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Session 3 - Reproductive carrier screening: What you should know?

Good evening everybody.  Welcome to the final of our three-part illumina webinar series, Integrating Geonomics into General Practice, non-invasive prenatal screening beyond the common trisomies and reproductive genetic carrier screening.  Tonight’s webinar is reproductive carrier screening, what should you know about it.  My name is Dr Nicole Hall, and I will be your host this evening.
Before we get started, I would like to acknowledge the traditional owners of the lands from where each of us are joining this webinar today.  I wish to pay my respects to elders past, present and emerging.
Just a few housekeeping notes. This webinar is being recorded and will be made available to you later this week.  If you cannot see this control panel on your screen, please move your cursor over the bottom of your screen and the control panel should appear.  This control panel provides you with the audio tools for adjustment and is also where you are able to ask questions tonight via our question and answer 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 please interact with us via the question and answer box at the bottom of your screen.  Please do not enter any personal information aside from your name and question as other attendees will be able to see this.  Also, if someone has asked a question that you would like answered please give it a thumbs up because questions that get more thumbs up will be answered first.  We will have a dedicated question and answer session at the end of the webinar but please ask questions throughout and if relevant we will answer them as we go.
Now for a disclaimer, I would like to let you know that the opinions expressed during this presentation are those of the speaker and illumina does not endorse any unintended use of its products.
Tonight’s webinar is proudly sponsored by illumina and our presenter for this evening is Prof Edwin Kirk.  Edwin is a clinical geneticist at Sydney Children’s Hospital and a genetic pathologist at New South Wales Health in Randwick Genomics Laboratory.  He is a conjoint professor in the School of Women and Children’s Health at the University of New South Wales.  His research interests include gene discovery and mendelian disorders and the genetics of congenital heart disease.  In recent years, reproductive genetic carrier screening has been a major research focus and indeed he is the co-lead of the 20-million-dollar Medical Research Future Fund, Mackenzie's Mission Project which I am sure many of you would have heard of and that completed recruitment earlier this year.  He is the author of a popular science book The Genes That Make Us: Human Stories from a Revolution in Medicine.  We will get started now and I will handover to Edwin to commence his presentation.
Okay, thanks very much for that.  I must say I never thought of improperly using an element of product, I am going to try and imagine now how I might go about that, right, here we go slideshow hopefully that is working alright.  Is it working alright.
Yes, that is all good.
Alright so Reproductive Genetic Carrier Screening.  So we are talking about screening for carrier status for autosomal recessive and X-linked conditions and we are talking about testing people from the general population, so it is distinct from cascade testing in a family we already know that somebody is a carrier.  People used to talk more about preconception carrier screening, but the reality is that although in the ideal world you would do this in a preconception setting, I will talk more about why that is later.  In practice, about two thirds of everyone who accesses carrier screening is pregnant already by the time of screening and that is partly because about half of all pregnancies in Australia at least are unplanned which is actually pretty good by world standards and partly because it is just not something that is the top of people’s minds until there is actually pregnancy to focus their attention, so the reality is that we do have to do it and able to provide screening during pregnancy.  Brief reminder, we are talking about autosomal recessive inheritance where both partners are carriers of a variant that does not usually impact their own health in any meaningful way and they have one in four chance with each pregnancy of having an affected child and also X-linked conditions where the female partner is heterozygous for a variant on the X chromosome and has a one in four chance of having an affected male child with each pregnancy and one in two chance of passing the variant onto each of her daughters as well and the reason that is relevant is that for many X-linked conditions the heterozygous can have a phenotype as well and I will mention an example or two of that. That can complicate things sometimes in carrier screening we identify someone who has been tested as being a carrier in a test that is done in relation to her future offspring, but also then identified that there are health implications for her.  Individually, we are taking about rare conditions.  Our idea of a common condition in genetics is something like cystic fibrosis that affects something like one in two and half and one in three thousand babies but collectively they are not so rare, collectively we are talking about quite common conditions that contribute quite importantly to disease burden particularly in childhood but also through life and there is more than two and half thousands genes now linked to recessive or X-linked conditions of which the majority are autosomal recessive conditions. And the estimates vary quite a lot, but a typical person probably carries about two severe recessive variants and obviously that only matters if their reproductive partner carries a variant in exactly the same gene.  For X-linked condition all that is required is female is the carrier. And the conditions can affect all body systems and all age groups but many of these are ______ and many are severe.  There is quite a lot of debate by the way about what constitutes a severe condition and I don’t have time to go into that now but clearly there is a spectrum from very mild conditions like uncombable hair which is fortunately curable through to lethal conditions that affects children and shortens life spans. So that can lead into why you might offer carrier screening.  Here are a couple of MRI scans, the one on the left you can see my cursor, you can see these areas here of alterations that are reflective of a condition called Leigh syndrome an autosomal recessive usually sometimes mitochondrial condition that has complex features but is neurodegenerative and lethal in the first years of life … and on the right an MRI from a boy with X-linked adrenal leukodystrophy, a condition in which boys are healthy and well until sometime usually in the first decade when they may have onset of again a potentially lethal neurodegenerative condition, quite a complex and interesting condition but the point about this is that from my point of view as a geneticist I have many times found myself sitting with families giving them grim news about an X-linked or autosomal recessive condition in their child and increasingly as the technologies have developed, it seemed to me that there might be something that could have been done to prevent us all being in that room having that conversation. And so that has been my motivation for my involvement in carrier screening.  So I guess just repeating what I’ve said, but just some examples of conditions you may be familiar with that include cystic fibrosis, spinal muscular atrophy, autosomal recessive conditions.  I will talk a bit more of about both of those, Fragile X syndrome and Duchenne muscular dystrophy are examples of X-linked conditions so I will discuss those as well.  Most couples only learn about carrier status after the diagnosis of an affected child and most couples who know they are carriers for severe conditions, then take action to avoid having subsequently affected children. So it seems to us that it is a good idea to give them that chance.  Conditions obviously have impacts on the affected person but also on their families in terms of grief and loss, financial and career impacts, often you get one member of the family, particularly the mother staying home and looking after a disabled child.  The effects on siblings, society costs and we are talking about things like the needs for additional services not just on the health system of course and then cost for the health system that are rising considerably with new targeted therapies.  Some of those therapies are quite dramatic in their impact but nonetheless convert the condition from a life-limiting condition to a chronic condition that may actually require a lot more support and services during that person’s lifetime.  So what are the goals of screening.  There actually is a bit of controversy about the way we should think about this and the mantra is that we should be providing reproductive choice giving people the opportunity to make an informed decision that they would not otherwise have.  I said before that I did not want to be in the room telling people that their child had a lethal condition if I could avoid it, so I guess from my point of view, there is a preventive goal but there has been a eugenic critics raised against the idea of preventing the birth of children with particular conditions and a pair of ethicists that we work with have mounted a critique of that, you know, a response to that eugenics critique, you can see the paper there.  It can also be used to prepare for the birth of an affected child and there are some conditions where early management can make a difference and conditions that may not be on newborn screening in particular and perhaps the sort of best example of this is a congenital adrenal hyperplasia and there are some conditions where you can have a baby who is born for all intents and purposes looking fine and then has an Addisonian crisis and potentially dies in the first weeks of life and obviously treatment for that is quite straightforward and the outcomes are extremely good but if you do not know well in advance, you do not have the opportunity to make that intervention. So it is not always about avoiding an affected pregnancy sometimes it is about being prepared.  If you think about the possible approaches to identifying at risk couples, traditionally, for a long time, when we have had genetic testing we have thought about looking at family history and also ethnicities for example screening for thalassemias in people from the appropriate populations, but clearly that is going to miss most couples who have got an increased chance of having an affected child.  You can do targeted community screening, I will talk a bit about that and that will miss most couples that has a chance, but if you do population screening you can focus on the most common genetic conditions, a small number of conditions and that will miss most couples as a recurring theme here … and lastly you could look at expanded panels of conditions hundreds or even more than a thousand genes and that is actually still going to miss some, I will talk about later on about why that is, but nonetheless the more genes you look at generally speaking, the more pickup there is, but there can also be some problems associated with that.  A bit about the history of carrier screening, it is actually not a new idea.  Now, I do not know how much time you spend thinking about Cyprus in the 1970s, probably not a great deal, but if you did, you are probably thinking sun, sand _____ and maybe something about the political issues that happened in 1970s as well but when I think about Cyprus in 1970s I think about thalassaemia and the background actually goes back to 1955 when ______ a pair of Italians suggested the possibility of what they call preventive counselling for thalassaemia.  In the 1960s late Prof George Stamatoyannopoulos who went on to become a luminary in gene therapy by the way, screened the population of a village in Greece and counselled the carriers against marriage.  He went back in a year or two later and found he had absolutely no success at all but that still laid the groundwork for him being invited to visit Cyprus by the World Health Organisation in the early 1970s and planning for a screening program began with a public education program.  Why Cyprus, 17% of the population were carriers for beta-thalassaemia and 1 in 135 babies were affected at the time when they started and obviously that had quite substantial impact on both the affected individuals and the health service.  In 1978, 45% of the entire output of the Nicosia Blood Bank was being used for treating people with thalassaemia.  In 1979, 6% of the entire budget of the Ministry of Health was used for this one drug deferoxamine which is used to treat the chronic iron overload you get with repeated transfusions for thalassaemia, so an enormous impact on their health.  This is a paper from 1981 and you will see that they did not shy away from calling this preventive medicine and they talked about health economics.  The yearly cost of prevention including antenatal diagnosis which in those days was expensive and difficult represents just five weeks expenditure for the treatment of patients so very very cost-effective and they said there are four interdependent aspects to our program, public education, population screening, genetic counselling and antenatal diagnosis.  Now we have just spent 20 million dollars on Mackenzie’s mission and our view is that we need public education, population screening, genetic counselling and antenatal diagnosis, so do not tell the government about how we have spent the money because really there is nothing new under the sun.  The essentials had been worked out for more than 40 years and here you can see the effectiveness of the program and the expected number of births in the third column there growing with the population and the actual number falling.  Tay-Sachs disease is another example of a community screening program.  The first carrier screening began pretty much the same time in the early 1970s, initially with enzymatic carrier screening and programs were established for Ashkenazi Jewish communities around the world.  In Australia, we have been doing this since 1995, initially with enzymatic testing and then molecular and subsequently adding other conditions for which there are higher carrier frequencies in the Ashkenazi Jewish population.  It is really effective, so no child has been born who is affected by Tay-Sachs disease to screen parents since the program began nearly 30 years ago and it has been shown to be cost-effective as well.  Right, so thinking about models of screening.  So sequential carrier screening is by far the dominant approach and that means testing one partner usually the female partner and then only testing the male partner if the female partner is a carrier for an autosomal recessive condition.  The alternative is couple based reporting where you test both at once and you can either give them an individual set of results or just give a combined result.  The latter was the approach we used in Mackenzie’s mission and there were pros and cons to each of these which I will talk about in a bit.  People talk about expanded carrier screening and that is relative to the kind of focused screening that I was talking about that had been done historically and screening for panels of genes, typically, a few hundred, and the expansion has been driven by the rapid improvements in the technology and the fall in costs and it is largely offered by commercial providers.  There are varied gene lists although there are quite a few genes that tend to be common between them and also varied reporting policies and I will talk a bit more about that.  Just a bit about Mackenzie’s mission which may be familiar to some of you, so this was the project I referred to and was named after Mackenzie Casella who sadly died in 2017, age 7 months from spinal muscle atrophy and after the diagnosis was made her parents learned that carrier screening for spinal muscle atrophy was possible and already available in Australia _____ and there were very organised people who had done what they could to ensure a safe pregnancy but had not heard about carrier screening.  They became powerful advocates for screening for spinal muscle atrophy in particular but also for other genetic conditions and lobbied the federal government and that is what led to the Mackenzie’s Mission Project and that project aimed to screen initially about 10000 couples for carrier status for what ended up being 1300 odd genes before or early in pregnancy and we had as you can imagine a fairly comprehensive research program that went along with that and you saw one of our ethics papers that came out in the project early on and we did as a couple screening where we either gave them a high chance or low chance result without any individual carrier results.  So why was that, for a very large panel like this and this comes to the issue about sequential screening versus doing both at once.  For a very large panel, you expect that more than 90% will be carriers of at least one condition and that requires a fair bit of counselling.  There is an estimate of 64 minutes seems a bit high to me to be honest.  I do not think it probably mostly takes that long, but nonetheless at population scale it is completely untenable to be thinking about that and from a laboratory point of view if you have to look at every single variant in both partners that is an awful lot of work and the reporting requirements of a really intensive as opposed to focusing it down to things that are potentially relevant for them as a couple that actually have clinical utility.  There was recruitment by healthcare practitioners perhaps including some of you, interested parties were given a web address and a unique code, received education online to assist in decision-making which meant that recruitment to the project was hopefully a very brief process for the recruiters online, they completed questionnaires and consent.  We posted them out screening kids and there was an option for hard copy information and questionnaire and consent completed for those who needed that.  We were asked by the government to demonstrate that it was possible to do this Australia wide and we worked hard to get out into remote areas and to cover the population as a whole.  This is a map of where all the recruiter couples were and of course there are a lot of people on top of each other in some of the more densely populated regions but as you can see, we generally did pretty well.  As it turned out, we were a bit COVID affected but still managed to recruit just over 9000 couples and about 2% had a new increased risk result meaning something they did not know about beforehand.  Now, that will be somewhat low if you consider those who did not already have a family history of something and ruled out consanguineous couples and it also made a difference what the referral source was so we had overrepresentation compared with we might expect a population scale from clinical genetic services because of the pandemic and just by the nature of the people referred by clinical geneticists the pickup rate was higher in that group and so for a population scale it was probably going to be a bit less than 2%, would be picked up with a very large panel like this.  An 81% of them were not of the three common genes CFTR______ and we had increased results for a really long list of different genes, 89 different genes, I think demonstrating that you do need panels with quite a lot of genes to have a decent pickup.  But it doesn’t necessarily have to be 1300 though.  What did we find, online education and consent were very effective, minimal time we hope was needed for referral and certainly for those that I referred I do not need to spend a lot of time talking about it.  We did online education and tested whether it worked, and we did a quiz before and after that … and before education only half scored more than 80%, which I still think is pretty good actually and after education 89% scored more than 80%, so it was effective.  What is the current state of play in Australia, and I assume New Zealand is similar for those maybe from New Zealand watching us, but I don’t know for certain.  There is plenty of commercial screening happening, there are multiple different labs.  They are mostly international.  There are Australian groups that refer out to international labs and also a little bit of testing that is happening in Australia, quite a lot just for the three genes, for CFTR, fragile X and SMN1, but not very many Australian labs doing big panels as a local test.  Cleary the fact that its user pays raises equity concerns because of the cost of testing and there are also some reporting issues, and I will talk a bit more about that.  There was some community genetic screening happening in Ashkenazi Jewish population in NSW and also of course the screening that goes on just routinely really for thalassaemia which is kind of ad hoc but is actually very effective.  It is quite uncommon for babies to be born with thalassaemia without prior knowledge that there was a risk.  The medical service advisory committee supported the idea of funding for carrier screening for those three genes and in the 2022 budget there was an announcement this would start in November 2023.  We do not know what the new government is going to do about that whether they will maintain that plan or not.  We have put an application in for couples screening of somewhat of a cut down version of the Mackenzie’s list about 1050 genes and we are expecting any day now to hear the outcome of that application, but it is likely to take years before we will be able to implement that at population scale.  What about professional guidelines, the most relevant really is this one, the _______ guideline which says that information on carrier screening for genetic conditions should be offered to all women planning a pregnancy or in the first trimester and they talk about the option of either the most common conditions or a larger panel.  They also say that variants of uncertain significance should not be reported, and I will be talking about variants of uncertain significance in a bit more detail.  So what are your options right now, you could offer just the three genes or a large panel, either way the patients are going to pay and I guess you will want to think about consideration such as value for money because it is surprisingly not a lot more expensive with some of the companies to get a panel of a couple 100 or 300 genes that is just to get three.  What are the advantages of three genes it is still less expensive to do that.  There is the possibility of Medicare funded follow-up carrier screening for example of the partner of a CF carrier that is identified that way.  Clearly if you have got fewer conditions there is less chance of getting something complex or difficult, although you can still get reports from some companies that may cause you difficulties but clearly the disadvantages is there is much lower pickup than for a large panel.  For a large panel the main advantage is the high pickup, the disadvantages clearly the higher costs and particularly if you do it sequentially there is a higher chance that you will need not as much as 90% but still fairly substantial that you will need to test the partner as well.  The reports are often complex and it will take a bit to getting used to it and reporting of variants of uncertain significance and mild variants or even benign variants in some instances. So there is a need for good pre-test information and the reality is that I know that you know it is not realistic to expect that you are going to be able to spend a lot of time talking about these complex issues with your patients, so you do need to be able to direct them to appropriate information and some of the groups offer carrier screening, you have got quite good websites that you can direct your patients to that will give them good information.  Things to think about that might come up, you need to think about the reasons for considering screening it, it may not be for everyone so you have to think about what would this couple do with the information and what their options are and in particular there are some people who would not intervene in a pregnancy under any circumstance and for them it may not really be that helpful to have the information about carrier status. You have to think about timing and especially if they are pregnant already, doing this late in a pregnancy may not be optimal, you do not want to get a result that says that someone is at risk of having a child affected by severe condition when they are already after 30 weeks for instance, in fact, the earlier the better … and obviously there were differences in different jurisdictions regarding options for intervention in pregnancy if there is a prenatal diagnosis that says the baby is affected by a condition.  There is that possibility of a result that may be ______ significant costs.  Just a bit about some gene specific considerations, I worried a little bit when I put this stuff in because it is a lot of detail and most of the time you are not going to have to deal with this but I thought for these three common conditions it would be worth just going into some of the complexities just mainly so that you are aware that these complexities exist. You may be aware of it of course and I guess the main point is that there can be tricky results or results that do not mean what they seem to on the face of it. So Fragile X is a common form of intellectual disability.  The main mutation mechanism is a triplet repeat expansion.  So, in the upstream part of the gene there is this section that goes CGG-CGG-CGG-CGG- repeat and the normal range is around 5 to 44 repeats. 45 and up there is a chance that when this is transmitted at myosis there will be an expansion and the bigger it gets, the higher the expansion is likely to be and from 55 upwards there is a chance of expansion into the full mutation range which is 200 and above and again the larger pre-mutations of around 100 to 130 mark will certainly expand to full mutation if they are transmitted by a woman.  There is a difference in males and females in this regard, whereas the small ones have got a very small chance of expanding.  Additionally, male and female carriers of pre-mutations have a risk of having this neurological condition ______ ataxia syndrome which is a late onset adult condition and women are at risk of having premature ovarian failure, so there is a bit going on there. Now most of the repeats are small and most of the pre-mutations are small with a low risk of expansion to full mutation so it is a mixed blessing knowing about them.  There is additional testing you can do looking at AGG interrupt so in this case, it goes CGG-CGG-CGG and then it is AGG and that stabilises the thing and makes it less likely to expand and it is quite common in this small pre-mutations and greatly reduces the risk of expansion to full mutation and in practical terms what this means is you might do carrier screening, get a result that it says that this patient is a carrier for Fragile X syndrome and it will seem like there is a high chance or one in four chance that they will have a baby with this intellectual disability condition. But the expansion might be 56 repeats and so really there is only quite a small chance of it passed on that it will go to a full mutation although it might get a bit bigger and there is something you can do to refine that risk and provide more information.  Spinal muscular atrophy is a progressive neurological condition that has varying severity, very variable actually from a condition, the most common form is quite severe and leads to death in the first year or two of life but at the mildest end we are talking about a later adult-onset neurological condition.  The earlier the onset, the worse the prognosis as you might expect and the main mechanism for this is deletion of least exon 7 of the gene but it is a complex region of the genome and there are all sorts of rearrangements that are seen, there is a second gene called SMN2, they copy number for that is relevant severity of the condition. And when we do screening we count, there are other mutation mechanism but really all we do is recount copies of exon 7 and the usual number obviously is 2, one on each chromosome but it is not that uncommon to have three copies because you have got two copies of one chromosome and one copy on the other.  It also possible to have two copies of one chromosome and none on the other and that means that the test that looks to find two copies and reassure people actually does not completely exclude carrier status, it greatly reduces it but does not rule it out. So when we do screening you could find one copy which is someone who is a definite carrier and then you screen the partner, two copies, they are probably not a carrier, the risk goes down from 1 in 50 to 1 in 650 and that obviously combined with their partners prior risk if they got no family history 1 in 50 means a very low risk of having an affected baby. Or they might have three copies which means they are almost certainly not a carrier.  Those probabilities above can be obviously affected by whether there is a family history and it can get quite complex working this out. And there are new treatments that change in the outlook for spinal muscular atrophy which complicates things further, so this is one of my favourite things about the PBS, if you look at this the cost of the drug to the government is $110,000 a dose and the maximum safety net charge is $40 and 30 cents, that is good value for money. But what this means is that you are talking about a very expensive treatment, this was given intrathecally and in fact it is nothing compared with at least per dose, with the gene therapy for the same condition called _______ which is I think something on the order of three million Australian dollars for one dose, the difference being that it is thought that you can be able to give just a single shot and you are done which is different from _______ which is an ongoing treatment.  About cystic fibrosis, I think you probably have heard of this, so it is a severe child onset multisystem disorder that particularly affects the lungs and the pancreas.  Severity of this has also changed with new treatments.  It is caused by variants in the CFTR gene and there is a really wide spectrum of severity so the reason why you do the screening is for classical cystic fibrosis but some people who have got two variants in the gene are fine but if the males can have congenital bilateral absence of the vas deference that has caused infertility or they can have what is called a CFTR-related disorder which can include various other usually mild things like sinusitis and maybe mild lung disease.  Some of the variants are associated with what they call varying clinical consequence so you can have a severe variant on one copy of the gene and what are these varying clinical consequence variants on the other copy and that can mean that it is very hard to predict the outcome, you could have someone who has got mild problems or someone who has got quite severe problems.  There is no way to tell in advance what will happen.  There is a common mild variant called _______ that 10% of the population are carriers for, mainly associated with CBAVD but there are some circumstances in which some other features can be seen as well.  As you can imagine with that, it is not uncommon to have a variant combination in a couple that is absolute harmless or is associated with a low risk of any kind of serious phenotypes.  I have mentioned variants of uncertain significance a couple of times and I have realised now that this slide should be earlier in the talk. So when we classify genetic variants again, this may be familiar to many of you, there is a classification system that is on a five point scale, ranging from pathogenic through likely pathogenic, variant of uncertain significance, likely benign and benign … and pathogenic means that the lab is very confident that this is a disease associated variant, likely pathogenic means that they are still very confident enough to use it for medical reasons such as prenatal diagnosis but there is not quite same level of evidences as for a pathogenic variant.  The same thing applies to the other end benign means the lab is very confident, likely benign again fairly confident but not quite enough evidence to put it into that really solid category and in the middle is this big group variants of uncertain significance and that means what it says it means, we are not sure whether this is a disease causing or lot and clearly there are different levels of evidence for a particular variant that mean you might be close to the likely pathogenic end of the spectrum or close to likely benign … but that dividing line between VUS and likely pathogenic is the key one because that is about medically actionable variants. And if you have got a variant that is not considered medically actionable we think it is not terribly helpful for that to be reported in the carrier screening setting, in fact worse, it can cause anxiety and concern, particularly if the other partner has a got a pathogenic variant if we talk about recessive condition. So one part has got pathogenic variant the other VUS, what you do with that, so if you are using a lab that reports variants of uncertain significance you would hope that would be covered in information that is provided to patients, some labs even report variants that we know are benign so this one for example, in the gene ________ it is completed harmless, but there are some labs that report that as though it were disease associated variant and that obviously has a potential to create havoc with no benefit at all and we are strongly opposed to that.  There are even genes of uncertain significance, so there is this phenomenon that unfortunately has happened quite a lot where there are reports in the medical literature linking a particular gene with a phenotype that then is not born out by subsequent research and evidence … and sometimes there may be a low risk of a phenotype but most people with the condition which is typically a biochemical condition in the carrier screening setting, we do not think that is a basis for carrier screening and some of these genes remain on some of the panels and I have listed some examples, one of them MCC 2 that is associated with ______ deficiency which was thought to be a nasty neuro-developmental condition and possibly associated with severe metabolic decompensations and then turned out to be much more common than what was expected when the expanded newborn screening came along … anyway that one is mostly benign but it is actually on the list from the American College of Medical Genetics, so no matter how authoritive seeming the source, unfortunately there can be mistakes that creep in. So what can you do about these, now clearly their interpretation is specialised complex and often quite difficult so I think the realistic thing and the main thing for you is to be aware of the issue and I guess most importantly just because the lab found something in both partners that does not mean it is definitely medically important or needs intervention, so a bit of caution is needed when you are interpreting the reports that you receive, particularly because they sometimes are quite dense and contain a lot of information. And clearly you are going to need to refer to clinical genetics from time to time as appropriate.  So, when should you phone a friend, clearly, if you have got a likely pathogenic or pathogenic variant in an X-linked gene or if both partners carry a likely pathogenic or pathogenic in the same gene associated recessive condition or if you got one with a likely pathogenic or pathogenic and the other with a variant of uncertain significance.  Generally speaking, if only one partner is a carrier for a variant in a particular recessive gene you do not need to go any further.  What are the options for carrier couples, clearly that depends on the timing, if they are pregnant their options really are whether they have prenatal diagnosis or they do not … so they either have a CVS or amnio depending on the stage of pregnancy and what they want to do or they do not. And that comes back to what I was saying before, what would they do with the information remembering that these are invasive procedures that carry a really quite small but not zero risk of causing a miscarriage. So if you would not have a termination of pregnancy for the particular condition then probably for most people a prenatal diagnosis is not the best choice but sometimes people decide to anyway.  If you are not pregnant there are additional options, so you could choose not to have children, you could adopt, you could use a donor gamete or more relevantly for most people, preimplantation genetic testing and in the Mackenzie’s mission had really high uptake of preimplantation genetic testing, we provided one round of PGT for free for couples who identified through the project and the majority of those who made a decision decided to undertake PGT for those who were not already pregnant.  PGT now has item numbers around it so although there may be some out-of-pocket costs it is not nearly as bad as it used to be.  Some other conditions, clearly you have got think about other family members especially for X-linked conditions if your patient is a carrier for an X-linked condition then that potentially has implications for her female relatives. Recessive conditions especially for common conditions like CF or if there are ________ loops in the family then there may be implications for other family members.  What about where you have had some screening, and someone has got a new partner clearly if it is X-linked condition, the female partner’s risk goes with her and it has not changed but if you think about recessive conditions then really you need to redo the screening and if one partner is a carrier then the new partner would need to be offered screening as well.  I mentioned that X-linked conditions may have health implications for heterozygote.  The assays we use are not perfect, firstly obviously you cannot find what you do not look for and no gene list covers everything but also many genetic conditions are not recessive or X-linked or are X-linked but arise de novo and so a carrier screening is not going to identify those risks.  Even if a gene is included in the panel it is possible to miss things that are clinically relevant and that might be technical reasons due to just the limitations of the assay or the variants might be detected, but not interpretable, so there might be rare private ______ variants that have not been reported in the medical literature, and so you cannot interpret them as pathogenic and obviously most of the time something you find like that is going to be benign, but sometimes they would be pathogenic and it is just the nature of the beast that there are going to be things that are missed. So a low risk result greatly reduces the chance of an affected child but does not exclude it, it is a screen it is a not an absolutely perfect diagnostic test.  So in conclusion, autosomal recessive and X-linked conditions there are many of them, many of them are severe, child onset life limiting or disabling, it is much better to have information before we think, before the birth of an affected child. I have been talking about quite a lot of complexities and I hope I haven’t put you off, pleased do not be daunted by those, more than 98% of the couples you screen even with a very big panel will have reassuring results and the potential benefits for the 1% to 2% are really very considerable. So you know I hope that you will consider offering your patients if you are not already, I’m sure many of you are, but consider offering your patient’s carrier screening. So the main thing about all those limitations and complexities is just to be aware that they exist I think … and this really is a population scale issue, it is absolutely essential for GPs to be engaged in carrier screening because nobody else can do it.  There is not really anybody else who is in a position to reach the numbers of people that you need to have the most benefit from carrier screening but obviously there will be situations where you need to refer and please do not hesitate to do so.  Some resources here, so the Mackenzie’s Mission website recruitment has been completed but the site is still up and that includes a lot of information about carrier screening including information about some of the providers and The Centre for Genetics Information has got a facts sheet that may be helpful as well.  I just want to acknowledge my co-leads, Mackenzie’s Mission Martin and Nigel and the other members of our executive team, Tiffany and Jade and the very large number of people who have contributed to the project and also our funding bodies and the academic institutions, clinical genetic services and labs that were involved in the project and that is the end of the talk.  We can start with the questions if there are any.
Thank you so much for that absolutely wonderful presentation.  I think you explained that very well so thank you and the fact that there have not been too many questions, I think really supports the fact that you explained it very well, but there are a few.
I do not know, I’m not sure if that is what it means
So first things first, anonymous has asked, I have a patient who has had three miscarriages and is currently pregnant, would she and her partner be suitable for this sort of testing.
Yeah there is no reason why note, it is not very likely but not impossible that you might find something that is relevant to the miscarriages, there are some exceptional circumstances where you might, but yeah they are no more or less likely to be carriers for some other condition than anybody else, so I would not think of that as a reason not to offer screening.
Okay, Catherine has asked why would you offer extended or the expanded panel over basic screening
So it is in those numbers, the Mackenzie’s mission offered a very large panel but even some of the sort of 400 gene panels pickup more than 80% of everything we picked up with our 1300 gene panel … and 80% of what we found was not the three genes, so the more you test the more you potentially could find, and so you know I think that is a good reason to consider an extended panel because there are going to be lots of people who have children affected by conditions that are not just those three.
Following on from that, Susan has asked, at a population screening level would you recommend sequential screening or combined couples screening for a couple that is not yet pregnant.
The reality is that it is going to cost more to do the combined screening.  I think combined screening is the ideal model, in that you get all the information at once and so you do not create anxiety for an individual who has shown to be a carrier and it can cause quite a bit of anxiety for some people, so I guess it depends on the patient, you know if they are relaxed kind of individual and not pregnant yet, so you got a bit of time at your sleeve and then it could be fine to do it sequentially.  In the ideal world you would do it is as a combined thing, but it does cost more.  Some of the companies offer a discount for doing it both at once. Whether that is enough to make a difference in terms of the overall cost for any given couple obviously depends on their circumstances so, ideal world all altogether, real-world there are certainly circumstances where it is perfectly reasonable to do it sequentially.
Okay and Tim has asked how do you address counselling around insurance implications, for participants who may find out something during this process that has implications for their own health.
Yeah, that is an interesting point and a fair one.  The probability that they will find something out that has insurance implications is small but it is not zero, so for example, one of the conditions that is included in quite a lot of the screens is Alport syndrome, X-linked Alport syndrome and that is a condition that causes renal disease and hearing loss and although it is X-linked, the effects are most severe for males, some female heterozygotes can have significant renal disease and some even can have renal failure … so I guess the question is what type of insurance might be affected by that, the life insurance companies in Australia have a voluntary moratorium on discriminating against people on the grounds of genetic conditions for policies up to half a million, it is voluntary, we do not know how long it will go for but it is there. Clearly if you have already got a life insurance policy and then find out about the information you are fine, it does not affect that, it does not affect health insurance, may affect income protection insurance.  For that particular condition most women are not likely to run into problems even if they are heterozygotes. I mean, clearly, that is a lot of detail on that one condition … it is a relatively minor consideration but it is not nothing, so I guess we did not put a lot of weight on this issue in our pre-test counselling for Mackenzie’s.  In my experience when you do talk to people about it, for a low-risk like this, most people are pretty relaxed but I guess if you have got someone who is you know is an information seeker and is concerned about all possible considerations, then it may need to be mentioned, the chance of it impacting any one person is very small I would say.
Interesting question, thank you for that Tim.  Anonymous has asked is there any significant differences between the providers.  You may not be able to say anything … or is there anything we should look for as GPs I guess, when we are picking which company to use per se.
Yeah, look the gene lists the larger providers use overlap a lot and the stuff they overlap with mostly includes the more common conditions.  So you know a gene list of 400 genes may not be an awful lot better than a gene list of 300 genes so I would not just get the biggest gene list because it is not necessarily the only criterion, but it is something to think about.  I do think that the issue of what kind of resources they offer and what support they give you pre-test and post-test is really quite important.  So that ranges from nothing at all, so you send a test then you get a result and you are on your own, through to really quite good websites, some of them have got you know excellent websites actually that provide a lot of information, some of them have genetic councillors that that laboratories employ and provide you know some additional support and information pre-test and then also some post-test support … so you know I will be looking for those kinds of things, what kind of information support do they give to me or my patients … and then once you have started ordering I guess you will get a feel for the reports and I actually do not order a lot of commercial carrier screening because of where I work, but as I said that there are some companies that produce reports that include a lot of information that may not be entirely helpful, so lists of variants of uncertain significance, and so on and so if you order with a particular provider and then you find that their reporting is opaque or worrying and perhaps not helpful so that might be a reason to think about a different provider.
Yeah I think from a practical perspective, ensuring that you have access to a genetic counsellor should an abnormal result come up is crucial.
Yeah, so hopefully everyone has got access to a local clinical genetic service that would provide support, although I know obviously that varies from place to place in terms of ease of access.
Is it possible for you to I guess summarise how we should explain this to patients as a GP, we do not have much time, it is all very complicated, what is a good summary that we can say to patients when we are talking to them about this.
Yeah, so I would say, you know that there are tests for conditions like Down syndrome but that is only one kind of genetic condition, there are lots of other genetic conditions, healthy people can be carriers for genetic conditions and have a chance of having a child who has got something severe.  There are tests available that can pick up who is more likely to carry a condition and might have a chance of having an affected child, here is some information about that.  I guess those would be the key kinds of things I would want to convey and if you want to have one of the tests, but some of them you can or the patients can order the test online directly through the companies and they will get sent out a mouth swab or something like that, so that is something else you might want to consider in terms of ease of ordering if the patient is able to do that themselves then that might be a plus as well. 
Yeah, great and finally can you just comment again on some resources that we could possibly have a look at, I know you mentioned one earlier but there have been a few comments in the chat about resources that we can go to as GPs to get more information and also for information sheets for patients that are not company specific.
As well as the Mackenzie’s site and the centre for genetics education.
Centre for genetics education is probably a good start is not it.
Yeah, yeah, so one thing I want say about that is that you have to type in the whole web address https there we are, if you just, it is my experience in the last couple of days the site does not work, I do not know why, usually that works but you do need to put the whole https: and so on, the whole bit, up to and then you can search for carrier screening on the website … and then as I said the Mackenzie’s Mission website has quite a lot of information on it about carrier screening.  So I mean those will be my preferred sources of information I think.
Wonderful someone has just posted in the chat that they are launching a new website and that explains why there has been some problems accessing it in the last few days, there you go.
Alright okay.
Finally Gwendolyn has just commented about couples who had Mackenzie’s Mission who may have split up since then, so they obviously need new screening with their new partners or need to be relooked at.
Yeah, unfortunately that is the case, you might have to start from scratch, I mean having said that you can get in touch with the labs, there are only three labs that do the testing and it might be possible to organise something for the new partner.  I cannot speak for the other labs.  I think the one where I work would probably be willing to do something but there would be a fee involved unfortunately.
Okay well I am afraid that is all we have time for this evening.  Thank you everyone for attending this webinar, and Edward, thank you very much for your wonderful chat and enlightening us this evening and just a reminder to everyone that these slides will be available with the links for the resources later in the week.  Thank you and have a good evening.

Other RACGP online events

Originally recorded:

11 October 2022

Session 3 - Reproductive carrier screening: What you should know?

Many professional societies now recommend that all women, regardless of age, be offered screening and diagnostic testing for aneuploidy during pregnancy. Non-invasive prenatal screening (NIPS) is the most sensitive and specific screening option for common foetal aneuploidies, which analyses the cell-free DNA in a pregnant woman’s blood to analyse chromosomal variations in pregnancy. General Practitioners (GPs) are often the first touchpoint for newly pregnant patients. In order to maximize the patient’s options for prenatal screening for chromosomal conditions, GPs should be able to introduce and offer the appropriate prenatal testing options to their patients.

This webinar series will provide insight and expertise for successfully implementing NIPS beyond the common aneuploidies into clinical practice. Pre and post NIPS counselling considerations will be addressed using case examples. In addition to NIPS, the series will also address the current state of reproductive carrier screening.

Learning outcomes

  1. Recognise the current and future state of reproductive carrier screening in Australia
  2. Discuss pre and post-test counselling considerations
This event attracts 2 CPD points

This event attracts 2 CPD points

This event is part of Integrating Genomics into GP practice. 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


Prof Edwin Kirk
Clinical geneticist

Edwin Kirk is a clinical geneticist at Sydney Children’s Hospital and genetic pathologist at New South Wales Health Pathology’s Randwick Genomics Laboratory. He is a Conjoint Professor in the School of Women’s and Children’s Health, UNSW. His research interests include gene discovery in Mendelian disorders and the genetics of congenital heart disease. In recent years, reproductive genetic carrier screening has been a major research focus, and he is co-lead of the $20 million MRFF-funded Mackenzie’s Mission project, which completed recruitment earlier this year. He is the author of a popular science book, The Genes That Make Us: human stories from a revolution in medicine.



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