Genetic testing: Getting it right : Oman Journal of Ophthalmology

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Genetic testing

Getting it right

Paredes, Diego I.1,2; Haefeli, Lorena M.1; Okoye, Onochie1,3; Capasso, Jenina E.1,4; Wyman, Celeste1,4; Khetan, Vikas1,4; Levin, Alex V.1,4,

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Oman Journal of Ophthalmology 16(1):p 1-3, Jan–Apr 2023. | DOI: 10.4103/ojo.ojo_11_23
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The latest advances in genomics have enabled better diagnostics and opened the possibility of new therapies. Ophthalmology has led the way on many fronts. Since the recognition of the role of mutations in the RB1 gene as the cause of retinoblastoma in 1986, there have been amazing advances in ocular genetics with the discovery of over 300 genes involved with inherited retinal disorders and many more involved with other forms of genetic eye disease ranging from optic atrophy to anterior segment dysgenesis.[1,2] The recognition of genetic causes of ocular disease has led to a plethora of research into therapeutic options that were previously dreams that are now translated into multiple clinical trials and the approval of the first gene therapy for biallelic RPE65 disease restoring vision to many.[3] This explosion in information has necessitated a paradigm shift in delivery of ophthalmic care. Instead of being limited to clinical or “phenotypic” diagnosis, clinicians must now entertain the possibility of genetic diagnoses along with everything a genetic workup entails: providing genetic counseling, ethical considerations, test interpretation, continued discovery, more precise prognoses, and connecting patients with clinical trials. This represents a new era in the management of ocular genetic disorders, giving hope to patients that years ago had blindness as their only future outcome.

The increased accessibility to genetic testing has had many benefits and also has been associated with challenges. Industry sponsored “free” genetic panels have removed billing and insurance barriers to accessing genetic testing in some countries. Thus clinicians are more easily able to order genetic tests and often do so without providing genetic counseling to the patient or having the ability to interpret the results.[4] Large panel tests yield a high false genotype rate, which in turn can be inefficient, increase expense both in time to sort out extraneous results and the additional testing needed to do so, and yield overly inconclusive results.[2,5,6] Rather than simply reaching for the nearest “free” panel as the first line genetic test, it may be more prudent for clinicians to go back to basics to narrow the gene hypothesis, when possible, allowing for more focused testing. A complete detailed ocular and medical history must be taken. Knowing the age of onset, pace and character of vision loss, and associated systemic symptoms, such as obesity, developmental delay, hearing loss, or kidney disease in the presence of a retinal dystrophy, can refine the clinical phenotype. Systemic clinical examination, looking for specific abnormalities in different body parts such as dental enamel defects, polydactyly, or abnormalities of gait, also help define the phenotype. Where relevant, results of systemic testing such as magnetic resonance imaging or laboratory findings, a history of medications known to affect the retina such as hydroxychloroquine or pentosan polysulfate, and pre- and perinatal complications, may be important. Furthermore, the family history, with construction of a minimum three-generation pedigree, may offer clues to the inheritance pattern of the disease, further narrowing the gene hypothesis. Examining other family members may help characterize the ocular phenotype. And of course, a precise ocular examination along with appropriate diagnostic testing, such as electroretinogram, optical coherence tomography, fundus autofluorescence, visual field, and color vision testing, can perhaps get the gene testing down to a single gene, if not a single mutation to test. Despite the efforts to get a narrow genetic hypothesis, sometimes phenotypes can overlap as for example in retinitis pigmentosa. In these cases, a large panel can be considered the most economically and clinically appropriate option but requires that the analysis be done by providers experienced with genetic counseling and result interpretation.

In general, there are four possible results for a genetic test: positive, negative, inconclusive, and incidental/unexpected results. A positive test is when a result provides a pathogenic genotype, consistent with the inheritance pattern and phenotype in the patient. A negative test is one which reveals only benign sequence variations, or ones which are inconsistent with the phenotype even if they are pathogenic. An inconclusive result, or variant of unknown clinical significance, occurs when there is inadequate data to determine the pathogenicity of variant(s) identified. Incidental and unexpected results, such as apparent carrier status for a recessive ocular genetic condition can occur. These situations are clear examples of the importance of posttesting genetic counseling. Meticulous analysis of the results by an experienced genetics team familiar with the individual's history and clinical presentation is mandatory to make these distinctions. Analysis will include the predicted biochemical effect of a sequence alteration, the evolutionary conservation of the affected genetic region, prior literature and database reports, in silico modeling, and in some cases testing of family members to ensure that the variant(s) segregates with the disease as expected. This analysis should be done following the standards and nomenclature provided by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology which classifies sequence variants in five categories: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign.[7] This process is dynamic, as variant interpretation may also change over time based on new reports and findings reported by the scientific community. Ideally, disclosure and counseling should only ensue after this process is completed.

Appropriate genetic tests should be ideally recommended and interpreted by qualified personnel. Apart from being well trained at interpreting and disclosing genetic test results, genetic counselors are also skilled at communicating relevant information on the basic genetics, inheritance patterns and recurrence risks to concerned persons and families in a manner that is easy to understand.[8] While the genetic counseling profession has existed in the United States and Canada for over 50 years, and has an estimated 5,000 members in the United States today, it is continuing to develop globally.[9] The value of genetic counseling, in contemporary medical genetic practice, cannot be overemphasized. Formal genetic counseling must be offered to patients and family members before, during and after ordering the relevant genetic tests. Some companies have offered genetic counseling by phone or video conference. While this has the benefit of increasing access to genetic counseling services, there are potential disadvantages to this delivery model as it cannot replace the impact of in-person conversations with a genetic counselor who knows the patient and their circumstances more intimately and can observe body language and other communication indicators in real time. Telephonic and video telemedicine genetic counseling services may also be provided by a genetic counselor who physically practices in a different geographic region, leaving them unfamiliar with the patient's landscape of local resources and specialists in their area. Ideally genetic counselor should partner closely with ophthalmologists who provide the phenotypic information that drives the test selection as well as providing posttest medical management.

So what should today's ophthalmologist do? Genetic testing is now a desired service, but to do so most effectively requires knowledge, experience, a wide range of phenotyping strategies, and genetic counseling. It is estimated that there are <100 ocular geneticists and <50 ocular genetic counselors world-wide. This can be particularly challenging in low income settings and underdeveloped countries, where such resources can be particularly scarce. It is difficult to genotype without the necessary tools and personnel to pursue the process in a skilled and ethical manner or the funding to pay for genetic testing. Networking with experienced colleagues can be a solution in some scenarios, as samples might be sent to research laboratories at little or no cost and such programs may accept out of country samples. Yet research results are just that, Research. They should not be shared with patients until verified in a clinically certified laboratory.

Ultimately, the access to clinically informative genetic testing cannot be completely fulfilled without trained professionals. Ocular genetics specialists are a small percentage of the universe of ophthalmologists. The subspecialty is new, and mostly confined to academic settings where programmatic support is necessary, as the specialty practice lacks the throughput to allow for adequate patient volume and revenue streams to be self-supporting. During recent years there has been a progressive increase in the availability of training programs in the field. Fellowships generally range from 1 to 2 years with varying degrees of research and clinical exposure. For example, we have two funded 1-year fellowship positions, available to both American and foreign trainees. The idea of an ocular genetic counselor training program is novel. We are developing an international fully funded 6-month program to train genetic counselors or ophthalmic professionals such as ophthalmic technicians or nurses who wish to subspecialize as an ocular genetic counselor.

While we wait for an increase in the pool of trained ocular genetic professionals, what can the ophthalmologist less familiar or under-resourced offer their patients? Every ophthalmologist can phenotype, even if only to a limited degree. A careful relevant history and even a rudimentary family tree are the best place to start, followed by a complete ocular examination and whatever ophthalmic diagnostics ones available. Partnering with a clinical geneticist, or even a good thorough general physician, can help complete the systemic piece. Before reaching for the large genetic testing panel for any indication, especially when one may have limited knowledge, skills and resources to do so, it is best to seek a consultation with trusted colleagues. In Oman, you have Dr. Anuradha Ganesh at Sultan Qaboos and there are other experts in the Middle East. Contact one of the authors of this editorial. Post the case on the international pediatric ophthalmology listserve. Use on line resources such as OMIM (,, International Society for Genetic Eye Diseases and Retinoblastoma (ISGEDR, and GeneReviews ( There are books available that can also help.[10,11,12] Orbis offers genetics education via including courses and webinars on ocular genetics. These resources may allow for a solid specific clinical diagnosis which might even obviate the need for genetic testing. If testing is needed, seek the help of clinical geneticists and their genetic counselors when available. Networking with ocular geneticists and laboratories (research or clinical) may also allow for testing to be pursued even when cost is a challenge. Blood or cheek swabs may be shipped worldwide.

Genetics has brought the future to the present in ophthalmology. We must avoid the misuse of genetic testing, and optimize the patient experience with testing. This is done by providing proper pre-and post-test genetic counseling, accurately interpreting results and sufficiently phenotyping the proband, and their family members when indicated, to allow for appropriate test selection. Our patients deserve clinical diagnoses and when possible, genotype confirmation to access a better understanding of and hopefully, someday, treatment for their condition. Now, is the time to get it right.


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