Australasian Science Magazine

By Dyani Lewis

Clinical and research geneticist Prof Ingrid Winship discusses the use of genetic testing to improve the lives of people with inherited diseases and their families, as well as the pitfalls of direct-to-consumer genetic testing.

DYANI LEWIS
I'm Dyani Lewis. Thanks for joining us. Not too long ago, if you wanted to know whether you were at risk of breast cancer or Alzheimer's disease, you looked at your family tree. Did a parent, an aunt, or an uncle succumb to the disease? Do any of your siblings have the condition? For an increasing number of life threatening diseases, genetic tests now exist that can help predict whether you're likely to develop the condition. The cost and time needed to sequence a single gene, or even an entire genome has plummeted over the last two decades. It's not only doctors wanting to diagnose an illness who are taking advantage of the genomic riches now so readily available. Today, people can send their own blood or saliva samples to a growing number of direct-to-consumer genetic testing companies. The future of this trend is uncertain though as it has attracted the scrutiny of both the research community and government regulators.When it comes to genetic testing, knowledge isn't always power. Divining your medical future based on the code in your chromosomes can have far-reaching consequences for yourself and for those around you. To discuss how clinicians, patients and their families navigate the often uncertain waters of genetic testing, I'm joined on Up Close today by clinical and research geneticist, Professor Ingrid Winship. Professor Winship is Executive Director of Research at Melbourne Health and Professor of Adult Clinical Genetics at the University of Melbourne and the Royal Melbourne Hospital. Welcome to Up Close, Ingrid.

INGRID WINSHIP
Thank you.

DYANI LEWIS
Ingrid, when you conduct a genetic test, what are you actually looking for?

INGRID WINSHIP
Well, I think I’d like to take you back a step and say we don’t just conduct a genetic test. What we do is we assess an individual and that individual within a family. So, the test is a part of an assessment. And what we're trying to do is establish whether there is a significant inherited component of that disease process. So, is there an inherited part of the cancer, or the cardiac condition, or whatever it is in that family, and then is it possible to test for it? Is the test accurate? Is it useful? Can it be used either to change the course of that individual's treatment of their health, and can it be used across the family?So, it's complex blend of a clinical assessment of technological testing, and couched in a lot of counselling, of education and of support.

DYANI LEWIS
What sort of conditions are you dealing with?

INGRID WINSHIP
A whole range of conditions. There are many, many single gene disorders. So those are the sorts of problems that are caused by one gene exerting its influence over someone's human health. So, probably in the western world, cystic fibrosis would be the best known single gene disorder, where one inherits from each parent a change, technically known as a mutation in a gene, and inherits the symptoms and signs that we know go with this conditions that causes respiratory and other sorts of problems.So, lots and lots of single gene disorders that cause a wide range of ill-health and some disability. But then, if we look across the spectrum of other disease, there is what I call a heritable or inherited component to a lot of other diseases. So, an area of particular interest of mine is cancer of the colon, bowel cancer, where most people don’t inherit that predisposition, but a small proportion of people who have colon cancer have developed it because they have an inherited predisposition.So, colon cancer is not all genetic, but a small subset of people can know in advance that they have a risk and then maybe do something about it. So, it comes down to a kind of an evaluation of the here and now and of risk, and then built on to that, a strategy of management of that risk.

DYANI LEWIS
Are there any routine tests that everyone gets?

INGRID WINSHIP
Well, I'm not a paediatrician, I'm a physician. So, I work with adults. There are routine tests in many countries of the world and in Australia, certainly, with obviously consent, newborn babies are screened for a number of potentially serious conditions, some of which can be treated or managed and some of those are inherited. But, in terms of your regular health when you go to your GP, you don't routinely have genetic testing.

DYANI LEWIS
How do researchers go about identifying genes that are the basis for a genetic test?

INGRID WINSHIP
The most important thing is to determine how much of that problem is inherited and how much is not and how significant the role of the genetic component is. If we take colon cancer for instance, not everybody who inherits a mutation in one of the four genes that cause something called Lynch Syndrome. So, Lynch Syndrome is a well-understood inherited colon cancer predisposition, where there are four genes called mismatch repair genes and a change genetic mutation in one of those genes causes a vulnerability to colon cancer and a range of other cancers, particularly gynaecological cancers. Now, not everybody who inherits that mutation will develop the cancer and this is a concept we call penetrance; how likely the presence of that gene changes to cause the predictable problem. So, it's understanding the way that the gene interacts in health that forms the basis of much of what we do. In terms of gene discovery, this has been going on for a long time now, probably the best part of 50 years. I think DNA has been known about in some shape or form for a lot longer. And it's a very long time since Gregor Mendel did his research that looked at those genes, what he described as particles of heredity that go from parent to child. So, the first thing is understanding the pattern of inheritance, where the gene is likely to lie, and then there have been some very elegant studies, particularly using mathematical approaches to changes in DNA in large families in order to map whether a particular gene seems to be causing a problem or not. And this has come across from linkage studies and families to direct sequencing of genes one by one to the new technology now where you can look at the exosome or cloning regions of the gene, or indeed, the entire genome in one go.So, the technology has opened up all sorts of opportunities to study the genes, going from in the middle fifties being able to look at a whole chromosome to see if there's an additional chromosome or a missing chromosome or a piece of a missing chromosome, to now a technology that a simple vial of blood can give you the opportunity to look at every gene from beginning to end in a human being.

DYANI LEWIS
How long does it take now for a gene discovery in the lab to get into the clinical practice?

INGRID WINSHIP
How long is a piece of string? That's a very good question, because the most important thing is that once we think that a gene might be the cause of a problem, it's really important to validate that information before we start using it. If I take us to the clinical end, what we would do once we knew that a gene was definitely linked to a problem and that you could accurately predict disease, you might then tailor a treatment programme doing surgical interventions, lots of screenings, some of which might be irreversible. So, for instance, a young woman with a mutation in the BRCA1 gene would have discussions with the team about prophylactic surgery or risk reduction surgery, so perhaps mastectomy to remove breast tissue to reduce the risk, or what is called BSO, bilateral salpingo-oophorectomy, removing the fallopian tubes and ovaries, which reduces the risk of breast cancer and of ovarian cancer, which are the two risks associated with those genes.Now, that is an evidence-based strategy, which is useful if the mutation exists and the person is at risk. But, it would be inappropriate to be offering that kind of surgery if indeed you didn’t know that that risk existed. So, there's a lot of validation work and clinical understanding that needs to be done between a gene discovery and being able to talk to somebody one on one about their own health and about how we would use that genetic information in order to try and manage the risk of whatever their risk was.

DYANI LEWIS
And genes that cause very distinct conditions like you were talking about cystic fibrosis before, is that a simpler test to develop if you're not talking about levels of risk?

INGRID WINSHIP
So, the genes that have a higher penetrance, in other words the genes where there is more likely to be an impact on your health with the presence of that gene mutation might be easier to interpret in that sense. But, I would like to think that every gene that's investigated for human health goes through a level of rigour in order to understand that when something is used in a clinical sense - and there's a difference between research and clinical service. In research, there's a protocol, it would be approved by what we call an ethics committee, what in the US is an IRB.

DYANI LEWIS
Those are the internal review boards?

INGRID WINSHIP
Exactly. So, there would be a review by a properly constituted group of people to determine whether the work was scientifically valid and ethically acceptable. That protocol would be applied in that setting without necessarily an expectation of changing that individual's health. There may be no particular gain for the participant in a research project, but rather an altruistic gift of their information to the greater good. Whereas, in a clinical service an individual comes in to talk about themselves and their families and so that is a test that should be already through all of those protocols and validated and useful.Let me just add something to that. Clinical decisions about surgery and about surveillance and about scans and management as such are generally not made on the basis of research on that individual. Research will determine the evidence for the protocol that then becomes the clinical practice. So, for instance, if we found novel genes through a gene discovery programme, in order to use them clinically, we would validate them through an accredited laboratory in a health service before we used them in a clinical sense.

DYANI LEWIS
Do you always know what gene to test for?

INGRID WINSHIP
Not all clinical problems are caused by one gene. So, there could be three or four or more genes that cause the same sort of clinical problem. One of the approaches that we're doing now is when you know that there's more than one gene causing a problem, then rather than testing sequentially the first one, the second one, the third one, one might do a panel looking at the six or eight or 10 genes that might be causing the problem, so that you can answer the genetic problem in a more efficient way.But, the genetics of human diseases are very complicated, so it's not always just one gene that causes one problem.

DYANI LEWIS
Is there a reason why genetic causes for some really common conditions like obesity or type 2 diabetes still elude us?

INGRID WINSHIP
Yeah. It's very difficult. These are very complex processes. One of the interesting areas and not an area that I'm an expert in, but one that's extremely valuable is that of twin studies, because identical twins are obviously genetically identical, or as close as identical as you can be. So, the more likely a pair of twins is to have the same sort of problem, the more likely there is to be a genetic component. So, looking at those common conditions like diabetes, heart disease, obesity, the wide spectrum, you get a lot of insights and understanding how many twins have the same sort of things.The problem is that these are not single gene disorders. And our genes, they’re not in appropriate blocks. So, if you go to a shopping centre, all the ladies' fashion will be in one section and the sports gear in another. But, our genome isn't quite that neatly structured. So, you can't say, well, over - on chromosome one, you're going to have all the genes about risk of metabolic problems, and on chromosome eight, will be genes about something else. They are scattered throughout the genome.

DYANI LEWIS
This is Up Close. I'm Dyani Lewis and in this episode, we're talking about how genetic testing can change lives with geneticist Professor Ingrid Winship.Ingrid, some of the tests you've spoken about are looking for mutations in single genes. But, there are other simple changes in genetic sequence, so-called single nucleotide polymorphisms, or SNPs, which occur throughout the genome and they can also be linked to particular conditions. Can these SNPs also be used for genetic testing?

INGRID WINSHIP
SNPs are used quite extensively as association studies to see where propensity may be to genetic disorder. As clinicians, at this stage, we're using mainly genetics rather than genomics. This is an evolutionary change, but in order to make a clinical decision, we would want to analyse that gene for changes rather than go with things that are an association. So, there may be changes in the genome that are more common in people with a particular kind of condition, but that may not be enough specific information about the individual in order to manage their own health.

DYANI LEWIS
So, you really want to hone in on the gene, hone in on the faulty protein that's involved.

INGRID WINSHIP
Exactly, because within gene changes, even those are difficult to interpret. There are some changes in the gene which are quite clearly disease causing. The point of the gene is that it's the kind of recipe that makes a protein product and if the recipe is altered in such a way that the protein is altered, then it's quite straightforward that you can link the two together as a causative phenomenon. So, those we would call clearly pathogenic mutations. They probably caused the problem.On the other hand, we have what are called polymorphisms, which are changes in the gene, which are just natural variation and they don’t change the product and they are very unlikely to cause the problem. Somewhere in the middle is what we call variance of uncertain significance or VUS'. These are difficult to interpret because some will be pathogenic and some will not. Now, there are a lot of different ways of analysing these changes, looking to see whether this change is consistently inherited by people with the condition and not by people without it. There are tests that can be done which are known as functional studies where you actually look to see whether that gene changes the protein or not. And there are lots of computer models that can be used, algorithms and hasn’t actually been seen before.But, that is a clinical conundrum for us, because whoever has had the gene test has a problem. We would only start doing testing in somebody who has already manifested that problem. It's difficult to interpret whether that's going to be of significance or not. And I'm very cautious that we should not use uncertain information in making decisions that are potentially life-changing, because if we get it wrong, then we got it wrong.

DYANI LEWIS
At what age would someone generally be referred to a genetic clinic for testing?

INGRID WINSHIP
Any age at all. We would work with people not necessarily the same team of geneticists, but it may be a childhood problem that a child is born with the problem or develops the problem in childhood. The area that I work in is very much the conditions that one is predisposed to as an adult, or the adult issues of something that's chronic and transitioning from being a child to an adult brings with it different problems for people with genetic disorders.But really, it's all age groups, because we do preconceptual counselling. So, a couple who are at risk of a single gene disorder might come to discuss what the likelihood is that their child would be affected by a genetic disorder and what the reproductive options are, whether it's pre-natal testing or pre-implantation genetic diagnosis, or nothing at all. So, we might work pre-conceptionally and sadly, sometimes we work with the coroner, the medical examiner where an autopsy is performed on somebody who's died suddenly and unexpectedly, particularly young people, where we do the so-called molecular autopsy, where as part of the investigation of the cause of death, we would do genetic tests for an arrhythmia that might be inherited.So, we really would work with people of all ages across the whole spectrum before even conceived and sadly also after death.

DYANI LEWIS
Aside from the people who need to get a condition diagnosed through genetic testing, who are the other people that would come to a genetic clinic for testing?

INGRID WINSHIP
Most people who would come to a genetic clinic will either have themselves or have a close relative with the signs and symptoms of a genetic problem. In the clinic that I work in, we have a wide range of different problems. For instance, we talked a little bit about cancer at the beginning. So, we know that there are a number of genes that predispose to breast and ovarian cancer. There are genes that predispose to colon cancer. A particular interest of mine is genes that predispose to kidney cancer. Now, breast and bowel cancer have been recognised as having a hereditary component for a long time, but the understanding that kidney cancer, particularly certain types of cancer might have an inherited component is a relatively newer understanding.This is important, because if a urologist or surgeon is doing surgery for a kidney cancer, understanding the type of tumour might trigger a referral that would help with the management of that individual later on, but also open the opportunities for later on, but also open the opportunities for scanning, early intervention and possibly better outcomes for their siblings.So, having said that, the sort of people who come into the clinic - and there are a whole lot of different endocrine tumours within the cancer spectrum, a number of conditions, where it would be appropriate to come into the clinic. That first individual would be the person who was tested. The person who manifests that problem would be the person tested and then correlating their clinical problem and their gene tests, we may then be able to offer what we call predictive testing; to all their family members, so that an at risk relative could either say yes, you do have that gene problem, you do have the mutation that runs in your family and this is the strategy that we're going to employ to maintain the best possible health for you. Or, we know what's going on in your family and, no, we've done the test, you have not inherited that. So, nobody is at no risk of cancer, but what you can say is that you have escaped your family's high risk of cancer and that you just need the same surveillance as the general population, that you don’t need the high-risk surveillance. There's a 50-50 inheritance of these genes, so 50-50 to each individual that they're going to get the news that they didn't want to hear, along with the management strategy, or the news that they did want to hear, that they had actually escaped that risk.Of course, this has profound implications for their own children, because if they haven't inherited that mutation, they haven't got it to pass on.

DYANI LEWIS
What sort of things do people need to consider when they're making that decision of whether to have a predictive test or not?

INGRID WINSHIP
One of the important things, I know this is not grammatically very correct, but once you know something, you can't un-know it. And that's the important thing. So, one of the areas that I firmly believe in is the counselling process that empowers people to make decisions. If people don't want to know if they've inherited a mutation, they can still undergo surveillance, so long as it's not risky. For instance, if you're at risk of breast cancer and you're 28 and you don't wish to know yet, or ever if you've inherited that mutation, you may yet want to have the MRI scans to ensure that you're having the surveillance. So, it's empowering to make a decision as to whether you want to know or not know. But with that needs to be equally empowering a safety net, a health management strategy that goes with it, because not knowing and walking away and not having an intervention that could help you is not empowering.

DYANI LEWIS
Does that mean then that conditions like Alzheimer's disease or Huntington's disease, serious neurological conditions that don’t have any known cure that you wouldn't test for those?

INGRID WINSHIP
Not at all. The choice of testing rests with the individual. The use of a genetic test is not predicated on there being something that you can do about it. Because, if you had a risk of Huntington's disease, you might wish to know so that you can plan your life decisions. You may plan when you have your children around how old you are and how well you are. You may wish to avail yourself of the technology known as pre-implantation genetic diagnosis where you can, if you're at risk of a single gene disorder, through the IVF process, test an embryo to see whether the potential baby will be affected or not affected, and so select an embryo free from the disorder from which you're at risk. This of course doesn't guarantee a perfectly healthy baby. It tests one problem. It's not technology that everybody wishes to avail. In Australia, there's a very high cost to it and highlights a little bit of a disparity in health opportunities on a socio-economic basis.But, it's our responsibility as clinicians to put those options before the families, the individuals that come to the clinic and support them to make a decision with which they can comfortably move forward.

DYANI LEWIS
How do you go about consent then when an individual's own genetic test does reveal information about their relatives?

INGRID WINSHIP
This is part of what a clinical discussion entails, that when somebody consents to genetic testing, they are aware that their genetic material may have impact on other people's risk. Oftentimes, a person will come and talk about genetic testing with a focus not necessarily on themselves, but more on their children and probably one of the important areas is to say the children are adults. Have you discussed this with your children? Do your children want to know? So, the communication aspect of genetics is very important.

DYANI LEWIS
I'm Dyani Lewis and my guest today is geneticist Professor Ingrid Winship. We're talking about genetic testing here on Up Close. Ingrid, genetic testing can also reveal infidelities and other skeletons in people's family closets that might be stumbled upon in the course of genetic testing. How do you go about navigating people through those awkward situations?

INGRID WINSHIP
Well, when we're doing a genetic test, what we're looking for is a simple answer related to the genetic basis of that health issue. So, we don’t seek other information. We're not looking for sociological information. We're not doing paternity testing. We may do testing on multiple members of a family, which could potentially, if sought, answer those questions, but we're not looking for those sorts of markers. We're looking for markers of human health and that's what we agree to look for and that's what we give to people.

DYANI LEWIS
There are now several companies that offer direct to consumer genetic testing. Some offer this just for ancestry information, but others offer health risk information as well. What's your take on these companies?

INGRID WINSHIP
In order to learn about issues about one's health, there is a well-worn track now, an evidence based track where an individual who wishes to test genes about their health, has the assistance of [a] genetic counsellor, clinical geneticist, other health professionals, in order to make a decision that empowers them, that gives them the decision making prerogative, but with the assistance and the benefit of all the multi-disciplinary team of health professionals. Most importantly, once one gets the information, to have the context and the knowledge that goes with that.So, for instance, knowing that you've got a gene for colon cancer, but the context that tells you that that particular gene gives you 27 per cent risk rather than high or medium or low or I don’t know. And a lot of people overestimate the risk that goes with a gene and without the context, without that evidence based pathway, it's quite difficult to have context. Finding out genetic information without all the back-up and without the counselling and without the education, the understanding of what that means can be very confronting.

DYANI LEWIS
So, it's mostly about the framework that comes along with the clinical setting rather than the accuracy of the tests?

INGRID WINSHIP
To the best of my knowledge, most of the direct to consumer testing is done using SNPs rather than whole genes. And again, as I've said, in a clinical context, it's actually understanding the way that gene has been altered and inherited in an altered form and the way that it impacts on the downstream proteins and human health that really is the evidence based way.

DYANI LEWIS
Does this mean that you don't envision a future of everyone having their genome sequenced at birth?

INGRID WINSHIP
Well, the idea of having your genome sequenced at birth is not mutually exclusive from what I've said, because if we could have that information and if it was all interpretable and if filters were placed upon what you could know and when, there may be a place for sequencing an individual once in their lifetime. So, this is quite speculative and possibly a little controversial, but because one of the principles of particularly predictive testing to see whether you are at risk of something that you may develop as an adult is that you don’t usually do those tests in childhood. So, there have to be good reasons to test a young child for a gene that may or may not cause a problem in their thirties, or forties, or fifties, or even older. So, I’d like to think that we protect the innocence of youth by not giving people burdensome information when they're not equipped to deal with it.But, there are conditions that are very useful to know. For instance, at the beginning, we talked about the newborn screening programmes. So, if there is something that could be picked up at birth and a diet, a strategy, surveillance, whatever, that made that child's life easier, that prevented long term problems, that would be potentially quite useful. And you could do that at different stages of life. You could reinterrogate that sequence, because once you've got that whole genome sequenced, you can go back and reinterrogate it. So, you don’t have to take all the information. You can put filters on.So, if you knew everything that you needed to in a newborn baby and then maybe, as a child, as a person approaching reproductive age, as an older person, there could be merit in that sort of thing.But, to do something like that, the technology is important and the sequencing, as you've said, is becoming much, much cheaper. The informatics is the big challenge, because the amount of information that you would get from a bottle of blood is vast. The interpretation of all those thousands of genes is profound. So, we would need enormous amounts of informatic capacity to do that, as well as storage. Then probably as important as all that technology, or maybe more important, is we would need to have enormous amounts of community input to see whether this was acceptable or not. Just because something is technically possible, doesn’t mean that we should be doing it. We actually need to understand how this impacts on the human condition and whether people actually want to know. There are cultural mores, spiritual, religious – different countries of the world will have different views, but this is information that really is important to gauge, because if we're going to give people information, we have to be sure that they want it.

DYANI LEWIS
Ingrid Winship, thank you for being our guest on Up Close today and telling us all about genetic testing.

INGRID WINSHIP
That's a pleasure. It's been fun chatting.

DYANI LEWIS
Professor Ingrid Winship is Executive Director of Research at Melbourne Health and Professor of Adult Clinical Genetics at the University of Melbourne and the Royal Melbourne Hospital.