EyeNet Magazine

Genomics in Ophthalmology: On the Cusp of a New Era
By Lori Baker Schena, Contributing Writer

Meet five researchers who are helping move genetics from the lab to the realm of patients and your clinic.

In front of thousands of Academy members, Francis C. Collins, MD, PhD, proclaimed last year that information generated by the monumental Human Genome Project “is changing the scope of care for all physicians, and, clearly, ophthalmologists are at the leading edge of this revolution. The Human Genome Project, which mapped and sequenced all human DNA, has dramatically accelerated efforts to uncover the genetic mutations responsible for eye diseases.” Dr. Collins, director of the National Human Genome Research Institute at the NIH, addressed the crowd during the Opening Session of the 2005 Chicago Annual Meeting.

Little more than one year later, Dr. Collins’ words are vividly reflected in research laboratories throughout the country. From coast to coast, U.S. genetics labs are making inroads into identifying the genetic defects behind ophthalmologic diseases from age-related macular degeneration to von Hippel Lindau syndrome. Researchers see their potential ability to predict the course of a disease and to arm patients with knowledge about how to best manage their risk factors as valuable payoffs for their efforts. What’s more, these researchers have hope for developing diagnostic tests that in the not-too-distant future will be used as routinely as the bacterial cultures and fundus photos that clinicians currently take for granted.

Ophthalmic genetics researchers exude excitement about the field, its progress so far and its potential for forever changing how ophthalmology is practiced.

Ophthalmology Leads the Way

According to Nicholas Katsanis, PhD, ophthalmology is clearly at the forefront of genetics. “The field of eye medicine takes responsibility for the first mapping and first cloning; the tissue is accessible; and with the breakthroughs we have made in the past few years, we are beginning to see the continuum between diseases. If we can cure one, maybe we can cure another one.

“As molecular genetic tools become more sophisticated, we will be able to more clearly attribute diseases to particular genetic defects as opposed to a collection of clinical observations,”

Dr. Katsanis added. “This is just beginning to happen, but I suspect it will escalate over the next few years.” Dr. Katsanis personifies the new generation of ophthalmic genetic researchers who are building on the technology developed by the field’s pioneers. His lab focuses on Bardet-Biedl syndrome, a genetically and clinically heterogeneous disease characterized by retinal dystrophy, polydactyly, obesity and a constellation of neurological and behavioral abnormalities.

Dr. Katsanis explained that the field has become very good at starting with a disease and going to the gene, with more than 150 disease genes cloned. “However, we are not good at going from the gene and predicting what the disease will look like and then how to treat it. I have children who start losing their photoreceptors at age 5 and peripheral vision at age 20, and then have a sibling with no profound vision loss. I want to understand why this occurs.”

Dr. Katsanis, who has an intellectual fascination with variability—“It is the differences that make things interesting”—said Bardet-Biedl is particularly intriguing because while most patients have retinal degeneration, some present with other clinical symptoms but no problems with their retinas. And vice versa. “We had a recently diagnosed case of retinitis pigmentosa (RP), with no other clinical symptoms, and lo and behold, found a mutation of Bardet-Biedl syndrome,” Dr. Katsanis said. “This illustrates the extreme variability of clinical diseases, and our goal is to help patients predict the course of disease. If a 2-month-old with Bardet-Biedl syndrome has RP, will she subsequently experience renal failure? What will be the impact on IQ? Understanding the genetics of diseases will provide a predictive tool.”

A Complex Field

Leonard M. Hjelmeland, PhD, summed up the field of ophthalmic genomics saying it’s a case of good news-bad news. “The good news is that tremendous progress has been made to identify genes and mutations within the genes. The bad news is that the field is extraordinarily complicated. I feel for the clinical ophthalmologists who must interpret the complexity of genetic findings to the patient.”

Dr. Hjelmeland, who is involved in genetics at the animal model level, actually got his research start in another field—membrane proteins and their physical properties. He earned a patent for designing detergents for membrane biochemistry, a discovery recently named one of the top 20 patents granted for work out of the NIH. From there, he transitioned into the NEI, where he worked on the molecular and cell biology of neovascularization and cellular proliferation of retinopathy. Ironically, he lost his sight at age 33 to diabetic retinopathy, a life-changing experience that led to a career switch and a transition to the University of California, Davis. Several years later, the university tapped Dr. Hjelmeland to assist in the launch of a genomics initiative. Now the campus is graced by a six-story, $100-million building housing the Genome Center.

Dr. Hjelmeland’s genetic research involves the use of a mouse model to identify significant genetic loci that contribute to hyperoxia-induced retinal degeneration. “Our hypothesis is that there is a set of genes whose function is related to oxidative stress that are susceptibility genes both for hyperoxia-induced retinal degeneration and also for age-related macular degeneration,” he explained. “We are looking for genes that are good candidates that can be associated with AMD in humans.” He also recently received an NIH grant to look at epigenetic changes in oxidative stress genes that are responsible for changing the susceptibility to diseases like AMD.

Dr. Hjelmeland noted that several research efforts in ophthalmology involve the National Human Genome Research Institute’s current initiative to develop a haplotype map, or “HapMap,” of the human genome. (As a refresher on haplotypes: Single nucleotide polymorphisms [SNPs] are sites in the DNA sequence where individuals differ at a single DNA base. Sets of nearby SNPs on the same chromosome are inherited in blocks, and this pattern of SNPs on a block is a haplotype.) “There are groups who are looking at the HapMap in terms of susceptibility to AMD,” he said. “In the future, for each person, we are going to know the sequence changes that are important and if he or she has a high probability of getting AMD. If that is the case, the patient can better manage related risk factors such as smoking.”

While this research will no doubt bring answers, it also presents problems. First, do patients really want to know their genetic risks for disease? If so, who will possess the expertise and take the time to walk patients through this potential minefield of information? “This is why there is a need for ocular genetic specialists and genetic counselors to help the clinical ophthalmologist interpret results for patients and explain the implications of genetic tests,” said Dr. Hjelmeland. “Second, with new genetic information come privacy issues, and the big question for ophthalmologists is the ethical medical use of this information.”

Information Tools

Stephen P. Daiger, PhD, stumbled into the field of inherited retinal diseases in the 1980s, never envisioning the eventual explosion of complexity in the field.

“When I began working on RP in the early to mid-1980s, we were talking about finding the one or two genes responsible for the disease,” Dr. Daiger noted. “We could not have predicted that autosomal dominant RP alone involves 16 different genes. The bottom line is that the field has become very complicated.” Consider that in just a single gene, various mutations can cause a disease to take a different course, as with, for example, late-onset RP. Other mutations of the same gene cause congenital retinal damage—same gene, different disease.

The complexity of genetic research in the retina alone prompted Dr. Daiger to launch the Retina Information Network (RetNet), a Web-based resource for the research community and others interested in conducting research. The site, www.sph.uth.tmc.edu/RetNet, provides tables of those genes and loci that cause inherited retinal diseases, along with related information. The extensive summaries on the site illustrate just how far ophthalmic researchers have come in identifying these genes.

The discovery of these genes has given rise to some specific drug treatments geared to the underlying disease. However, the missing link is molecular diagnosis. “We are right at the cusp of where genetic information will become a standard part of a medical workup for patients with inherited eye disease,” Dr. Daiger said. “However, the challenge is making that concept a reality, as autosomal-dominant RP alone is associated with many different genes. The costs associated with commercializing DNA testing has kept companies away. Additionally, doing appropriate DNA testing involves a multidisciplinary approach as patients will need information about prognosis, counseling information for family planning, and discussion for gene-specific and mutation-specific treatments.”

Yet while the challenge is huge, Dr. Daiger predicts that within 10 years, the diagnosis and treatment of very common diseases such as AMD will also involve molecular testing—similar to cancer centers in which molecular testing and molecular diagnostics have become routine. “Any oncologist who sees a family history of breast cancer would be derelict if he or she didn’t offer genetic testing,” Dr. Daiger said. “That level of care doesn’t exist for ophthalmology, but it will.”

The eyeGene Project

Brian P. Brooks, MD, PhD, heads up the NEI’s national collaborative network for ophthalmic research and diagnostic genotyping that began in January 2006, when the NEI launched the National Ophthalmic Disease Genotyping Network. Also known as eyeGene, the project is designed to give patients greater access to diagnostic genetic testing and genetic information. In addition, clinicians and researchers will have access to diagnostic genetic testing, centralized specimen collection, processing and repository services, standardized phenotypic descriptors and a shared database of genotype/phenotype information.

This approach is unique, said Dr. Brooks. “We are creating a DNA repository for the general use of vision researchers while at the same time giving information back to patients that will be of medical use today,” he noted. “We are opening up this program to the vision community now. However, we plan to take a measured pace; we are still working out some of the particulars. There are several legal, ethical and medical issues that must be taken into consideration. Patient protection and confidentiality is paramount, so we need a lot of careful planning.”

Dr. Brooks added that one of the two major groups involved in the project consists of the 12 CLIA (Clinical Laboratory Improvement Amendments) labs based in academic research institutions across the country. CLIA is the government organization that approves labs for molecular testing to ensure quality. The second group is a steering committee of experts from around the country who are not running the laboratory side of the project but are helping guide the process. These experts include ophthalmologists, geneticists, genetic counselors, policy experts and optometrists.

In fact, one of the participating CLIA labs is Dr. Daiger’s. Of participation in eyeGene, Dr. Daiger said, “There is a small community of 100 people in the United States who have been working on inherited eye diseases for many years, and the eyeGene project will facilitate our collaboration. It is exciting that the long-term goal is to bring diagnostic testing into the mainstream. Additionally, we will be doing DNA testing and some of the samples will be vital for research projects down the line.”

Genetic Testing Focus

Edwin M. Stone, MD, PhD, runs a research- driven lab that, since its inception in 1996, has received more than 45,000 blood samples from over 15 countries worldwide. The Carver Nonprofit Genetic Testing Laboratory is dedicated to offering nonprofit genetic testing for rare eye diseases, and currently offers 15 tests (involving 24 genes) with plans for an ambitious expansion of these tests in the next two to five years.

The focus of the Carver Lab is on diseases that are sufficiently rare that commercial tests are unlikely to be sustainable. Dr. Stone noted that it is now technically and logistically possible to test every person in the United States affected with diseases such as Bardet-Biedl syndrome and Leber’s congenital amaurosis—diseases for which many of the associated genes have been identified. The question often arises: Why bother offering genetic testing when there is not yet a treatment for the disease? Dr. Stone noted that information from these tests may help align patients with future trials of new treatments and may also provide insight into future outcomes for some patients. For example, parents of children with these disorders may find comfort in learning that a patient with a similar genetic profile is doing quite well in adulthood.

Dr. Stone cited the case of a 45-year-old woman with Leber’s congenital amaurosis. Although the woman is blind, she has no other symptoms and is a professor at an East Coast college. “I had a conversation with the professor, who initially expressed some skepticism about the value of genetic testing because at the present time there is no way to cure her blindness with or without this genetic information,” said Dr. Stone. “Yet when I explained that knowledge of her good health and academic accomplishments would be of great comfort to the mother of a 6-month-old patient with the same genetic form of Leber’s congenital amaurosis, she happily submitted a sample. Providing comfort and hope is a powerful motivation for a laboratory like ours.”

Dr. Stone realized that to offer useful tests to the public for an affordable fee, the lab needed to be operated on a nonprofit basis and directed by ophthalmologists with firsthand knowledge of the diseases. “The nonprofit model keeps costs down, which will help make the tests available to many more people,” he said.

Dr. Stone has also worked to make genetic tests more user-friendly for ophthalmologists so they can better help their patients interpret the results. (See “User-Friendly Genetic Tests,” below.) For example, he developed a standardized method for estimating the pathogenic probability of individual sequence variations. “This allows us to clearly communicate the likelihood that something we find in a patient’s sample is truly responsible for their disease,” Dr. Stone explained.

The Future

Dr. Stone envisions the day when ophthalmologists will routinely order genetic tests for inherited eye diseases. However, for this day to come, “ophthalmologists must become more active participants in the entire process,” Dr. Stone said. “We now have the technology and the capacity to test every patient with Leber’s congenital amaurosis and Bardet-Biedl syndrome in North America; and, as we do this, we will find the disease-causing mutations in 50 to 75 percent of these patients. However, to accomplish this worthy goal, we will need every ophthalmologist who has ever seen a patient with Bardet-Biedl syndrome or Leber’s congenital amaurosis to send samples from these patients to a laboratory for testing.1 So, from my perspective, practicing clinicians are now the most important players in the genomics revolution.”


1 To send a sample, see directions at www.carverlab.org.

User-Friendly Genetic Tests

What good are genomic discoveries if they cannot be translated into practical genetic tests that can be used by ophthalmologists in the clinical setting? Dr. Stone asked the same question and, in response, developed a definition of a “clinically useful” test. Dr. Stone defines a genetic test as clinically useful if it has an average cost of less than $500, a turnaround time of eight weeks or less, an easily understood report written in a standard format, and a greater than 50 percent chance of a clinically meaningful result.

“Indeed,” said Dr. Stone, “most laypeople and a surprising number of physicians have the notion that a gene has a ‘normal sequence’ and that any deviation from this sequence will cause disease. Yet in reality, normal individuals harbor millions of small variations in their DNA sequences and the vast majority of these don’t cause any problems.”

As a result, whenever one screens a gene for variations as part of a genetic test, the answer one obtains is often not a simple yes or no. “If one wishes to estimate the disease-causing potential [pathogenicity] of a given mutation as accurately as possible,” said Dr. Stone, “one needs to have access to mutation screening data from hundreds of normal and affected individuals as well as an updated summary of the published literature about this gene.” With this information, a reproducible estimate of the pathogenicity of a sequence variation can be made. While practicing clinicians may understand pathogenic probability, Dr. Stone said, “It is a wholly unreasonable expectation that they will have access to all the necessary information to perform such a calculation themselves each time they interpret a test for one of their patients.”

To address this challenge, Dr. Stone created a system for providing clinicians with a standardized estimate of the pathogenic probability (EPP) of individual sequence variations. “The EPP is useful because it gives a doctor a good estimate of the likelihood that something we find in their patient’s sample is actually responsible for the patient’s disease,” Dr. Stone explained. “We use a four-point scale that distills a lot of complicated information from our database and the world’s literature. A zero denotes variations that are extremely unlikely to cause disease, while a 3 is used to refer to variations whose pathogenicity is strongly supported by all available data.”

It is important to note that the clinical skill of a doctor who orders a genetic test is a very important factor in achieving a clinically meaningful result. “Genetic testing will never replace the need for knowledgeable clinicians,” said Dr. Stone. “It is just another tool that will help good doctors take even better care of their patients.”


A list of tests that are currently offered by the Carver Laboratory as well as detailed instructions for submitting a sample for testing can be found at www.carverlab.org.


About Us Academy Jobs Privacy Policy Contact Us Terms of Service Medical Disclaimer Site Index