Ophthalmologists Receive New Genetic Testing Guidelines

Ricki Lewis, PhD

March 13, 2012

March 13, 2012 — The American Academy of Ophthalmology (AAO) has published new recommendations for genetic testing.

New genetic test panels for eye diseases can improve diagnostic and prognostic accuracy, as well as identify presymptomatic individuals who may need preventive therapy or need to be monitored frequently for early signs and symptoms of a treatable condition, according to the recommendations.

Genetic testing also enables physicians to provide mechanism-based care, which may be important for distinguishing among genetic subtypes of diseases such as retinitis pigmentosa (RP) and Leber congenital amaurosis.

The growth of direct-to-consumer genetic testing during the past 4 years inspired the recommendations. "There was concern about genetic testing companies soliciting over the Internet without involving physicians. Ophthalmologic conditions can be complex, and since many have a genetic basis, we wanted to ensure that trained personnel (physicians and genetic counselors) were involved," task force member Mathew MacCumber, MD, PhD, an ophthalmologist at Rush University Medical Center in Chicago, Illinois, told Medscape Medical News.

5 Steps for Implementing a Genetic Test

The recommendations establish 5 steps for implementing a genetic test: clinical indications of a known inherited eye disease, DNA samples from the proband and/or family members, analysis of results, interpretation of the results in the context of the patient's presentation, and counseling. Physicians should either provide counseling or partner with a skilled genetic counselor.

The new recommendations address the potential problems associated with obtaining genetic information beyond that necessary for the ophthalmologic diagnosis, particularly as the cost of whole-exome and whole-genome sequencing plummets. Genetic "incidentalomas" may arise when more comprehensive testing reveals a mutation associated with a different disease or finds a variant of unknown significance. Therefore, the recommendations suggest restricting such testing to research studies conducted at tertiary-care facilities.

However, a larger-scale approach may be the only option for patients whose mutations are not among those included on test panels, John (Pei-Wen) Chiang, PhD, director of the Casey Eye Institute Molecular Diagnostic Laboratory, Oregon Health & Science University, Portland, told Medscape Medical News. In contrast, "[n]arrowing the analysis to known genes will offer an alternative and much cheaper approach." He agreed that working with reputable testing facilities is critical.

Informing Treatment Decisions

Task force member Elias Traboulsi, MD, an ophthalmologist at the Cole Eye Institute at the Cleveland Clinic in Ohio, describes a situation in which genetic testing can inform treatment decisions. "An adult who is diagnosed with RP, when in fact they have end-stage Stargardt disease, may be on vitamin A because it slows RP. In Stargardt disease, vitamin A damages the retina further. If we find the ABCA4 mutation of Stargardt disease, we tell the patient not to take retinoids."

The recommendations distinguish monogenic disorders (such as RP and Stargardt disease), which are rare, but for which tests are highly accurate, from complex disorders (such as glaucoma and age-related macular degeneration), which reflect input from multiple genes and the environment, and for which routine genetic testing is not highly predictive.

Genetic testing for complex disorders may become available once clinical trials demonstrate clinical benefit of multigene genotyping, according to the recommendations. Until then, the task force cautions against routine genetic testing for patients with complex eye diseases.

To manage costs, the task force supports "clinically relevant turnaround time." For patients with slow-progressing rare inherited eye diseases, seen yearly, a longer turnaround time at lower cost is advised. Labs should test at timetables to suit the clinical situation, maximizing clinical benefit while minimizing costs. Genetic tests that meet the specific recommendations from the task force are available at no cost through the National Eye Institute's eyeGENE program, Joan O'Brien, MD, chair of ophthalmology at the Scheie Eye Institute at Penn Medicine in Philadelphia, told Medscape Medical News.

The statement from the AAO presents genetic testing as a next step after an expert clinical exam. "We stress that it all starts in the clinic: A physician does a good exam and comes up with the very best possible guidance for testing, and then genetic testing is done," summarizes Dr. Traboulsi. Adds Dr. O'Brien, "The task force carefully considered both the potential benefits of genetic testing, as well as potential problems that could develop with this evolving technology and this highly personal information."

The task force presents 7 recommendations:

  • Offer genetic testing if symptoms suggest a Mendelian disorder, and ensure the patient receives adequate genetic counseling.

  • Use tests from Clinical Laboratories Improvement Amendment–approved laboratories.

  • Give patients test reports, so that they can research clinical trial opportunities.

  • Discourage use of direct-to-consumer genetic tests.

  • Restrict whole-exome and whole-genome sequencing to research projects.

  • Avoid genetic testing for complex disorders.

  • Avoid testing asymptomatic individuals younger than 18 years for untreatable disorders.

The authors and commentators have disclosed no relevant financial relationships.

Recommendations for Genetic Testing of Inherited Eye Diseases . American Academy of Ophthalmology. Published online February 2012.