Genetic testing in ophthalmology can provide vital information about complex retinal diseases, particularly when used to confirm an ophthalmologist’s diagnosis. In a review of molecular testing for hereditary retinal degenerations conducted over a 5-year period at the University of Michigan Kellogg Eye Center, scientists were able to confirm a clinician’s diagnosis in half of the cases.1

The testing took place in the laboratory of Radha Ayyagari, PhD, Director of Kellogg’s Ophthalmic Molecular Diagnostic Laboratory and was reported in the Archives of Ophthalmology.

Dr. Ayyagari and her colleagues reported on 350 genetic tests conducted since 1999. For each test described in the current study, the scientists analyzed one or more of eight genes known to cause diseases of the retina, according to a news release from the University of Michigan. Of the 350 tests, 266 were performed to confirm a clinician’s diagnosis, by far the most common reason the test was ordered. Another 75 tests sought to determine whether an individual was a carrier of a disease, and as such may pass it to offspring. Nine tests were requested to determine if a nonsymptomatic individual had inherited the mutation that had caused the disease in other family members: In predictive tests, a negative predictive test result indicates that the individual is not likely to develop the genetic eye condition that is present in the family.

CONFIRM OR RULE OUT DIAGNOSIS
Dr. Ayyagari’s team determined the molecular basis of the disease in half of 266 tests conducted to confirm a diagnosis. The researchers said these results are significant because many retinal diseases present similar symptoms, and it is sometimes difficult for even the most skilled specialist to distinguish one from the other. By comparing a patient’s DNA to DNA from normal individuals, scientists deliver information needed to confirm or rule out a diagnosis.

More than 130 genes associated with retinal diseases (ie, retinitis pigmentosa and macular degeneration) have been identified to date, according to the report. The authors wrote that genetic testing for ophthalmic conditions is a relatively new and evolving practice.

“Molecular diagnostics does not replace the necessary expertise of the ophthalmologist; rather, it adds a new tool to the ophthalmologist’s diagnostic arsenal,” Dr. Ayyagari said.

In the report, there is one case in which parents with no family history of retinal degeneration requested genetic testing in hopes of revealing the specific nature of their son’s eye disease. They also wanted to know whether the younger son, who was experiencing more subtle symptoms, had the same disease or a milder vision problem due to a different disease. Testing revealed that both boys had mutations in the gene linked to Stargardt’s macular degeneration.

GENETIC COUNSELING
Dr. Ayyagari noted that genetic counseling is a crucial part of the genetic testing process. The family must prepare for all possible test results, understand the implications of test results for the patient and other family members, and be aware of the limitations of genetic testing. If physicians do not have the time or skills to provide this background, Dr. Ayyagari urges them to refer their patients to genetic counselors.

The study also reported that a diagnosis could not be confirmed in half the tests conducted. “It is very difficult for patients to understand that the test may not be definitive,” Dr. Ayyagari said. “Genetic testing may not always yield the definitive results we receive in other kinds of testing, such as blood tests for cholesterol levels.”

STILL HAVE A WAYS TO GO
A related point of confusion, according to the report, is that an inconclusive result does not necessarily rule out a diagnosis for a given disease. Limitations still exist in technologies for genetic testing, Dr. Ayyagari explained. In addition, very slight genetic variations believed to be benign may have either a cumulative effect or may alter the way another gene functions. Finally, while there has been great progress, scientists have yet to identify all the genes that contribute to disease of the retina.

“Tomorrow we may discover a new gene that explains many of the previously inconclusive test reports,” said Dr. Ayyagari.

In an accompanying report, Stephen Daiger, PhD, of the University of Texas Health Science Center, writes on the promise of genetic testing for eye disease.2 He said, “Across all of the categories of inherited retinopathy, careful screening of known disease genes leads to the detection of pathogenic mutations in 25% to 90% of patients; an extraordinary accomplishment.”

It is to the patient’s advantage to have a molecular diagnosis on file, Dr. Ayyagari said. “When treatments begin to emerge for these complex genetic diseases, the individual’s genotype may determine whether a new treatment will be the one that works for that patient.”

Radha Ayyagari, PhD, is Assistant Professor of Ophthalmology and Visual Sciences in the Department of Ophthalmology and Visual Sciences, at the W. K. Kellogg Eye Center, University of Michigan, Ann Arbor. She may be reached at eyegenetest@med.umich.edu.

1. Downs K, Zacks DN, Caruso R, et al. Molecular testing for hereditary retinal disease as part of clinical care. Arch Ophthalmol. 2007;125:252-258.
2. Daiger SP, Bowne SJ, Sullivan LS. Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol. 2007;125:151-158.