Oman Journal of Ophthalmology

: 2011  |  Volume : 4  |  Issue : 3  |  Page : 105--107

Genetic testing in retinal dystrophies

Anuradha Ganesh1, Rosanne B Keep2,  
1 Department of Ophthalmology, Sultan Qaboos University Hospital, Muscat, Oman
2 Ocular Genetics, Wills Eye Institute, Philadelphia, PA, USA

Correspondence Address:
Anuradha Ganesh
Department of Ophthalmology, Sultan Qaboos University Hospital, 123 Al Khod / Muscat

How to cite this article:
Ganesh A, Keep RB. Genetic testing in retinal dystrophies.Oman J Ophthalmol 2011;4:105-107

How to cite this URL:
Ganesh A, Keep RB. Genetic testing in retinal dystrophies. Oman J Ophthalmol [serial online] 2011 [cited 2021 Apr 10 ];4:105-107
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Full Text

Developments in genetics and technology are bringing with them incredible possibilities in the management and potential cure of patients with retinal dystrophy. In this editorial, we address the issue of genetic testing in retinal dystrophies. In the first section, we provide some background information about genetic testing. In the second section, we discuss how genetic testing can be helpful to patients and families with retinal dystrophy. In the third section, we introduce some important considerations that one must be aware of while contemplating genetic testing.

 Background Information

Genetic testing is the use of laboratory methods to look at the genes. Genes are deoxyribonucleic acid (DNA) instructions that we inherit from our parents and in turn pass on to our children. These instructions direct the synthesis of various proteins that collectively mediate all body functions. Normal retinal function is dependent on a continuous interplay of thousands of proteins. The story of genetic testing for retinal dystrophy begins with the genes that direct the synthesis of these proteins.

DNA, housed within genes, which are packaged along chromosomes in our body's cells, is made up of units known as bases that occur in a certain sequence known as the genetic code. When there is a change in the sequence of the bases, there is a change in the genetic code or DNA instructions. The outcome of this change depends not only on how it alters a protein's function but also on how vital that particular protein is for the body function. If important, it might result in altered body function and disease. A sequence variation that results in a disease is called a mutation.

Genetic testing involves detection of variations in the DNA instructions. For testing purposes, DNA samples can be obtained from any tissue in the body including blood. Other tissues that might be used to obtain DNA samples include cells swabbed from inside of the mouth, saliva, hair, skin, tumors, or the fluid that surrounds a fetus during pregnancy.

One of the great success stories in retinal dystrophy research in the past decade has been identification of many genes and many disease-causing mutations. To date, we are aware of approximately 200 genes associated with retinal dystrophy. [1] We are aware of an additional 50 chromosomal locations associated with retinal dystrophy, but the genes in these locations have yet to be cloned. [1] The currently known genes account for 75% of the retinal dystrophies. It is expected that with rapid technological advances that we are witnessing today, new genes will be discovered in the coming years.

Clinical laboratories versus research laboratories

Although genetic testing shares some features in common with other kinds of laboratory testing, in many ways it is unique. Because most genetic disorders are rare, genetic testing is often done only by specialized laboratories. Genetic testing may be performed on a clinical basis or on a research basis. Clinical and research laboratories differ in their approach. Clinical laboratories examine the patient's DNA specimens for the purpose of diagnosis, prevention, or treatment of the individual patient. Because these are highly complex tests, in the United States, laboratories that perform genetic tests on a clinical basis need to be accredited by professional organizations, such as the College of American Pathologists, or need Clinical Laboratory Improvement Act (CLIA) certification. The cost for testing is covered by the patient. But test results from clinical laboratories are more likely to reach the patient in a timely manner.

In contrast, research laboratories examine specimens more for the purpose of understanding a disease condition better. The focus is not the individual patient. Research laboratories are not subject to CLIA regulation. The cost of research testing is generally covered by the researcher; however, results often take one or more years. In addition, an official printed report of the results cannot be issued for research testing. Clinical confirmation of the test result can be obtained by a CLIA-approved lab. Research laboratories provide an alternative pathway to test genes which are not yet being tested in clinical laboratories or when a patient is unable to cover the cost of the testing. Technological advances are likely to result in more economical tests making it possible to perform more genetic tests on a clinical basis.

Ocular genetics consultation

A number of commercial companies offer DNA testing directly to the consumer. However, genetic testing is more likely to be informative if done in the setting of an ocular genetic consultation. Before ordering a genetic test, the geneticist attempts to select a panel of genes that are likely to be abnormal in a given patient, and so when testing is done, it is more likely to yield a positive result. In order to be able to narrow down the list of potential genes, the geneticist resorts to a detailed history taking, a thorough clinical examination looking not only at what is obvious but also searching for subtle or mild changes in the eye or the rest of the body and performing intensive clinical/laboratory testing including performing procedures. In the case of retinal dystrophy, this includes tests such as optical coherence tomography/fundus autofluorescence/intravenous fluorescein angiography, electroretinography (ERG), and possibly some biochemical tests.

The importance of this process cannot be emphasized enough. Retinal dystrophies are a group of heterogeneous conditions caused by numerous genes, many of which have almost the same clinical picture, a phenomenon known as genetic heterogeneity. It is not feasible to test all genes in all patients. The experienced geneticist is able to obtain the requisite information from the history, clinical examination, and diagnostic tests to make the decision regarding which genes should be tested. Not all laboratories test all genes. The testing methodology also may differ from laboratory to laboratory for the same gene. Methods include targeted mutation analysis, microarray panels of all known mutations, complete sequencing of a specific gene, or simultaneous sequencing of many exons. Thus, not only does the geneticist need to select the genes to be tested but also has to find a laboratory that might perform the required test.

 How Genetic Testing can be Helpful?

We believe that most families dealing with retinal dystrophy are looking for answers to four basic questions: questions that relate to diagnosis, prognosis, treatment, and presymptomatic detection of the disease.


Making a specific diagnosis of a retinal dystrophy based on pattern recognition alone might not be possible as disease conditions with different genetic causes have near-similar clinical features. Consider the scenario of a 2-month-old infant who is brought in by his parents because he does not appear to see things and has nystagmus or searching eye movements. Based on examination findings, one can narrow down the diagnosis to one of three conditions such as Leber Congenital Amaurosis (LCA), achromatopsia, or Congenital Stationary Night Blindness (CSNB). ERG is an important tool in differentiating between the three disorders; however, it is technically difficult to perform in this age group, and due to a maturation process in early infancy, results might be equivocal and difficult to interpret. This leaves the clinician and the parents in a dilemma regarding the diagnosis which can be disturbing especially when one realizes that a baby with LCA is going to be severely impaired, and LCA is a progressive disease, while achromatopsia and CSNB are stable disorders with relatively better vision in affected patients. The disease may evolve over time, enabling a specific diagnosis to be made, but this will require multiple visits, a number of tests, and time, possibly years, which can create anxiety for the family. Genetic testing can help reduce the length of time required to make a more specific diagnosis. Successful identification of causative mutations in one of the CSNB genes, for example, can reduce years of stress and uncertainty for parents.

However, the results of genetic testing must be interpreted in the clinical context.

 Tests are not 100% Sensitive

A negative or normal test result does not always mean a wrong diagnosis or absence of disease. This may be due to technological limitations.

 Tests are not 100% Specific

A positive test (variation) does not always mean a mutation. A lot of research has to be done to analyze the significance of results and estimate the probability of the change being pathogenic.


When a patient receives a diagnosis, the next question which needs to be answered is what will eventually happen to his/her child's vision? Awareness of the prognosis is important in enabling a patient to cope and adjust to the diagnosis. By understanding the genetic basis of a disease condition, the patient can be accurately counseled regarding the prognosis. The patient can be forewarned about other ocular or systemic medical problems that may develop over time. This knowledge might also help in making personal decisions, such as education, employment, lifestyle, and family planning. Once again taking the example of LCA, a child with a mutation in the RPE65 or CRB1 gene is likely to have better vision than a child with a mutated AIPL1 or RPGRIP gene mutation which usually has a deteriorating visual function.

A word of caution however! Although several important patterns have emerged, and genotype-phenotype studies are still ongoing, it is important to realize that the relationship between a gene defect and resulting phenotype is not straightforward. Environmental, genetic background, and modifier alleles may affect this relationship. Even members of the same family carrying the same genetic mutation might vary in their clinical presentation. This is known as clinical heterogeneity.


The third important question is the possibility of treatment. The most exciting reason to perform genetic testing on all retinal dystrophy patients is to estimate their suitability for ongoing genetic therapeutic interventions. Even if found to be unsuitable for ongoing trials, it is important to prepare for future therapeutic interventions, many of which we believe will be gene-specific. Gene therapy is designed to introduce genetic material into cells to compensate for abnormal genes or deficient proteins.

In 2001, a dog model of RPE65 LCA was treated with a subretinal injection of viral vector bearing a normal copy of the RPE65 gene. This trial was successful in restoring some vision in the dog, and these effects have been long-lasting. [2] In 2008, three human gene therapy trials were reported using a similar technique. Most patients had some improvement in visual function, and there were no serious complications. [3],[4],[5] Obtaining a genetic diagnosis is the first step to enable participation in current or perhaps future clinical trials.

Presymptomatic and carrier detection

Genetic testing can also help with presymptomatic detection, identification of carriers, and prenatal screening. Disease-causing mutations run true in families. Once the disease-causing mutation has been identified in a patient with retinal dystrophy, genetic testing can rule in or rule out the presence of this causative mutation for other at-risk family members who might be currently nonsymptomatic. Again caution must be exercised because testing reveals the disease-causing mutation but not the disease. Penetrance of a disease causing mutation indicates the proportion of individuals with the mutation who exhibit signs of the disease. There are several factors that determine whether or not a particular mutation will result in disease expression.

Presymptomatic or predictive testing is particularly useful if timely medical benefits are associated with early awareness of the disease condition. With retinal dystrophy, however, this is not the case, because in the majority of retinal dystrophies, preventive therapy is unknown.

So, what does one gain from predictive testing when no cure exists? In this context, genetic testing may be used for personal decision making. The test results might help in making informed choices regarding education, employment, lifestyle, and family planning. As such the decision to undergo genetic testing for presymptomatic diagnosis or predictive purpose is very personal and must be an informed decision, taken after due consideration of all possible eventualities.

 Important Considerations

DNA banking

Approximately 30%-40% of all patients with retinal dystrophy who have undergone screening for the currently known genes will test negative. These patients potentially harbor mutations in novel, currently unknown, retinal dystrophy genes. These patients and their families are extremely valuable for further research, which can now be more focused on finding other chromosomal loci and subsequently the new genes. Improvements in testing methodology will lead to greater understanding of retinal dystrophy genes and mutations. Patients and family members can bank their DNA not only to participate in research but also to allow for future testing to detect mutations which are currently unidentifiable.

Genetic counseling

Genetic testing should ideally be preceded and followed by genetic counseling. An important goal of pretest genetic counseling is to facilitate informed decision making about whether to have genetic testing done. The genetic counselor will help patients understand the benefits and limitations of testing as well as the potential implications that the results may have for the patients themselves as well as for other family members. For those patients who choose to have genetic testing, it is crucial that they have a discussion with a genetic counselor after the results are received. S/he will be able to correctly interpret the significance of the results, facilitate testing of other family members when applicable, and offer support and guidance to the patient in making follow-up medical and personal decisions. Genetic counseling can also assist address cultural, moral, and ethical issues that patients may face.

In conclusion, despite a number of limitations, genetic testing has many benefits. When performed with the help of genetic experts, it is the way of the future.


We are very grateful to Prof. Alex Levin (Chief, Pediatric Ophthalmology and Ocular Genetics, Wills Eye Institute, and Professor, Departments of Ophthalmology and Pediatrics, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, USA) for his guidance in the preparation of this manuscript.


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