" ​Funding genetic testing to find a proper diagnosis to create the right solution."



                         ASK THE GENETICIST

                                                                        S. Ali Fatemi, M.D., M.B.A
                                                        Director, Department of Neurogenetics
                                                                        Kennedy Krieger Institute

What is genetic testing?
There are different forms of genetic testing with various degree of sensitivity, but in a nutshell they are tests usually done from a blood sample that will look at changes in the genetic material in our cells. In every cell, we have about 3 billion DNA letters. In each cell, the DNA is folded up in 46 complex structures called chromosomes. The oldest level of gene testing is so called "Karyotype analysis".  This test has been around for about a hundred years and allows us to find out if any of our chromosomes are missing or if we have too many of them. For instance this is the test that allows us to diagnose somebody with Downs syndrome, where the affected individual has three instead of 2 copies of chromosome 21. This test also allows us to see if there are larger pieces of a chromosomes missing or if we have extra copies of larger pieces of a chromosome

Who is a good candidate for genetic testing?
In children with intellectual disability, autism or neurologic regression in whom no acquired cause is identified - acquired causes are for example birth injury, infections, intoxications, trauma  - a genetic disorder is most likely the cause of their disability. Currently, we don't recommend the same kind of genetic test to every patient in whom we think a genetic disease is likely. The determination which test should be done is based on the presentation of the patient and the decision should be made by a professional health care provider.

Is there a certain age when you should start genetic testing?
Genetic testing can be done at any age even before birth. It depends again on the presentation of the disease. For instance in a family member where there is risk for a particular genetic disorder, we usually test the unborn fetus, or sometimes even the fertilized egg before it is even implanted into the womb. Other subjects who may be carriers of a disease, meaning they have an abnormal gene change that does not affect them but they could pass on to the next generation, may not undergo testing until they plan to have children.

In general, we feel that the earlier one is tested the better, specially since there may only be a limited window of opportunity to intervene.

If you have a child with a genetic disorder that is De Novo (meaning it wasn’t inherited) should the next child be tested and when?

De Novo mutations mean that the child has a genetic change which she did not inherit from the parents and it happened spontaneously in the egg or the sperm of the parents. The chance that two sibling will have the same De Novo change is extremely low at about 2-3 percent. So in general, most families opt to not test the next fetus when they become pregnant.

The earliest time point when the testing for the next child can be done is after the fertilization. 

How accurate is the Whole Exome Sequencing Test?
As mentioned before, whole exome sequencing aims to cover the important part of all genes which is still only 1.5% of the entire genome. There are several different variables that affect the accuracy of an exome.

First, even though it is called whole exome, most of the time not important parts of all genes are covered, meaning not every single DNA letter from the exome is actually read. This has to do with technical limitations. Sometimes certain genes are covered at 100% and others may be covered only up to 50% within the same exome. The technology is getting better and there are more and more labs that are aiming at 100% coverage of each gene.

The second variable is the very complex bioinformatics pipelines and algorithm that are used to analyze the raw data that the sequencing machine spits out. Pending on which algorithm is used certain genes may be covered better or worse, in particular if the gene change is towards the beginning or the end of a gene it may be missed.

Third, once the algorithm is complete, the data then is compared to existing databases of 'healthy people' trying to determine which gene changes are seen, this is a very complex analysis that needs high level of expertise by the analyzing lab and eventually the changes in a gene - we refer to l them 'variants" are 'called'.. Each normal person has hundreds of variants in their exome that may look worrisome, so ultimately we compare these results with the patient's clinical presentation and try to see if these genomic findings make sense clinically..

Because of all these variables, this is not a black and white kind of test result and has a lot of gray zones. In a study here at the Kennedy Krieger Institute, where we assessed the ability of this test to diagnose an underlying genetic cause in children from our pediatric neurology practice, we found a clear answer in about 40% of all cases. Another 40% had changes in their genes which may or may not be the cause of their disease and we call that "variants of unknown significance" (often called VUS).

So in summary, this is a complex test and its accuracy is increasing but a negative exome does not rule out a genetic disorder.

How often should someone redo the full exome sequence if there is nothing found?

Before, I answer this question it is important to point out that over the last few years there has been a dramatic number of new disease that has been discovered through exome sequencing. For example just within our practice here at the Kennedy Krieger Institute, we have done exome analysis in about 800 patients and have discovered 14 new diseases over the last 5 years.

Since there is every day a new disease that is being discovered, we try to repeat the analysis of the whole exome data every 1-2 years, meaning we dont repeat the blood test but repeat the bioinformatics and interpretation analysis. Some labs offer this for free, others charge. Some labs will do that automatically others you have to request.

It is also important to mention that there are online repositories where I can go as a clinician and say I found this variant in gene XY in my patient who looks like this, and another clinician in Europe may go to the same repository and put in her patient information, and if the genes are a match - the system will put us two doctors in touch so we can compare our patients. Through this method we have discovered several new diseases and have built multiple collaborations with other doctors from all over the world.

Do I have to know if I or my child has cancer causing genes from the screening?
When we do gene testing that includes many genes, there is always a chance that we may encounter a finding about a condition that we didn't ask for. For instance, one may be found to have a gene mutation that puts people at risk for stomach cancer, or a gene change that may put one at risk for heart disease. The American College of Medical Genetics has a group working on this issue and they have developed a list of so called 'actionable incidental findings'. This is a growing list of genes where one may be able to take action to prevent certain diseases form happening. When a patient signs up for the test, one can usually opt in or out from getting a report of these actionable findings.

Is there any type of risk associated with genetic testing?
The main risk is that one may find a result that was not anticipated which may cause psychological stress to the individual and family. And the fact that there is often a gray zone result, it may be stressful to the family.

What is done with the blood samples once the test is over?

Usually the labs will hold on to the left over DNA, but typically there is a consenting process and patients have to agree that the lab may use the left over DNA for research.

If my child has a genetic disorder, is there any reason to do the genetic testing again at a later age?
Again this is a complex question and depends on the presentation of the child. The resolution of the chromosomal microarrays has improved over the last 10 years identifying smaller deletions or extra copies and this will likely continue. So it may be indicated to repeat the test if the original one had a low resolution.

It is also important to point out that Whole exome sequencing does not necessarily detect deletions or extra chromosome copies. So these tests to some degree are complementary but again it depends on the presentation of the patient.