Diagnosis at the molecular level is quickly becoming standard of care. The national initiative in precision medicine will rely heavily on genetic diagnoses by taking into account “individual differences in people’s genes.”1
Gene therapy and genetic-based trials are increasing rapidly in success and number and are expanding in scope and concept. Gene therapy with Luxturna (Spark Therapeutics) for Leber congenital amaurosis received FDA approval December 19, 2017,2 and the first patient was treated on March 20, 2018.3 Eligibility for treatment includes biallelic mutations in the RPE65 gene confirmed by genetic testing.
It is incumbent on the practitioner to recognize potentially hereditary eye disease and discuss referral for genetic testing. Realize that not every patient will want genetic testing.
Two concerns with genetic testing are protecting privacy and—related to that—avoiding possible discrimination by employers. Title II of the Genetic Information Nondiscrimination Act of 2008 (GINA) became effective in 2009 and prohibits employment discrimination based on genetic information.4 This fact might reassure some patients, but others will have different concerns; they should know that genetic testing can be performed later if they change their minds. Consultation with a genetic counselor or medical or clinical geneticist might help them with this decision without committing them to testing.
Molecular level diagnosis
Retinitis pigmentosa serves as a good example of why diagnosis at the molecular level is important. In 2013, Daiger et al reported that over 3,100 known mutations, within about 50 genes, cause what we call retinitis pigmentosa clinically.5 That means over 3,100 different diagnoses could be made, and it is no longer sufficient to diagnose “retinitis pigmentosa” without offering genetic testing that could refine the diagnosis to the molecular level.
“Could” is the operative word because we may test and find nothing. If there are 3,100 known mutations, maybe there are actually 6,100 but we don’t know the other 3,000 so those may not show up with current test strategies. Or, if there are 50 known genes, maybe there are another 50 we don’t know about yet and hence may not get tested. These are overly simplistic examples, but it adequately conveys the concern that we may test someone with clinical retinitis pigmentosa but not find a causative gene mutation.
Gene or mutation-based therapies are being investigated and are having some success. Eligibility criteria for various clinical trials often states that candidates must have a confirmed diagnosis through genetic testing—another good reason for testing. Because results from genetic testing can take two to three months, it seems reasonable for a patient to get testing done so he has that information when or if a clinical trial comes along that interests him. The best resource for discovering what types of clinical trials are taking place is ClinicalTrials.gov (see “Genetic testing resources for ODs and patients” box).
Some, including third-party payers, may argue that genetic testing has little applicable value unless there is a direct connection to treatment; however, that is a very myopic view of what constitutes “treatment.”
The American College of Medical Genetics and Genomics (ACMG) points this out in a policy statement on the clinical utility of genetic and genomic services stating that: “…etiologic diagnosis prevents additional unnecessary testing, provides the opportunity for anticipatory guidance, and provides better information regarding recurrence risks for the family and the affected individual. Further, as increased numbers of individuals are diagnosed with specific genetic disorders, information will be obtained that will help predict future complications and risks, tailor medical interventions, and lead to the development of new specific therapies and management strategies.”6
Patient perceptions of the personal value of genetic testing that provided meaningful results from one study included four qualities:7
• Achieving a sense of empowerment over their own health
• Achieving a sense of legitimization of their suffering by no longer being a mystery or curiosity
• Achieving a sense of doing all that you can for your child, yourself, or family member(s)
• Achieving a sense of altruism by contributing to society to help others
Other patients have expressed relief at ending a “diagnostic odyssey” of multiple doctors’ visits and possibly unnecessary diagnostic testing, all with no answers and achieving hope where before there was none when a cause is found
What is involved
A patient interested in genetic testing will be referred to a medical or clinical geneticist experienced in eye disease. The evaluation will include a detailed history and construction of a family pedigree as well as a pathology-focused eye exam and additional testing to help determine what genetic test will be ordered provided that the patient wants to pursue it and gives informed consent.
Informed consent is an important first step. The patient needs to understand why testing is recommended and the potential outcomes—both pros and cons.
The test order form will have one or more areas for the patient to give consent for testing, stating that she understands the reason for the test and possibly for allowing her anonymized DNA to remain in a repository to be used for research.
Testing is not necessarily benign, and there can be adverse effects. For example, it may confirm a diagnosis with a poor prognosis when the patient was hoping it would do the opposite. It could reveal non-paternity or an additional genetic variant that was not suspected. The patient should understand this before agreeing to testing.