Demystifying Genetic Testing

Episode 8: Genetic testing

Genetic testing is complex with many different types of tests, and a range of terms used to describe the results of test, particularly in areas such as genetic epilepsy where research is moving so quickly. To help gain a better understanding of genetic testing and the results we talk to Dr Emma Palmer.

Hosted by Kris Pierce and David Cunnington, parents of Will, who has SCN2A.

Leave a review and subscribe via Apple Podcasts

You can also find SCN2A Insights on Spotify, and Google Podcasts or in your podcast app

Guest interview:

Dr Emma Palmer is a Clinical Geneticist working at the State-wide Genetics of Learning Disability Service, diagnosing the cause of inherited intellectual disability and counselling families. She is a Conjoint Lecturer at the University of New South Wales investigating the application of genomics for severe epilepsy and intellectual disability. She is a Visiting Scientist in the Translational Genomics Group at the Garvan Institute.

In additional to a busy clinical load and two small children, Dr Palmer has growing research expertise with multiple international and national research conference presentations, invited presentations and first-author publications and reviews.

Follow Dr Palmer on Twitter: @emmagentics 

Regular Hosts:

Ms Kris Pierce RN MHSc MWellness, is a rare disease advocate and mother to Will who has SCN2A. Kris has held a range of board, project management, advocate and consumer representative roles and has been instrumental in working with local, state and federal governments to secure funding for multi-million dollar projects. Kris is highly skilled in building teams to work together collaboratively and is a co-founder of Genetic Epilepsy Team Australia (GETA) and SCN2A Australia, and a RARE Global Advocacy Leadership Council member.

Follow Kris on LinkedIn or Twitter.

Dr David Cunnington is a sleep physician and father to Will who has SCN2A. He is director of Melbourne Sleep Disorders Centre, and co-founder and contributor to SleepHub. David trained in sleep medicine both in Australia and at Harvard Medical School in the United States. David’s clinical practice covers all areas of sleep medicine and he is actively involved in training health professionals in sleep. David is a regular commentator on sleep, both in traditional and social media.
Follow David’s posts on sleep on Facebook or Twitter


Intro: Welcome to SCN2A Insights bringing you the latest research and clinical updates on SCN2A and genetic epilepsy from around the world.

Kris Pierce: Hi, I’m Kris Pierce.

David Cunnington: And I’m David Cunnington.

Kris Pierce: In this podcast, we speak to Dr. Emma Palmer.

David Cunnington: Dr. Palmer is a Clinical Geneticist with a range of roles but largely, her role as well as working with families and people with genetic epilepsies has been in developing education materials around genetic epilepsy to help people better understand both the genetic epilepsy individual disorders and generic information related to genetic epilepsy, genetic testing, and genetic counseling.

Thanks very much for helping us out with the podcast, Emma.

Emma Palmer: Not at all. Thanks for inviting me

Kris Pierce: Tell us about what you do in your work?

Emma Palmer: I think I probably have one of the best jobs in the world. It’s a very privileged job because I get to talk to people from a whole range of backgrounds. I guess what a clinical geneticist does that’s different from other doctors is at the moment, we very rarely actually treat or provide medicines or care for individuals. But what we do do is try and help families and individuals with genetic conditions understand what the underlying cause for their condition is if that’s something they are interested into looking into.

We also guide on the most appropriate genetic tests and what the tests might be able to do, what they would not be able to do, and what the possible pitfalls of testing are. And then when we get genetic test results back then it’s about helping explain that to the families and the individuals we see. I do that as part of a team. I work with a genetic counselor who is often from a social work or psychology background and who is really expert at trying to simplify the very complex world of genetics into something that’s meaningful.

If genetic testing has found a diagnosis, then we try and explain what that means over an individual’s lifespan and linking them in with resources that helps them convert to genetic diagnosis to better management and support. Really important part of what we do is explain what that might mean, a genetic diagnosis to people who are planning more children and what that might mean for other people in the family like siblings. Then if we don’t have a diagnosis from a genetic test, then we took to what are other possible options.

Kris Pierce: There’s an increasing awareness of the role of genes in epilepsy and other neurodevelopment disorders. At what stage do people have genetic testing done?

Emma Palmer: There’s actually no one answer to this. But the point is that people should not feel afraid of talking about genetics early with their doctor. If they’ve got questions regarding the cause of epilepsy, if they’ve got say, a child with a severe epilepsy and they are thinking about what that could mean if they’re planning more children or if the management of the epilepsy is really difficult. And those are probably the three reasons that most families would come and say, “Could genetic testing be helpful for me or for my child?”

I think just being aware of it’s OK to ask that question as early as you like. The role of the neurologist is to give you some advice on whether genetic testing would be helpful. I might be able to offer you some answers to those questions. And if so, whether that’s testing that they can organize themselves and counsel you through or whether it would be ideal to refer to a clinical genetics service.

Kris Pierce: If a family comes to a genetics service, what different types of gene tests are there that they may have to make decisions about?

Emma Palmer: Traditionally, we sort of thought about two big groups of genetic tests. Those which in history have a Medicare rebate and which we have the evidence base to say, “These are tests that pretty much – anyone that’s considering genetic testing should consider.” Then we thought about what next, so the group of test that are covered by Medicare, that might be covered by an individual health service or sometimes by the family themselves or research. That landscape probably is about to change in the near future as we are likely to get a Medicare item number for more detailed type of genetic testing.

I will talk about what we do right now. That first group of testing where we get Medicare rebate, where there is a epilepsy and the global developmental delay or intellectual disability, that’s what has to go on to get the rebate from the government and that would be for chromosomal microarray which is a detailed look at the chromosomes, more detailed than we used to get from just looking at from down a microscope and screening for an inherited condition, Fragile X, which can be associated with epilepsy and intellectual disability or global developmental delay.

Also, particularly the child has a very early onset epilepsy within the first year of life or there are some other red flags then the neurologist may consider metabolic testing. So that’s screening for metabolic conditions which may involve a urine test as a first step. That’s really important when we are thinking about the possibility of treatable causes of epilepsy that start early in life.

That has traditionally been the first year of testing. And then after that, it has been difficult because over Australia and over the world, there’s differently ability of families to access more testing. But where we are moving towards is being able to offer families very detailed testing of the genes which are known to be associated with epilepsy and in particular, epilepsy and learning disabilities.

The point is that there’s not just a handful of those genes. There are hundreds of those genes. So we really needed to wait for revolution in genetic testing which enable us to look in detail at those genes. And that’s called Next Generation Sequencing or Massively Parallel Sequencing. We might hear words like Gene Panel Exome Sequencing or Whole Genome Sequencing. And I can explain that a bit more in detail if that would be helpful.

David Cunnington: What about the more consumer-available genetic testing? We get marketed – these things get your genes tested for 200 bucks, mail off some saliva in a kit. Where does that sit compared to what you are talking about?

Emma Palmer: I guess the families I see and the individuals I see generally have a very early severe epilepsy which is the difficult severe because it has been difficult to be managed by one or two medications. For that group of epilepsies, we are more confident that that is caused usually by a change in a single gene. So we call those single gene or monogenic or Mendelian conditions. And that’s what that diagnostic testing is looking to address. That testing is not great for much later onset epilepsies or epilepsies which are easily controlled with medication.

Those epilepsies, it may be not just one genetic change that’s causing the epilepsy, maybe a combination of changes. And it might be better to think of those as a little bit more like a predisposition to diabetes or high blood pressure in the family.

When we talk about the direct-to-consumer testing which is marketed, you can send off a saliva kit. You take a little bit of saliva. You send it back to the company. Those are not aimed at getting answers for conditions where there’s one big genetic cause. They are giving you an idea of your susceptibility or your risk of some of these broader medical conditions like diabetes and high blood pressure. And they are not particularly good at looking at your chance of developing epilepsy and they don’t give you the sort of answers that families are generally looking for as in why my child has epilepsy, what’s the best treatment, what would be the implications for my family? We do worry often as a profession about how good those tests are.

One study that I always think of was the researcher in Holland who looked at this direct-to-consumer testing and she sent off her saliva to about five different companies and she got completely different results back from each of those companies. So some said she is at high risk of developing high blood pressure, others said she was at a lower risk. And generally, taking a good family history, seeing your GP, getting checks for blood pressures and things like that is a better indicator then of your susceptibility for those type of conditions than doing direct-to-consumer testing.

It is certainly a good idea to talk to a health professional if you are considering that type of testing. Is that the best test for my child or for me or could I be spending my money best in another way?

David Cunnington: It’s a really nice point that the genetic testing is not just a test. It’s a package of clinical assessment and risks stratification and then a test that either equates with that or rules that out and then some interpretation by an expert like yourself to try to put in context. So we do have to see it as a package not just or the test that will give the answer.

Emma Palmer: Absolutely. I think you’ve got it in one. And I think this is a really common misunderstanding. So most people, you do blood test, you understand. You send off – you do a blood test. You get a yes/no answer. Yes, I’m anemic. No, I’m not anemic. I need iron. I don’t need iron.

Genetic testing is so much more complicated than that as you allude to. It may find a diagnosis. It may not. It may find some changes in the genes that we don’t really know what they mean right now but with some extra study and some extra work, we may be getting there.

In fact, a bottom line that I say to the families I see is that the genetic tests are much more advanced than our ability to understand an interpret them. So it really is a journey and it’s a journey which I think families need to be supported by clinicians who understand what the test can and can’t do and able to counsel and support them appropriately.

David Cunnington: Can I just bring you back to then defining a couple of those terms you mentioned earlier, so a gene panel or whole exome sequencing?

Emma Palmer: This is the big change that has happened in genetic testing over the last five years. And a big thing here with these types of tests is that they are able to find answers for many more families. So for early onset difficult to treat epilepsies, we were probably only getting a genetic diagnosis for about one or two families out a hundred in the past because it really relied on a gene being discovered and then that family being tested for that gene.

With these new tests, we are able to test tens if not hundreds of genes at the same time. That’s improving the chance of getting a meaningful answer back if your child has a severe early onset epilepsy to about 30-40%. So it’s a big game changer in genetic testing.

Gene panels will focus on maybe a hundred genes with good evidence linking those genes to a condition like sever early onset epilepsy. Gene panels have traditionally been a good first step because they are relatively cheaper. They have quite good chance getting known particularly for very early onset seizure condition.

However, there’s a big downside which is that every week one or multiple new causes of epilepsy are being described. So they rapidly become out of date. A test that was appropriate a year ago would not include the new genes that are being found and linked to epilepsy right now and into the future.

You can’t go back and look again when those new genes are found. So it’s great if that test finds an answer for your child or for you but it’s sort of then your journey almost stops.

Where we think that the government will be going if we do get Medicare funding will be for the next type of test which is called exome sequencing. And exome sequencing looks at about 1% of your DNA but it’s a very critical 1% of your DNA because it’s the amount of DNA that codes for proteins and proteins are one of the building blocks of our cells and our bodies. So it’s a way of looking at a huge amount of genetic information and also a way where the new gene is discovered. You can ask the laboratory to go back and look to see whether there was a change in that gene.

It’s kind of future-proofing. It means you have the genetic test at point A. If you don’t get a diagnosis, you can ask the lab and say one or two years’ time to go back and look at the data again in the light of what we now know from medical science which shown can improve the chance of getting a diagnosis by that one in size. It’s really worthwhile.

The other test that you mentioned right there, this whole genome sequencing, that’s looking at a hundred percent of an individual’s DNA. It also looks at DNA that hides in other places so within mitochondrial, little energy packs within our cells and it can look for quite unusual genetic changes that the other individual test might not be able to look for.

Probably that’s where we will be heading in the future. But at the moment, that test is very expensive and we’re still building the tools and the knowledge to understand all of the information it can provide.

David Cunnington: Then when families get their tests back, there are sometimes terms like pathogenic or variant of unknown significance in the report, what do those terms mean?

Emma Palmer: We have a lot of work to go in making reports more understandable for clinicians and for families. This is how I would explain the outcomes. And what I would suggest as well as a really good website is the Australian Genomics Health Alliance has developed some resources including some infographics about genomics or genetic testing which is

This is how they describe the possible outcomes of genetic testing. The test may find one or more gene variants that explain the condition for which the test was done. So that’s what a lab report would call a pathogenic variant. It’s a change in a gene which we think is the explanation for the condition.

Sometimes the report will put a little bit of a provider there, so they will say likely pathogenic. That means that we are 90% sure that this is the answer, but we may need a little bit more evidence to get us over the line to be a hundred percent sure.

The next term you mentioned was variance of uncertain significance. And this gives everyone a headache. What this means is that a gene change was found and it’s not something that the lab can rule out as being the cause. It’s a gene change that is not commonly seen in healthy individuals. And I think the really important thing to understand here is that we all have thousands and thousands of gene changes.

Gene changes by themselves do not cause a condition. A gene change to cause a condition has to affect a gene that is important for brain development and function. So variance of uncertain significance means we found something. It’s in a gene associate with the condition but the true significance of that change is not fully understood.

That can be a really difficult conversation to have and that’s why the package that you took to that of having – understanding what the test might find, having counseling and support through that is so critical because if you don’t understand, this may be found and actually this is the most common finding of this very detailed genetic test. It can raise a lot of anxiety.

When we find a variance uncertain significance, that’s often where we as clinical geneticists come in. The next steps may be seeing if that change is present in people who don’t have epilepsy in the family. If that’s the case, then it’s more likely this is just what we call benign variation. A change in the gene, that means the gene still works absolutely fine or we may need to go on and see if the family be interested in being more involved with research which could involve including a basic scientist who is interested in that gene and can join and do some lab studies to really knock down whether that change that has been detected actually cause the gene to not work properly and is the explanation or isn’t the explanation for the individual’s advocacy.

Kris Pierce: When someone has a genetic diagnosis and is looking for information, where do you suggest they find resources?

Emma Palmer: There’s no point doing all this genetic testing and then it doesn’t equate to improve management and care and support for the family. I would say first off, whoever you are getting the report from, that’s the question you should be asking them.

For example, when I talked about what a geneticist does, I actually missed out a really important part of what I do. When I’m seeing a family in clinic and started to discuss the genetic test report, I will spend many hours researching what that genetic rest report means and what are the best resources to be given as a package to the family when I see them. We are not just giving a bit of paper that is gobbledygook. We are giving something meaningful.

In particular, if there’s a great family support website that’s out there developed often by families who got a child affected by the condition, that could be a wonderful first point of call because that’s a way for the that like to connect up with other families who are walking a similar walk to them. I think those support websites are so amazing because they are developed by people who understand what the information needs are of families with a new diagnosis.

However, they don’t always exist because we are often talking about very rare conditions where there may be at the moment only a handful of children with that diagnosis around the world. Try and meet that need, there are some resources and websites that I would recommend looking at. One is the Human Disease Gene Website Series. I’ve worked on a number of genes that I’ve been involved in describing or getting more information about on that website. So really, what we try to do on those websites is produce pages which are for doctors and also pages for families.

It gives you information in the kind of a nutshell about what is known about those very rate conditions and ideally links you to some additional resources. And also, lets you know about the possibility of research that would be happening for that condition.

Through that website series, it also links to a sister site which is called GenIDA, so G-E-N-I-D-A, and links through from that website. That is very much developed by families to try and give an opportunity of a parent that has a child with a rare genetic condition and they would like to learn more about that condition and contribute to the global understanding about that condition. It gives the means for families of going in and putting information in a de-identified way, so that means not with the child’s name or a way that means that the child could be recognized.

But information about the condition to try and understand things like how this condition may affect sleep or what medications can be helpful, which medications are not helpful, all the kind of pragmatic practical information that families want. Those are two websites I would say are great to look at if you are not having much looking at patient support websites.

Another great website particularly because I love the way that they have developed their resources is called Unique. It’s a UK-based website and it’s And they produced booklets on genetic conditions which are written with families. They often include photographs of children or adults with the condition and some quotes from family members about how the condition affects their child and also just what their child is like.

Seeing the variety of how condition can affect a child but also just how they get on with their lives as a family I think can be quite empowering for families and give some hope at a time when a new diagnosis then roll and very challenging.

David Cunnington: What’s the PENNSW website?

Emma Palmer: In New South Wales, we have a website called And that is really trying to provide easily accessible information for families and for commissions about a broad range of issues to do with epilepsy. What we are actually doing at the moment which is why it was lovely to have this opportunity to answer some questions today from the community was developing some pages on genetic epilepsy for that website, a step-by-step guide for genetic test for doctors and for families. What we will also try and do on that website is also link to great resources.  

One thing that we hear from families, I have a PhD student who is doing in-depth interviews with families about their information and support needs, families often say that they find it really hard to find expertly written information that they can trust. They can spend hours at night time researching and it will be so great if they had a one-stop place they could go to to get expert information. That’s certainly something we would like to build towards in the future.

David Cunnington: That’s a great initiative. And you were so kind in coming and giving a talk for families at our Genetic Epilepsy Conference earlier this year and there’s a video of that talk online. That’s another really great resource if people want to hear in more depth some of the resources you talked about.

Emma Palmer: Yes. I try to highlight some websites and some web resources that are good points of starting your journey about understanding more about genetics and epilepsy.

David Cunnington: One of the other questions that have come through some of the patient forums is about parental testing and if people want to have more children. What does that process look like?

Emma Palmer: We are hoping that a genetic test will mean better therapies for children. But we are still in the space for many children of needing to do the clinical trials, really developing a good position meds and model to revolutionize the care of children. But in the meantime, a genetic test result can also some really important information for parents if they have say, one child affected and they are looking to have more children and they would like to know, “What could be the chance of my second child or my third child having the same condition?”

Genetic cause of epilepsy can be inherited which means that a parent may have the same condition, or they can be inherited in different ways where both parents are what we call a carrier for a condition because our genes certainly come in pairs. Each parent is a carrier of one working copy of gene and one faulty copy of the gene. They would only have a child affected if a child inherits both faulty copies of genes, which is generally a 1 in 4, 25% chance of each pregnancy.

These kinds of inherited genetic conditions are really important part of what we do in clinical genetic services explaining that to families if it’s an inherited type of genetic epilepsy identified. Talking through their options if they would like to have testing around a pregnancy. There are many options now available including using IVF to only start a pregnancy with a baby that they know is not affected by the condition.

However, for most genetic epilepsies when we are talking about the severe early forms of genetic epilepsies, they usually what is described on the form as a de novo genetic change. We, as doctors, have this terrible habit of relapsing into Latin. What that means is it is a new genetic change for the child which means when standard genetic testing is done on blood samples or saliva samples from the parents, they did not have the genetic change but the child who is affected has a genetic change. This generally arise when the egg and the sperm come together, all of our genetic material needs to be copied and packaged up and it’s real easy to get a small genetic change introduced at that point in time.

But if a genetic change affects the gene that’s important for brain development and function, that could result in an epilepsy. One of the ways I talk about that is say, you’re sort of copying a whole heap of books, it’s really easy to have that is photocopied twice or you might miss a page and that’s the same with ourselves. That’s a vulnerable point of time when genetic changes can happen but it’s also what makes us all different and otherwise identical copies of each other. So wonderful characteristics can come out of that process as well.

So traditionally, if we found a de novo genetic change for a child, we would have said that the chance of another child for those parents being affected with the same condition is low but never zero. This can be really quite hard time to stand. I can’t cover it in depth in this interview but I can give you at least some points and this will be something that will be definitely worth talking with a clinical geneticist about.

Why it’s not zero is because there may be a pocket of cells in the sperm or the eggs of the father or the mother which have the same genetic change that we find in all of the blood cells of the affected child. We use the term gonadal mosaicism for that. So mosaicism is like the mosaic tiles you might have. We have tiles of different colors.

Mosaicism in the egg or the sperm means that probably most of the egg and the sperm did not have the genetic change but some of them do. If one of those cells then went on to make another baby, that second child could be affected. That’s where we see families where both parents have no suggestion of the genetic change on their blood test but they get a second child with the same condition as the first affected child. We kept seeing this.

What has been happening over the last few years is some wonderful researchers have been looking more into this and doing very, very detailed genetic testing which is not for the genetic testing that is standardly available but looks at tiny bits like 1 in a 100 of a parent cells that might have the same genetic change as their child. That research – so there was a paper published with kind of method last year by Professor Ingrid Scheffer and that was suggesting that that type or mosaicism may happen in about 10% of families and even that might be an under estimation.

The detail testing that they did to show that mosaicism is not easily accessible right now in Australia but also, that testing is not fail-proof. They had some families their study with two affected children and however hard they tested the parents; they still couldn’t find evidence of the gene change in the blood or the saliva of the parents. That really is showing us that probably for those families, there’s a very, very low amount of mosaicism or it really is that the gene change is just within the egg or the sperm which we can’t test.

But all of these reasons, some families who have a child with a very severe condition, genetic condition, even with the report saying it is de novo, may choose the option of having a test in a pregnancy to know whether their second child is affected or not. That would be a test from about 12 weeks into a pregnancy and it would be for the additional reassurance of knowing that that child does not have the same genetic condition that is very severe in their first child.

There’s a whole amount of complexity about explaining that and supporting families through that decision but that’s not an uncommon decision that families make and certainly, a clinical genetic service would help explain and support them through that process if that is something that they would like to know more about.

Kris Pierce: Thank you very much for your time today, Emma. I know our families are going to appreciate this information not only here in Australia but also our global families who really get a lot from what you shared with us today. We really appreciate your time.

Emma Palmer: Oh, my absolute pleasure. I hope it helps.

Kris Pierce: Emma shared some fantastic resources and we will make sure all the links of all of those resources will be available in the show notes.

David Cunnington: And you can keep up with the latest updates by subscribing to this podcast. Get regular updates on SCN2A through SCN2A Australia’s Facebook or Twitter at SCN2A Australia.

Outro: This podcast is not intended as a substitute for your own independent health professional’s advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider within your country or place of residency with any questions you may have regarding a medical condition.