Why is a genetic diagnosis so important?
Most genetic tests examine DNA, the molecule in our cells that gives our bodies instructions to grow, develop and function. Changes in genes or chromosomes are called mutations. You could think of a mutation as a spelling mistake or a series of words changed in a sentence. Mutations are very common and we all carry a number of them.
The effect of a mutation can be good or bad. In some circumstances, changes or misspellings in your DNA can give rise to, or contribute to a medical condition such as an inherited retinal degeneration.
The instructions within our DNA are written out as a code made up of four letters: A, C, G and T. Scientists can examine the precise sequence of the code in a particular gene to see if there are any errors or misspellings. Genetic tests therefore examine our DNA to find the disease causing mutation in a particular gene (or chromosome).
Knowing the gene responsible for your condition can mean so much. Firstly, a positive genetic result can allow your ophthalmologist to confirm a diagnosis and better advise you on how to manage your condition and how it is likely to progress.
Knowing your genetic diagnosis is also becoming increasingly important should you wish to participate in a clinical trial or receive an approved treatment.
But most importantly, a positive genetic result allows you and your family to have a greater understanding of the condition. It can provide greater clarity on the pattern of inheritance and also empower you with the knowledge to make informed decisions regarding any healthcare and life choices.
Watch this video where our colleague, Dr Steve Rose at Foundation Fighting Blindness explains the importance of a genetic diagnosis for a person with IRDs.
How does genetic testing occur through Target 5000?
- During your appointment at the Target 5000 clinic, a blood or saliva sample will be taken for genetic testing. This sample is sent to Trinity College Dublin where the team will extract the DNA and ensure that it is stored securely.
- The research team will then start their analysis of your DNA to find the gene defect associated with your condition. They use a variety of sequencing techniques to search your DNA. The main one that they use is a technique known as next generation sequencing (NGS) or gene panel testing. This means that scientists can analyse your DNA against a panel of known IRD genes in an attempt to find the one associated with your condition. The panel at present contains 264 known IRD genes. Of interest, a single gene can consist up to 10,000 or more letters of DNA code. As you can imagine, this analysis generates a large volume of ‘genetic data’. Genetic experts and computational scientists must read through and interpret this data accurately to find what is the underlying genetic cause of your condition. In many cases, scientists will also test the DNA from unaffected family members such as parents or siblings who do not have the condition. This also helps with interpreting complex genetic data.
- In some cases, researchers may find genetic changes in your DNA but do not know whether this mutation is disease-causing or not. These are often referred to variants of unknown significance which are sort of false positives. This may be because the impact of the change in the DNA code is hard to interpret. The scientists will then check the details of the variants with databases of mutations in that gene. It may also require going back to the lab to determine whether these changes affect cell function and therefore can be interpreted as “meaningful” and “disease causing”.
- In approximately 65% of cases, the gene mutation associated with your condition is identified. As this has been discovered in a research environment, this genetic result is called a research-grade result.
- When your disease causing gene has been identified in the research lab, your sample is sent for confirmatory clinically-accredited testing. This is called a clinical-grade genetic test result. At this stage, a genetic counsellor can then deliver the results of the genetic testing process to you and your family.
- For the remaining 35% of cases, the scientists will continue searching using alternative research techniques and updated programming software. They may also dive deeper and look at your entire genome. It is important to remember that genetic testing techniques and our knowledge of genetics is advancing rapidly. Therefore, even if a mutation cannot be found now, there is still a possibility that new techniques will enable scientists to find it in the future.
To learn more about the research that Fighting Blindness is funding to address the unknown causes of inherited retinal degenerations, please visit here.
Watch this video where Dr Mathew Carrigan, a researcher at Trinity College Dublin and funded by Fighting Blindness takes us behind the scenes on genetic testing.
Additional resources on genetic testing
Video: Professor Andrew Green, a Consultant Geneticist explains the types of genetic tests are relevant to inherited retinal degenerations
Retina International have prepared a toolkit for genetic testing. This can be found here on their website.