Genetic Testing Gains Traction, Opens New Horizons in Eye Care
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.
One example of the utility of genetic testing can be found with inherited retinal diseases (IRDs), 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, director of the Ophthalmic Genomics Laboratory and head of the Medical Genetics and Ophthalmic Genomics Unit of the National Eye Institute, 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.
“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.
“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 [American College of Medical Genetics] 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. “In addition, more gene-agnostic therapies [work regardless of specific mutation] 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.
In contrast to IRDs, genetic testing is not currently recommended for AMD. Multiple genetic variants located in more than 30 loci contribute to the risk of developing AMD or progressing to the advanced stages of the disease. 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. According to the American Academy of Ophthalmology, “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. “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,” Anat Loewenstein, MD, MHA, chair of the department of ophthalmology at Tel Aviv University, said.
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Edited by Miriam Kaplan, PhD
Source: Healio, February 20, 2023; see source article