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Preconception genetic carrier screening and early pregnancy testing

Good evening and welcome to this evening’s webinar on preconception genetic carrier screening and early pregnancy testing.  This is the last webinar in this series sponsored by Monash IVF.  My name is Nicole Hall and I will be your host for this evening.  To start tonight’s webinar, I would like to make an acknowledgement of country.  We recognise and acknowledge the traditional custodians of the land and sea on which we live and work.  We pay our respects to elders past, present, and emerging.  I will now run through a few housekeeping notes.  This webinar is being recorded and will be made available for you in the coming week.  To interact with us today, you will need to use the Zoom control panel.  If you cannot see a panel like the image on the slide, hover your cursor over the bottom section of the shared presentations screen, and the panel should appear.  The control panel allows you to select your preferred audio settings and it is also where you can ask questions via the Q&A module.  We have put all attendees on mute tonight to ensure that learning will not be disrupted by background noise.  As this is a webinar, we are unable to see you as participants, so if you need assistance, please use the Q&A feature to raise any technical issues and to submit your questions throughout the presentation.  Please do not enter any personal information outside your name and question, as other attendees will be able to see this.  We will be addressing questions throughout and also after the presentation in a dedicated Q&A time.  You can upvote a question by selecting a tick icon on a question.  Tonight’s webinar is proudly sponsored by Monash IVF.  Our presenters for this evening are Tristan Hardy and Melody Menezes.  Dr Tristan Hardy is the medical director of genetics at Monash IVF Group, as well as, a fertility specialist based in Adelaide.  Dr Hardy completed his medical degree at the University of New South Wales and undertook specialty training in obstetrics and gynaecology at the Royal Hospital for Women in Sydney and the Women and Children's Hospital in Adelaide.  He completed a Master’s in Reproductive Medicine and a PhD focusing on new methods of preimplantation genetic testing.  He then went on to complete a fellowship in genetic pathology with The Royal College of Pathologists of Australasia.  His special interest is genetic testing for patients planning a pregnancy.  Dr Menezes is the scientific director at Monash Ultrasound for Women, alongside leading the genetic counselling department.  She received her Doctor of Philosophy in Medicine in 2011, studying foetal development in medicine and genetic counselling.  Her special interest is ethics in medicine and prenatal screening and testing.  We will get started now and I will hand over to Tristan and Melody to commence their presentations.
Thank you very much, Nicole, for the introduction.  I think Melody is going to be sharing her screen just shortly.  So, tonight's topic is reproductive carrier screening and early pregnancy testing, really focusing on single gene testing, because this is something that has really changed in the last few years, and so just as by way of introduction to myself at the Monash IVF Group, the next slide is really just an overview of the services that we provide.  So, I am the medical director of genetics for Monash IVF, and it is more than just an IVF service.  We have really specialised ultrasound units, particularly Sydney Ultrasound for Women and Monash Ultrasound for Women, and through these all diverse units, both IVF and ultrasound, we provide a lot of specialist services, especially in genetics, so really taking people all the way in the journey from preconception through to fertility treatment if required and then all the way through their pregnancies, and so the next slide shows some of the locations, and so many of you may not know all of the Monash IVF units that are in Adelaide apart from it, and in the Eastern Seaboard, there are a number of different locations for services.  We have a unit in Darwin and even some services in Alice Springs and Tasmania, and as I said before, Sydney Ultrasound for Women and Monash Ultrasound for Women really being our makeshift services for genetic testing, counselling, and beyond.  So, to start with, in terms of carrier screening, the definition of reproductive carrier screening is really that we are testing healthy adults to see if they have an increased chance of having a child with a serious genetic condition, and this is something that is ideally performed before conception, but can be done either in the preconception stage or during pregnancy.  The guidelines from the Royal Australian and New Zealand College of Obstetricians & Gynaecologists and also The Human Genetics Society of Australia were updated in 2018/2019, and they really focused on the idea that reproductive carrier screening should be offered to all women, who are pregnant, or who are planning a pregnancy.  So, the focus on preconception screening being preferable to antenatal screening is really just to keep all of the reproductive options available, and also to reduce the stress of the procedure, so that you do not have the time pressure of obtaining a result or the decisions that need to be made, but realistically, most people are really focusing or maybe hearing about this perhaps in the first trimester of pregnancy, and that is a large group of people, who are now having both non-invasive prenatal testing and carrier screening at the same time.  All couples should also have a careful family history taken with a view to identifying relatives with heritable genetic conditions, and the reason for that is that there are lots of different genetic carrier screening options available and sometimes very specific testing is required and referral to a genetic service, and the RANZCOG and HGSA are really recommended for information on carrier screening for more common genetic conditions that affect children should be offered or women who are planning pregnancy or in the first trimester of pregnancy, and the more common conditions that they mention are cystic fibrosis, Fragile X, and spinal muscular atrophy, as well as, thalassaemias, but I think realistically, there is now a movement towards expanded carrier screening, that is something that we will go through later on in the webinar.  So, one thing to say I think and something that we have all been really familiar with are screening for chromosome conditions in pregnancy, but reproductive carrier screening has really lagged behind that screen for chromosome conditions, despite really affecting a similar proportion of pregnancies, and I wanted to try and unpick some of the reasons for that, as to why that is, just to give an overview of some of the differences between screening, say with non-invasive prenatal testing for chromosome conditions versus carrier screening for single gene.  So, if you look at the chromosome conditions versus molecular or single gene conditions, they are really looking at the same molecule of DNA, a chromosome is just a really long stretch of DNA, the molecular conditions presuming are tiny errors, as opposed to chromosome conditions, where there tends to be larger and missing on extra pieces of DNA, so the first difference is really that in some sense, chromosome conditions are thought to be limited, so when screening either by first trimester biochemistry or non-invasive prenatal testing, it is really for the common chromosome conditions, such as Trisomy 13, 18, and 21, and equations, especially obstetricians are very well versed in that and can give some sort of overview of the type of condition and give some pre-test counselling about that.  Molecular or single gene conditions on the other hand tend to be quite diverse, so there is over sort of 5000 or around 5000 genetic conditions have been associated with single-gene conditions, and they are very, very diverse in the way that they present, so when you present it to someone, who has had all of these different conditions, they are all very different, it can be make the counselling quite difficult.  The second difference is that chromosome conditions are in a sense were predominantly thought to be de novo, and by that I mean that they occur in an egg or sperm, occurs prior to conception, just in the formation of an egg or a sperm.  Of course, they are inherited chromosome conditions, but people do not think of those in terms of screening in pregnancy, and because they are limited to each pregnancy and they have a chance of happening in each pregnancy and increase with maternal age, again that is something that makes obstetric providers quite feel responsible for it and we are very sort of aware of it, whereas molecular conditions, which were inherited, are somehow vast, you could have known about it at any time, it makes it sort of less relevant to pregnancy or people have not been so aware of it beforehand.  The next thing to say is that chromosome conditions really affect all populations, and really with the increasing maternal age, they have become more common, but they really are something that is not specific to any particular ethnicity, and there is a perception that molecular single gene conditions are specific to some ethnicities, and so we commonly _____ presentation that the most common cause of a single gene condition in a Caucasian population may be cystic fibrosis in 1/25 carriers, and there are obviously the thalassaemias, which affect particular populations, and that is because of the fact that different populations have different genetic histories.  On the other hand, that I see sort of a more panethnic approach, we would say, that we all have a chance of carrying these conditions, there are some conditions, which are not specific to any disease, and also people’s identification or understanding of their ethnicity may be very different to their actual ancestry as defined by genetics, so that is something we are moving away from, but definitely something that has prohibited the widespread application of this up until now, and lastly, I suppose when I present to my obstetric colleagues, I think that one of the things that they think is that the chromosome conditions and pregnancy really is a obstetric responsibility, whereas single gene conditions are really something that we only see in the paediatric population and a lot of obstetric providers would not even know about these conditions as they affect the child.  So, earlier attempts at carrier screening focused on single gene conditions, which were specific to ethnic groups, and the reason for that is there were of course higher rates of particular conditions, in particular groups, and they had some awareness of that and then tried with some effort to find a way in which they could reduce the chance of having a child with those conditions.  So, the sorts of conditions that were screened for included Tay-Sachs disease for people of Ashkenazi Jewish ancestry, Mediterranean ancestry, and other ancestries that have a high chance of having a haemoglobinopathy, Caucasian ancestry with cystic fibrosis and African ancestry with sickle cell anaemia.  Now, some of those then got expanded such as CF and SMA, at least in the United States would be recommended to all ethnicities, but some of the reasons for these being screened for in this populations are not only that they were of a high carrier frequency, but it was also there was another test that could be done and remembering that this is sort of back in sometimes the 70s and the 80s, where we did not actually have very good genetic tests available, and so these have surrogate markers, say for example, we all know that a blood count can show some evidence of haemoglobin electrophoresis, it can show some evidence of whether you have a carrier sickle-cell anaemia or another haemoglobinopathy.  So, that could be used as a surrogate maker without needing what was very expensive genetic testing.  The change that has happened recently, really we are talking about a bit longer than the last decade, is that there have been a lot of developments in DNA sequencing technology, and they have allowed a panethnic approach to carrier screening, and most of you probably have seen something about the thousand dollar genome and the decreasing cost of sequencing the genome, to give you an idea, the human genome project when it started cost about twelve billion US dollars, was the sequence one gene, obviously that was a very large effort, and even up until more recently, it would be either $10,000 to $1,00,000 to sequence a gene, now you do not have to sequence an entire genome _____ if you do have to get a lot of genetic information, so when you do so, the fact that sequencing costs have fallen significantly mean that now these sorts of tests are within the range of something that people are really willing to pay for.
So, there has also been, if you go to the next slide now, increased awareness of these conditions in the community, and one of the really big drivers of this is Mackenzie’s Mission, and some of you may have heard about this, or even be recruiting for it at the moment, and this is a federal government project, it is called the Australian Reproductive Carrier Screening project, and the plan is to sequence and provide genetic information to thousands of Australian couples and to give them basically either a high chance or a low chance result to say as a couple you are at a high chance or a low chance of having a child with a significant medical condition, and that is really inspired by and driven by Rachael and Jonathan Casella, who gave birth to Mackenzie, and Mackenzie was diagnosed with spinal muscular atrophy, and they really lobbied the government, had a lot of support from federal health minister to start this project and to see how carrier screening can work in the Australian population, and so that is an ongoing project that is due to finish next year, and the results of that will give us an idea of how carrier screening really plays out in the Australian community.  So, I will hand over to Melody now, and Melody is the head of our genetic counselling program, and she does a lot of pre-test counselling and post-test counselling with couples, and I think that when we go through these sorts of things, it is actually very useful to give an overview of what we talk about when we are involved with people for carrier screening, and it gives you certainly an idea of sort of the depth of the information I think we have to go to.  So, I will hand over to her now.
Thank you, alright, so usually what we do is we explain a little bit about genetics when we do one session, so we talk about the fact that each person contains _____ DNA and that DNA is made up of genes and those genes tell our body how to basically function and develop, and we discussed that children receive half of their DNA from each of the biological parent, a half from the biological mother and half from the biological father.  I would also try to I think normalise the fact that genetic conditions or genetic changes in our DNA are common, so we talk about the fact that genetic conditions occur when there are changes in the DNA, which cause genes not to work properly, but that being a carrier of the genetic conditions does not actually usually affect them on bone health because they have got another working copy of the gene to make up for that change.  Again, we tried to normalise that we are all carriers of genetic conditions, so we all carry three to five genetic conditions in our DNA, and we would usually never be aware of it again because these carriers do not have any symptoms themselves for the most part _____ partner is also the carrier of the same condition that we then have the chance of having an affected child, and that is 1:4 chance with a 3/4 chance of not having an affected child.  Now, this is slightly different for X-linked conditions of course, but we do I guess go through this information with patients, so that they I guess kind of have a good idea of what might happen if they come back as a carrier.  So, why is carrier screening important?  There are hundreds of inherited genetic conditions that present in early infancy, that were in early childhood and most aware, but when we group these conditions together, they actually affect about 1:400 people, so that is more common than you would think, and we noted the majority of babies born with these conditions are born into families with no other affected family members, and that tends to be the most common misconception that we hear from patients that they do not feel this is relevant to them because they do not have a family history of a genetic condition, there is no one in their family that has any issues, and we know that that is not a very good way of working at who needs screening, and there are a lots of studies, this one in particular done in Victoria to show that the majority of affected pregnancies and high-risk couples have no family history and do not really become very similarly in our own data that over 80% of people in our data who had been found to be the carrier of high-risk couple had no family history of that condition, so we are not aware of that, and the next most common misconception is people think they are either planning to have NIPT or they have had NIPT, and that test will cover carrier screening, in fact not realising that actually they are screening for two different things, so as Tristan kind of explained in the beginning of this presentation, NIPT is screening for chromosomal changes, whereas carrier screening is screening for molecular changes in DNA.  They are looking for completely different conditions.  NIPT tends to look for conditions that are de novo or sporadic in that pregnancy, whereas carrier screening looks for things that are inherited, so because of that, we are actually screening the reproductive couple when we do carrier screening, whereas when we do NIPT, we are screening the foetus with a placenta in actual fact because the placental DNA that we are screening is part of that test.  NIPT needs to be done in each pregnancy, so it is only relevant for that particular pregnancy, and again I will be looking for those chromosomal conditions, there are big, extra, or missing chromosomes across the foetal genome, depending on which test that you have ordered, whereas carrier screening is one-off test, so when we screen the reproductive couple, it is a one-off test in them, and it does not generally need to be repeated, and again NIPT is only a screening test in pregnancy, whereas carrier screening is ideally performed in a pre-pregnancy carrier.  It is difficult to try to discuss these things with clients, so I kind of talk about the fact that NIPT is more like a map, like a google map, it is looking at the big chromosomes, whereas carrier screening is a little bit more like a street view, like we are going one more level of detail to actually look at the houses on the streets, we are looking at the gene and looking for errors in them.  So, what are the options for carrier screening, you will probably be aware of the 3-gene carrier screening panels, so these include CF, SMA, and Fragile X syndrome.  These conditions are common in our Australian Caucasian population, they are severe, the tests are good for them, so they are sensitive and specific, again ideally performed pre-pregnancy, it can be done in a saliva or a blood sample, and the cost of this test varies, so it is usually between $350 to $400 for each individual, and if there is a family history of _____ but there needs to be certain criteria in that in order to access that and the turnaround time is roughly, at the moment, I am seeing a 3- to 4-week turnaround time for some of these tests, and the second option recommended by RANZCOG that you may have heard of is expanded carrier screening.  An expanded carrier screening tests hundreds, sometimes thousands of genetic conditions, and it is appropriate for all ethnicities, so it includes the three conditions common in all populations, CF, SMA and Fragile X, but it also includes lots of other inherited conditions or things like your thalassaemias, muscular dystrophy, and lots and lots of conditions on these panels that may get more appropriate for screening anyone with a variant history.  These panels are usually saliva or blood sample as well, again ideally performed pre-pregnancy, and the turnaround time for these panels is between four and six weeks by using a generation sequencing approach, when actually using DNA sequencing to sequence these genes and report variants that we know are pathogenic or likely pathogenic in the genome and the cost varies by provides, so the most cost-effective you will find is probably around $750 per reproductive couple, and it goes up to $1400 for a reproductive couple, depending on the provider, and it may even be more than that for some that I do not know of.  At the moment, there is no Medicare rebate.  I will say, I do think that expanded carrier screening is going to become the gold standard, as the cost continues to go down, and there has been recent American guidelines as well that have said that everyone should actually be offered expanded carrier screening, rather than the 3 gene screening, it is probably only a matter of time here as well.  Alright, so we know that for people that have expanded carrier screening, 1:40 reproductive couples _____ having a child affected by a single gene condition, and for those couples that are at increased risk, the reproductive options could be accepting that risk, I suppose, and considering a diagnosis later in life, so you know not to do anything basically and test the target for symptoms, or if it becomes apparent, natural conception and prenatal diagnosis, IVF with pre-implantation genetic testing, some people choose to use donor eggs or donor sperm or donor embryos to reduce their risk or adopt or not have children, so there are lots of options, and the earlier someone finds out, as ideally preconception, there are more options available to them, and we are just going to briefly cover the option of natural conception and prenatal diagnosis and IVF and pre-implantation genetic testing, as those tend to be the most common options for that, and it is considered in this situation.  So, when it comes to prenatal diagnosis, anything on these expanded carrier screening panels can be confirmed with prenatal diagnosis, and these tests are diagnostic, so it gives you a definitive result, so saying yes, as I am sure you probably know it is done from around 12 weeks of pregnancy, it involves a needle being passed through the abdomen to sample some of the placenta around that developing pregnancy, and it has a small risk of having a miscarriage of about 1:500.  It is a direct DNA sample from the placenta, so results from CDS are quite intensively a bit quicker than results from an amniocentesis because the DNA can be extracted straightaway from the villus.  Amniocentesis is done around 16 weeks of pregnancy.  Again, it involves the fine needle being passed through the abdomen to sample fluids from around the developing pregnancy.  In terms of single gene test, that really needs to be grown up into cells and DNA extracted from them, so it can take a little bit longer, and it is a later test, while it has a slightly better risk of miscarriage being around 1:1000, so those would be the options that we discuss with couples when they come through, so the option of natural conception, and we also discuss that as a confirmatory test, even if they have IVF.  So, I am going to hand back over to Tristan to talk about pre-implantation genetic testing.
So, pre-implantation genetic testing is really my main clinical interest.  I have a clinic where I see patients for having this, and as we said, these conditions are really collectively very common, and so actually whilst individually, they are rare, we are clinics, which are full of couples, who are undergoing preimplantation genetic testing to avoid their specific genetic condition in their family.  So, just to go to the next slide.  Really, the principle of preimplantation genetic testing is a little bit different to the testing _____.  When we test during pregnancy, we can perform pretty much exactly the same tests for a specific variant that has been identified on carrier screening, as we would on a blood sample from an adult or a saliva sample.  In a preimplantation test, we only have say three to five cells from an embryo, so in terms of when we perform an embryo biopsy on the left to draw in a little, as the blastocyst is the stage at which an embryo is biopsied and that is about a type of development, and by that stage, there is a little ball of cells on the inside called the inner cell mass, and that goes on to form the baby, and then the extracellular mass on the outside is the bit that forms the placenta and extra-embryonic tissues, and so it has been shown that is quite safe to biopsy an embryo at that time and take a few cells from the outside layer, and what we do is we extract DNA from those cells, and we actually amplify the DNA and look for what is called a DNA fingerprint, and a DNA fingerprint really is the same thing that the FBI uses or uses, and the reason that _____ is actually because again they have got a very limited amount of DNA that they are getting from any crime scene and so they actually utilise the same sort of technology to say that this profile is consistent with a particular person, and in this case what we do is we do a profile that is consistent with being affected by a condition or not affected by a condition, based on inheritance patterns in the family.  So, to undergo preimplantation genetic testing, first we do a fertility evaluation because really because PGT requires IVF, you really do need to actually know whether IVF is a valid option for you, and so as people get older and/or perhaps have a low ovarian reserve, it may not be an option for them because you do need to produce embryos in at least sufficient numbers to have some to test.  We then do genetic test designs, referred to as feasibility studies, whether that is possible or not, and usually that test is on process now takes about four weeks.  In the old days, it took about 6 to 12 months, where it designed a very specific test for each couple, but now we do more of a genetic test _____ we can just zoom into gene of interest.  Couples would then undergo an IVF cycle and that IVF cycle would be very similar to an IVF cycle in patients having reasons of subfertility, so a variant stimulation which would increase the number of follicles which are supported during that month followed by an egg pickup and an egg pickup to obtain those follicles is usually under sedation and look at the oocytes under the microscope, a semen sample is given on the same day, and individual sperm is injected into each of the eggs, and that is just to keep one copy of each parent’s DNA, and then as I said about day 5 of development, the embryos that have grown to that stage can be biopsied, but because the test takes a few weeks to perform, they need to be frozen on that day and wait till results are back.  So, the genetic testing of the embryos uses that DNA fingerprinting process, and in two to three weeks, you can identify which embryos are suitable for transfer, and so an embryo transfer then follows on from that, so embryo transfer cycles and a frozen cycle where an embryo is stored at the right time and during the window of implantation for that _____ embryo and we will transfer, which is just a very straightforward procedure, while the patient is awake, and then a pregnancy is performed about 10 days later or when you should know whether you are pregnant or not, and pregnancy care as now mentioned includes a recommendation for prenatal testing just to confirm that the result was correct, so PGT is that of 100% accurate, especially when you are performing a genetic test on such a small amount of DNA, we always recommend that you do a direct test during pregnancy to confirm it.  The other really important thing to know is that PGT has a cost burden, and IVF also has a cost burden, and previously, there was no Medicare support for patients who decided that they wanted to undergo PGT, so there is some Medicare support for the IVF component of the cycle, but not for the genetic testing part, and that has changed this year, so in the federal budget this year, they actually announced that they would be supporting couples to undergo this testing, and we are still awaiting the details of the specific item numbers, but the idea is that the couples will be supported both with the test design process and for some testing of embryos in each of the _____ to reduce the financial burden on couples who choose to have this reproductive option.  So, just to go through a common case, and to show some of flavour, I suppose, of some of the complexity that can have with carrier screening, as Mel mentioned, really you know when you test for hundreds of conditions, it is really overlaying one partner versus another and saying where do they match up, and in most cases, there will be 1:4 chance of having an affected child in each pregnancy.  There are other conditions, the carrier will actually have reproductive implications and _____, and so one of those that causes some sort of concern is Fragile X testing, and that is because it can be associated with parental ovarian insufficiency, so say in this case if you are seeing a 29-year-old, who is planning pregnancy, and her sister has recently had a child, who is being diagnosed with fragile X syndrome, your patient has had a test for the CGG repeat in FMR1 gene with the following result, and so CGG repeats are really, where there is a triplet repeat in the fragile X gene in kind of lead up to the gene or the drumroll of the gene, if it goes on for too long and the cell has too many copies of that CGG repeat, the cell actually switches the gene off, so if there is more than 200 copies of that repeat, then it means that that gene is switched off, and so people can be affected by fragile X syndrome, which is the condition associated with intellectual disability, whereas in terms of being a carrier of fragile X, it means you have got somewhere between 55 and 200 repeats, so we know that a female carrier has say in this case one of her fragile X genes has 75 CGG repeats, we know that that has a chance of expanding to over 200 repeats when she has a child, so it is not that 1 in 4 children will necessarily have fragile X, but 1 in 4 would be at a high risk of having fragile X, if that did expand. The other thing though is when you have what is called a premutation in the FMR1 gene, you will have about a 20% to 40% chance of having premature ovarian insufficiency, and so this sort of really compounds or sort of interacts with the fact that people now are asking for _____ gene testing in IVF, for example, because that is going to affect your likelihood of success with IVF, if you have reduced their variant reserve.  The other health impact that happens with fragile X syndrome premutation carriers is what is called fragile X tremor ataxia syndrome, and then that is about 10% to 15% of women and 40% of male carriers of fragile X will develop a tremor later in life after the age of 50, and that can sometimes be confused for a parkinsonism or other sort of neurological conditions.  So, there are obviously complexities that at the end of the day when you evaluate a couple, I think that what you are doing is trying to boil it down to whether they are a high-chance or a low-chance couple of having a child with one of the conditions that you have tested for, and then the post-test counselling is really key, and we spend a lot of time with people afterwards to explain what the test means for them, whether there are health implications of being a carrier, in most cases being very reassuring that there are not, but that they have a 1:4 chance of having a child with a condition they have screened positive for, and so I suppose, in summary, we would say, and we really recommend that anyone who is planning a pregnancy should be offered genetic carrier screening.  The aim of the test is to identify reproductive couples with increased chance of having a child with a single gene condition, and if your screen positive as a reproductive couple, there is generally a 1:4 chance of having an affected child, so each condition screened, we can design a test for embryos or test during pregnancy, and in most cases again, being a carrier will have no impact on your health, and for those who want to know more, a quick _____ for a course, which I developed with A/Prof Lisa Hui at the University of Melbourne, and it was genetics and pregnancy, really to try and go through in six modules the basics of DNA, prenatal screening for chromosome condition, carrier screening, and preimplantation gene testing, it is all obviously aligned and _____ earlier 2020 COVID projects that we had managed to do for a while and then we had compiled over the last year when we had the time, and I am really trying to give an overview to help people be comfortable _____ to know about _____ and to know the pathways of referral, and then another short thing to talk about, I will hand back over to Mel.
So, thanks Tristan, in response to lots of referrers, asking us to make things easier for them, and a lot of our obstetricians and fertility specialists as well, we have ordered that to launch an online carrier screening program, where we are able to offer these tests in any state really that has one of our Monash IVF Clinics or Monash Ultrasounds or Sydney Ultrasound for Women, and we are offering expanded carrier screening platforms, so these are the costs for an individual and a couple test.  We are recommending that couples be screened together at the same time, as it saves them a bit of money and also because we found that over 75% of our individuals, who have had this screening for about $289, I think collective _____ over 75% of individuals who have the test will need to have a part of screen anyway, so people can do it sequentially, but particularly when they are pregnant, we will much recommend a couple screening, just because it takes about four weeks for these results to come back.  People can come into our clinic to give a saliva sample or we will post them up a pack and with _____ and this is supported by a genetic counselling team, so all patients have a pre-test phone call, and the results are called through directly to the patient, and then we also will copy in the doctor, so we are like launching soon, we are just waiting for more kits from the US, so that we have a got a good number, so we have already got lots of people interested.  At the moment, we are all already offering that test through Monash Ultrasound for Women and Sydney Ultrasound for Women clinics in Melbourne, but if you would like some more information on anything we talked about today on our carrier screening _____ services, you can please feel free to contact us or send us an email, and we will be able to help you however we can, and you can register your interest as well by visiting and clicking on the GP tab.  Thank you very much, I think it looks like we have got another _____.  We have got another webinar coming up on polycystic ovarian syndrome on Wednesday, 1 September 2021.
Thanks so much, Tristan and Melody.  We have had quite a few questions come through, so I would just like to remind people to ask all the questions they really want answered.  Okay, so, I will start off with the first one.  So, a lot of the questions have been about cost, so you did mention what the cost of the testing is, but in terms of the genetic counselling, what is the cost involved with that, is there is a Medicare rebate, and things like that.
Now, the testing that we are offering and that we are developing include the genetic counselling as part of that fee, recognising that these results can actually be really difficult to interpret, and it sometimes is not as straightforward as just reading that the conditions do not match between the reproductive couple because sometimes it is more complicated than that, so we are offering that as part of our program.  I cannot really see as to what the other programs offer.  I think there are some carrier screen programs that have genetic counselling and others you have to refer in to a public hospital or some of th private genetic counsellors out there, they are offering that as well.
And does that involve any genetic counselling prior to doing the testing because a lot of the other feedback I am getting is that you know, as GPs we were very _____, we get limited, and we have enough to cover, let alone also then having to do counselling about whether or not people should have these testing done.
I think that probably when it comes to pre-test counselling, the core messages are that 1:40 couples will have a high chance of, you know, be identified by the test to have a high chance of having a child with a condition, but screening in general has no implications for your health and there are some specific ones, which we can go into _____, mainly being a carrier of a X-linked condition, so fragile X was the example that I gave, and Duchenne muscular dystrophy would be another, that a female carrier with Duchenne muscular dystrophy not only has a 1:4 chance of having an affected son, but also has a chance of say cardiomyopathy developing and some things that are relevant to your health, but in general, it is quite positive information, it needs to be clarified that you are not testing for cancer genes, you are not doing BRCA screening, you are not doing autosomal dominant conditions, as the Huntington’s, all of the things.  You can say that as a package, really that is the sort of the core message with our pre-test counselling.  We obviously provide more pre-test counselling when you go through the program, and then post-test counselling is really directed predominantly to the couples, the 1:40, because most people when they find out that they are a low-chance couple, then there is not a lot more to talk about, so yeah, appreciating your time for _____ I think it is also really important, and that is why we are trying to sort of take our burden off it and really try and support people to get through it.  We simply do not have enough genetic counsellors or chat box or whatever that we would need to cover all of these topics with everyone, and I suppose a similar thing happened with NIPT, I mean in the time that I have been practicing obstetrics, you know NIPT was introduced in Australia, it was a really you know a scary or new thing at the beginning, and people would have you know half an hour to an hour of counselling before having a non-invasive prenatal test, and that really has been cut down, as now people have a greater understanding of it, and even the couples coming in have a great understanding of it beforehand.
We do know that it is hard and I have heard that from my specialist as well and we will come up with like a one page, like notepad that people can rip off and hand to their patients, it is like the QR code that you extend to your website, and that is something that _____ provided _____ carrier screening for them, that will take patients to the website, and they now will be able to sign up and talk to a genetic counsellor, if they want to.
Excellent, and the next question that a few people have asked actually is they have had couples that are concerned about the possible implications on insurance, so health insurance or income protection insurance with genetic screening, if they come back as a carrier for something, any comment on that?
Hey, look, the first disclosure would be that Melody and I are not financial experts and not insurance providers, so you know, you should always speak to an insurance provider and clarify with them; however, that said, as we have talked about really, when we talked about health implications, the sorts of health implications are not those that would be expected to have a significant impact on either the cost of your health insurance premium, definitely not your ability to access it, and the same thing goes for income protection.  Now, if you are you know a neurosurgeon, and you find out you have a risk of FXTAS and you know _____ I do not know, there is always going to be a specific circumstance in which that information may be unwelcome, I mean I think that really there is a moratorium on these genetic results actually affecting people’s insurance in Australia, and so that is actually it is not something that is allowed to be done, but obviously everyone has a concern about these things, whenever they are having genetic testing, but again, you are not testing for things that are autosomal dominant and adult onset and likely to sort of lead to an early death or anything that would be really expected to affect your insurance.
Okay, Caroline has asked, how do we screen specifically for conditions in pregnancy?  Can this be done with NIPT or do we specifically need a CVS or amnio?
Whenever there is a specific genetic condition and specific genetic variants identified in a family, you need to have a diagnostic prenatal test or either a CVS or an amnio, and in most cases, it is organised through either a private or a public unit, in which case, there is a lot of prep beforehand, because the laboratory _____ what they are testing for, make sure they have appropriate controls from the family samples, and then the patient needs to be worked up, and so have that test provided, so it is really important to clarify that non-invasive methods are good for general screening, but they are screening tests only, they are not diagnostic tests.
And again, now we are going to look at chromosomal changes, though there is no way to screen _____ for these conditions that we carry like CF and SMA, we need to screen the parents.
Quite a few questions about preimplantation testing, so first of all, can you do these testing on fresh embryos?
You cannot at the moment, there used to be ways of removing one cell from an 8-cell embryo on day three and trying to get a diagnosis, which is usually just a chromosomic condition by day 5 when you are going to transfer the embryo, but that was shown to really reduce pregnancy rates by about 40%.  By performing it on day 5, it is the safest way to perform for the embryo, and so it does necessitate _____ freezing the embryo and the effect on viability.  Freezing the way that we do in IVF now by vitrification is such a fast method of freezing that actually does not impact on the viability of the embryo, the majority of them the upwards of 95% will survive the process and when you transfer them, they actually have, if anything, a slightly better chance of pregnancy, so because in IVF, you have actually not only stimulated the ovaries, you have stimulated the lining of the womb, and that has an impact on implantation success, so a lot of people are actually doing freeze-all cycles as a general principle in IVF, because of the improved pregnancy outcomes from transferring frozen embryos, so both the biopsy and the freezing process are perfectly safe, and so there is no real need to do it on the fresh embryo.
In IVF pregnancy, is it mandatory for people to do preimplantation genetic testing, and the second part of that question is what are the actual costs involved with that?
So, it is definitely not mandatory, and even for couples who are coming, there are the couples who are coming for fertility reasons or for an IVF, and know that they are at increased chance of having a specific condition, and they may elect not to have PGT as part of their IVF cycle, so it is very expensive, and that can influence people, and some people find that not acceptable and would prefer to have a test, and it means you are interested, and also it is important to know that none of the things that we have mentioned are mandatory, that it is really just trying to outline all of the options for couples, who are in the situation.  When it comes to test costs, it is difficult you know without specific details to it, but to give a ballpark figure, we usually tell people they are currently without their Medicare rebate, it is about $10,000 to $12,000 through our program to get from having a genetic test design and an IVF cycle and some embryos tested, and then getting an embryo transferred as part of that process.  So, you know it is a significant out-of-pocket cost still at the moment.  We expect that the Medicare item will give some rebate to that, and obviously it is very much influenced by the number of embryos you generate, the number of embryos you test, and all of these sorts of things, so that is a very ballpark figure, but at least something to keep in mind, it is certainly not expected, some people think it to be $20,000 or $50,000, it is not that sort of range, and we do obviously hope that the Medicare rebate will actually make that much more affordable for couples as well.
Okay, Anna has asked basically confirming, so we test the couple for both 3-condition screening and also for expanded carrier screening, or do we test the individual first, what do we do for which basically?
So, the expanded carrier screen actually includes the three conditions, so it includes CF, SMA, and fragile X.  It just includes lots of other common genetic conditions as well.  So, if you had a couple who were wanting to have carrier screening, the option would be offer the 3-gene or the expanded screen, and if they have the expanded screen, it is just the expanded screen that they need to have that are intended for us, and we would recommend you test the couple at the same time to save time, but if cost is an issue and they are not pregnant, you can certainly screen _____ because _____ explained the condition, and if she comes back as the carrier of something, then screen her reproductive partner next.
It is also just to do with the number of people who turn out positive, so if you do screening for CF, fragile X, and SMA only, as basically, it is 1:25 people, who will be carriers of CF, 1:40 will be SMA, and 1:250 or so will be fragile X carriers, so most individuals if you test the female first, just for the three genes, we will still not be positive for one of those, and if you are not positive for them, then there is no point performing a 3-gene test or in fact a 2-gene test, you do not test the male partner for fragile X.  So, you do not do a CF and SMA screening, unless it is relevant.  So, you say some people do the 3-gene sort of sequentially, whereas with expanded carrier screening, the reality is that because we are all carriers of conditions, as soon as you get the one result back, you end up having to screen the partner in the vast majority, so as to say just for sort of logistical reasons, most people do them together.
Okay, Nazila has I guess basically said that you know should we be asking couples to defer and see the _____ testing done, and I think there is a little bit of concern from some of the people on the webinar tonight that we are opening a can of worms, and there is just not a lot of confidence about raising it.  So, can you comment on that please?
So, I do not ever really get anyone to defer conceiving, you know, for the purpose of population screening.  So, this is something that applies to everyone, as you say, this even in people who have no family history, someone who has a specifically very increased chance from a particular family history that may be different while they clarify their genetic situation, but when we talk about population screening, whilst it can be done preconception, it is really even you can start at preconception, and many people will fall pregnant.  We are really trying to support people, who have not had the testing prior to pregnancy, if they do come in for NIPT, to offer it at the same time, and recognising that really the first trimester of pregnancy may be still the majority of people first finding out about it.  When it comes to you know should we make people aware of it, not only RANZCOG, which is my college, but RACGP also recommend that we talk to people about it, and they recommend the _____.  That does not mean you have to have a half an hour to one hour discussion with someone, but really just to say that this is something that is available.  It is so can give then information about, and as Mel said, we have got really you know a short, cutdown version of counselling on a rip-off pad, that is actually quite useful, because then you can say, look, if this is something you are interested in, this is the general spiel, you can find out more information and link that through with it.
Okay, Sabrina has asked, can you do telehealth consults with patients in Western Australia, or if not, do you know if there is anyone in Western Australia, who offers this service.
So, yeah, we do telehealth consults for anyone anywhere and the preconception carrier screening service will be online, so that will be available to everyone, when it comes to IVF and ultrasound and diagnostic services, we may not have a footprint there, but we still have colleagues to help out, and we always direct people to their local options.
We were trying to you know base the surface where we had clinics, which is why at that, but I am more than happy to have your patients from wherever, and we have a couple of _____ telehealth, who are very good at Zoom these days, and so, if you would like to do that, we are more than happy to help.
And obviously that service is coming about where people could sort of refer themselves, but before that is available, can someone refer themselves at the moment, or does it have to be through a GP?
So, there is no referral required for a genetic carrier screening or genetic counselling because there is no Medicare rebate for genetic counselling, so anything that is non-MBS related can be self-initiated, and so that we do try and support people, if they do want to do it themselves, but really, it is still something that we would prefer to do in collaboration and to not necessarily have even a referral, but at least support from the GP, because that is really a bit more important for their profession.
_____ you know cannot refer themselves, we will find out who their GP is, and we will copy them into results, and if they end up being a high-risk couple, we will be in contact to take you through that and to help you however we can.
Yeah, fantastic, _____ you know that is a scary bit, getting a couple with an abnormal result, and not really knowing what to tell them about it.
So, we will do all that for you, and yeah, also happy to take you through it as well.
Okay, this is a good question actually, because I want to know as well, Peter has asked, where can we get these information sheets with the QR code, maybe that is something we cold email the link out on?
I will just share my screen.  Yeah, I will just go back to the last slide.  So, I think that you can email or you can go to the Monash IVF website, and there is a GP tab that you can click on, head to our website, or if there is something maybe we can organise at this centre, and you can contact us, if you want some more information about this.
Right.  And a question from Ben Craig, which is not specifically related to genetic testing, but more IVF in general, basically what are the success rates for fresh embryos transfers versus frozen embryo transfers?
The fresh embryo versus frozen embryo, as I said before is relatively consistent, and in fact you know in some clinics will be actually higher in the frozen group, so you can use the website to have a look at sort of general population statistics and read about the success rates of IVF of a particular person of a particular age.  It is probably the most important thing and also the fertility factors that are involved.  When it comes to an individual patient deciding between fresh and frozen transfer, a very common way is to transfer your first embryo fresh and obviously the remainder frozen in frozen cycles, and in these cycles, we obviously just do not have that fresh transfer as a part of those, and we transfer all of them frozen.  So, they are very comparable, and it is really dependent mainly on the female age.
Okay, that is all the questions that we have tonight.  A very, very big thank you to our presenters, Tristan and Melody, for sharing their knowledge and their time this evening.  Thank you also for providing that email address and links to your website.  That is very much appreciated.  So, thank you everyone for attending, and I hope you all have a good evening.
Thanks very much.
Thank you.

Other RACGP online events

Originally recorded:

18 August 2021

We are all carriers of at least 3-5 genetic conditions, but we may never be aware of this. Most carriers are healthy individuals who have no family history of the genetic condition(s) they carry.
General practitioners play a key role in assisting patients planning a pregnancy to navigate the genetic screening options available.
Genetic carrier screening is now recommended as part of routine pregnancy care. However, testing patients before conception gives them an opportunity to discuss all reproductive options including preimplantation genetic testing.
In this webinar, Monash IVF specialists will discuss:
  • The importance of genetic carrier screening
  • Current options for patients with regards to genetic carrier screening (basic screen vs expanded panel screen)
  • Non-invasive prenatal testing (NIPT)
  • How to order both NIPT and genetic carrier screening during pregnancy to provide comprehensive genetic screening
  • How to deal with the results of genetic carrier screening
  • Reproductive options, including preimplantation genetic testing

Learning outcomes

  1. Understand the process of genetic carrier screening including pre-test and post-test counselling
  2. Compare the current options for genetic carrier screening
  3. Understand the difference between genetic carrier screening and non-invasive prenatal testing
  4. Understand next steps - how to interpret results for patients and discuss reproductive options for carrier couples
This event attracts 2 CPD points

This event attracts 2 CPD points

This event is part of Monash IVF Series. Events in this series are:


Dr Nicole Hall

MBBS (hons) FRACGP GP and GP VMO in high risk antenatal care, Liverpool Hospital, Sydney. Co-chair Antenatal Shared Care Working Party, South West Sydney PHN RACGP representative Stillbirth CRE and Centre of Perinatal Excellence (COPE) Deputy chair, RACGP antenatal/postnatal care special interest group


Dr Tristan Hardy
Medical Director Genetics - Monash IVF Group.

Dr Hardy is the Medical Director of Genetics at Monash IVF Group as well as a Fertility Specialist based in Adelaide. Dr Hardy completed his medical degree at the University of New South Wales and undertook specialty training in Obstetrics and Gynaecology at the Royal Hospital for Women, Sydney and the Women’s and Children’s Hospital, Adelaide. He completed a Masters in Reproductive Medicine and a PhD focussing on new methods of Pre-implantation Genetic Testing. He then went on to complete a fellowship in genetic pathology with the Royal College of Pathologists of Australasia. Dr Hardy’s special interest is genetic testing for patients planning a pregnancy.

Dr Melody Menezes
Head Genetic Counsellor and Scientific Director - Monash Ultrasound for Women

Dr Menezes is the Scientific Director at Monash Ultrasound for Woman, alongside leading the Genetic Counselling Department. She received her Doctorate of Philosophy in Medicine in 2011, studying fetal development and medicine, and genetic counselling. Her special interest is ethics in medicine, and prenatal screening and testing.

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