel, MD, PhD, said.
“We call this ‘variable expressivity.’ In some cases, even individual family members who have inherited the same genetic change may have a different course of their condition,” he said.
Hufnagel is director of the Ophthalmic Genomics Laboratory and head of the Medical Genetics and Ophthalmic Genomics Unit of the National Eye Institute. His research focuses on the mechanisms of human genome variation that cause blindness in children, and he uses genomics, stem cell engineering and gene editing to establish patient-centered disease models for translational and preclinical studies.
“Genetic testing in general is very widely used for inherited conditions, and for IRD specifically, the diagnostic yield of genetic testing is over 50%. This means that in the various studies, in more than half of individuals, you can confirm the gene and the specific DNA changes using genetic testing,” he said.
Molecular diagnosis may also give information on the risk for other systemic features, such as hearing loss in Usher syndrome or liver and kidney disease in Bardet-Biedl syndrome, and some sense of the natural history of the disease for any specific patient.
Detailed clinical evaluations and genetic testing for IRDs are often provided in large academic centers where there is often a specialist in ophthalmic genetics or a retina specialist working in team with medical geneticists and genetic counselors.
“Genetic counselors are of utmost importance. They provide counseling before the test, so that the patient understands what is being tested and what the implications could be, and post-test counseling, where they explain the outcomes and what they mean for the patient and at-risk family members, including whether changes to clinical management are warranted,” Hufnagel said.
Access to genetic testing for IRDs has often been limited by lack of expertise and insurance coverage in the U.S. However, more recently, within both the United States and Europe, genetic testing has become more accessible through acceptance by insurance companies or incorporation into public health care systems. Access has been broadened also by testing programs. In the early 2000s through about 2015, the eyeGENE program provided free genetic testing for individuals largely across the U.S. and North America, and more recently, Foundation Fighting Blindness launched the My Retina Tracker registry to provide genetic testing at no cost for people with IRDs.
Testing upfront if treatments are available
“Genetic testing is performed after the disease is clinically diagnosed. In familial instances, once the genetic testing analysis report has confirmed the genetic changes in a particular individual, surveillance is performed on individuals who are at risk for inheriting those variants. Typically, for unaffected minors, we will continue to see the patient, and if there are signs that the disease might have started, then they can get the genetic testing,” Hufnagel said.
One case in which genetic testing is performed upfront in children of affected parents, before any clinical manifestation is detected, is the RPE65 gene mutation.
“RPE65 is what is defined by the ACMG as a ‘medically actionable’ gene because an FDA-approved therapy, voretigene neparvovec, is available. Therefore, in families where one case of RPE65-IRD is detected, at-risk members can be clinically evaluated and tested so that the treatment would be available for them at the right time if needed,” Hufnagel said.
Besides RPE65, more than 10 other gene targets are currently in some phase of clinical trials, he said. For the most part, the adeno-associated virus-based approach is used to deliver the normal complementary DNA. Some recent clinical trial results have been disclosed and look promising. Other strategies using antisense oligonucleotides or CRISPR gene editing are used to target specific mutations.
“In addition, more gene-agnostic therapies are currently in clinical trials. Depending on the stage of disease, these other therapies will be very important for the IRD community, including those without a genetic diagnosis, and we hope that they will work just as well as the gene-targeted therapies,” Hufnagel said.
Not recommended for AMD
Multiple genetic variants located in more than 30 loci contribute to the risk of developing age-related macular degeneration or progressing to the advanced stages of the disease. These include variants in the complement system, such as CFH, CFI, C9 and C2, genes not involved in the complement cascade, such as ARMS2 and HTRA1, and also lipid genes such as ABCA1, among others. Commercial genetic testing for some AMD risk variants is currently available, but there is no definitive evidence that genetic information can help retina specialists in their treatment decisions for AMD.
“We have established that there are genetic factors that can predict the risk of progression to late AMD, but this is still not enough to change our management of the disease. Today, disease progression is mainly established by multimodal imaging-based phenotyping; a genotype assay could potentially make a small difference, but I don’t think it warrants a screening of all the population,” Anat Loewenstein, MD, MHA, said.
Loewenstein is chair of the department of ophthalmology and Sidney Fox Chair in Ophthalmology of the Sackler Faculty of Medicine at Tel Aviv University, Israel. Her research interests include early detection and novel treatment modalities for AMD, but it is her opinion that the time is not ripe for genetic testing to play a major role outside research.
“Like most of my colleagues, I believe that genetic testing for AMD should only be used in research. In the future, if we gain more information on individual genotypes and the promise of gene therapy is unlocked, genetic testing may become very important,” she said.
For the same reason, the American Academy of Ophthalmology does not recommend genetic testing. Citing one of its statements, “gene therapy is not available for prevention or management of the disease, so there is no benefit of identifying which genes are involved in any individual’s case of macular degeneration.”
Currently, several gene therapies for AMD are undergoing clinical trials, but there are challenges that will need to be overcome to bring them to fruition.
“Gene therapy is a promising option, but it is complicated and still facing many hurdles. The advantage is that it is a one-time treatment, but this is also a disadvantage because it is not reversible, and there are concerns about the immune response,” Loewenstein said.
In specific situations, however, she does recommend genetic testing for patients who present with potential signs and symptoms of AMD.
“We must be aware that we have situations that are mimicking macular degeneration and are actually dystrophies. If we don’t diagnose them correctly, we may treat them inappropriately or include them erroneously in clinical trials, compromising the validity of trial outcomes. There are many variants of Stargardt disease that look very similar to geographic atrophy, for instance,” Loewenstein said. “When something goes wrong with the treatment, we should stop and think if it’s not actually an IRD. And also, before we engage the patients in clinical trials, we might want to make sure that it’s not an IRD. Multimodal imaging can usually provide the answer, but whenever I suspect that it may not be AMD, I do genetic testing for specific dystrophies such as Stargardt.”
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- For more information:
- Robert B. Hufnagel, MD, PhD, of the National Eye Institute, can be reached at robert.hufnagel@nih.gov.
- Anthony P. Khawaja, MD, PhD, of Moorfields Eye Hospital, London, can be reached at anthony.khawaja@ucl.ac.uk.
- Anat Loewenstein, MD, MHA, of Tel Aviv University, Israel, can be reached at anatl@tlvmc.gov.il.
- Janey L. Wiggs, MD, PhD, of Harvard Medical School, can be reached at janey_wiggs@meei.harvard.edu.
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