E39 Genomics 2

THIS TRANSCRIPT IS AI-GENERATED AND WILL CONTAIN ERRORS!

This is important for Primary Care 

[00:00:00] ​ 

[00:00:00] Dr Munir Adam: In this episode we're going to teach you about or remind you about some common terms and concepts in genomics that are important for primary care and what to do if a patient comes along to you who has a or potentially has a genomic related situation. 

[00:00:19] So you're doing your Friday evening clinic and you see the notes of the next person who's about to come and see you you.

[00:00:25] And it says something about chronic disease. Anyway, man comes in, . Okay, he's 38 year old man. He looks a bit worried. I just need a referral to the chronic disease or dementia clinic, please. Why is that? Well, the thing is, my grandmother, she had advanced dementia. And so I know what it's like dealing with this firsthand. You know, being a carer. And it's not a nice experience and I don't want to end up in that situation. So what I did is I went along and I had a genetic test and apparently I've got this, um, hang on a minute, let me have a look. It's the, oh yeah, it's the ApoE4 Allele. So anyway, apparently it means I'm going to be getting dementia. So, uh, well, you know, prevention's better than cure. So yeah, just a referral, please, and I'll be out of your way. 

[00:01:10] What do you do? You might think these experiences are rare, but I wouldn't be surprised if we find more and more patients coming with these kind of presentations to us.

[00:01:19] Welcome back! It's Munir Adam here, and this is the second episode in our genomics series, sponsored by the North Thames Medicines Genomics Service. 

[00:01:28] Claire Green: Oh, hi there. I'm Claire. I'm one of the paramedics working in primary care. 

[00:01:32] Dr Munir Adam: In the first episode, we talked about how interesting genomics can be and how exciting it can be.

[00:01:37] And actually that was learning for me 'cause I often saw it as a bit bit of a dull thing actually, and how powerful it can be as well. And what I really learned was that is so relevant to primary care. I honestly didn't think that it was. The other point that was made in the last episode was that genomics can be made simple.

[00:01:55] But you know, I was glad to hear that, because it's not the kind of thing that we need to sort of understand, you know, that's not good enough. Because we don't just need to understand genomics, we need to be able to explain it to patients. We need to know what we're doing with it. For me, you know, it's a bit like, when it comes to knowledge, it's a little bit like, you know, we hear the rich get richer and the poor get poorer.

[00:02:13] It's a bit like that with the application and utilization of knowledge because if you know something, the things that I know really well, I really use those. I explain these things so much to patients that I get really good at it and very confident and they can see that. Things that we don't know well at all, what happens is we tend to shy away from discussing those.

[00:02:31] We pretend they don't matter and so we lose even the knowledge that we have. So it's really important to get the basics really properly embedded so that we can confidently have those conversations with patients.

[00:02:42] This is going to be a reminder for others this is going to be new learning. 

[00:02:46] Claire Green: Absolutely. I think the whole point of this episode is kind of covering basic terms like alleles, genes, and chromosomes, and thinking about basic concepts such as inheritance patterns, um, and also our role as primary care clinicians and sort of when thinking about when to look at sort of genomic and genetic testing, um, and sort of thinking about how and when, as clinicians, we would refer all those sort of factors we're going to look at today.

[00:03:11] Dr Munir Adam: You mentioned allele. Can I ask you, do you know what an allele is? 

[00:03:27] Claire Green: I wish you weren't. I was sort of, I was hoping you'd avoid that and we'd go on to our, to our guest speakers because nope. I have no clue. Well, you 

[00:03:35] Dr Munir Adam: know what? I'm backing 

[00:03:36] Claire Green: my brain for biology, I've got to be honest. 

[00:03:38] Dr Munir Adam: You're not alone. In fact, I feel, I feel more guilty about that because I can't make any excuses.

[00:03:43] This was all covered very well when I did genetics, albeit a little while ago. And uh, and I guess it's just as well then, me and you are not the experts here as such, but we have the experts with us... 

[00:03:52] Dr Angela Brady: hello, I'm Dr. Angela Brady. I'm a consultant in clinical genetics at the Northwest Thames Regional Genetic Service and I'm also involved with the North Thames Genomic Medicine Service Alliance and I'm the joint clinical educational lead with that.

[00:04:10] Dr Faye Dannhauser: I'm Faye Danhouser, I'm a Portfolio GP. I basically work in the West Essex and Greater London area and I've got a special interest in genomics. I completed my master's degree last year. I'm here in my capacity as a GP lead for the North Thames Genetic Medicine Service Alliance and part of our role is to educate GPs about genomics so that we're prepared for what's coming.

[00:04:35] Dr Munir Adam: Must admit, and finding myself thinking, what is an allele? And that's the kind of basic stuff that we're going to start with, but I'm still a little bit skeptical. Can genomics really be made easy?

Basic Terms & Concepts

[00:04:48] Claire Green: I think starting with basic terms and concepts would be really, really helpful. So if Angela and Faye could start with this, I'd be grateful. 

[00:04:55] Dr Angela Brady: So in terms of basic terms and concepts, so if you think somebody has a blood sample taken, and then you look down the microscope, and then within the centre of the cell you see the nucleus, and then within that you'll see strands, and these are our chromosomes, and packed onto our chromosomes are all our cells.

[00:05:15] Genes. So usually in the cell, you have 46 chromosomes. You've got 1 to 22 pairs, which are known as the non sex chromosomes, the autosomes, and then you've got two sex chromosomes. So a female has two X chromosomes, whereas a male has 1 to 22 pairs, and an X and a Y chromosome. So altogether 46. And if you have a variant in particular, gene, then, then really an, an allele refers to a gene variant.

[00:05:46] So if you think of an also dominant condition, say neurofibromatosis type one, and, uh, that's caused by one variant in, in one, uh, CO one gene. Um, so you, because you have your genes in pairs, you get one from your mother and one from your father. Then if you've got a faulty copy in one of those genes, then the chance of you passing that on to your offspring is, is 50 50. And so when you have a faulty copy in, in one of the genes, that's, you're known as a, as a heterozygous for that variant. 

[00:06:20] Whereas if you think of autosomal recessive, Inheritance say for conditions such as cystic fibrosis, then if you've got a fault in one copy of an autoimmune recessive gene, then you're healthy because the other gene can compensate for the effect of the faulty gene.

[00:06:40] However, if both copies of the genes have faults within them, then you're affected with the condition. And if both of the copies of the gene have the same genetic change, the term used then is homozygous for a particular variant, so it's the same variant on each copy of the gene.

[00:07:00] Whereas if you've got two different variants, so you've got one variant on one copy of the gene and a different variant on the other copy of the gene, then the term used is compound heterozygotes. So that can happen in conditions, you know, which are inherited in an autosomal recessive way. 

[00:07:21] Dr Faye Dannhauser: So I've got a nice little analogy for that. So, um. If you think about pairs of socks, so if you're homozygous, your socks match and the chromosomes pair up. Um, but if they're not matching socks, then you'll be heterozygous. I don't know if that helps. 

[00:07:37] Dr Munir Adam: Okay. I think I get that. Claire, what do you think? Does that make sense? Yeah, no, 

[00:07:40] Claire Green: I, I do like the sock analogy, keeping it simple. 

[00:07:43] Dr Munir Adam: Yeah, absolutely. Okay. So homo just means they're both the same and hetero means they're both different.

[00:07:49] Uh, yeah, just once more then. So you've got chromosomes with lots and lots of genes in pairs. Each pair of genes different people will have different variants and we call those variants alleles. Right. Um, and then you may have an abnormal allele, and if you've got one abnormal allele, you'd be heterozygous.

[00:08:04] If you've got two abnormal, you might be homozygous for that particular condition, or whatever it refers to. And then you mentioned there's 22 pairs of, you've got 23rd one is the X or Y. 

[00:08:15] Dr Faye Dannhauser: So a patient that might come to us might be someone with a BRCA abnormal variant, and that's an autosomal dominant condition.

[00:08:22] So if a parent has that condition and the other partner doesn't have the condition, There's a 50 percent chance that the offspring will be affected by that condition. Because they only need one abnormal copy of that gene in order to get the disease. And in contrast, autosomal recessive conditions are, um, so we see this in cystic fibrosis . They need two abnormal copies of the gene. So if you've got two parents that are both carriers there is a 25 percent risk that their offspring will be affected by the disease. They'll be unlucky enough to receive two abnormal copies of that gene. 

[00:08:59] Dr Munir Adam: Yep.

[00:08:59] Dr Faye Dannhauser: There are other, there are other inheritance patterns that probably, but in general practice, the more common ones we're likely to see are autosomal dominant and recessive, uh, but you can get X linked you can get spontaneous changes that happen to the genetics. It's called de novo mutations and there are also some mitochondrial diseases because funnily enough we've got DNA in our mitochondria as well, the powerhouses of our cells, it's in a circular form.

[00:09:29] Dr Munir Adam: Some of this is coming back to me from medical school days and some of it sounds quite new to me. I have to say, even genomics seems quite new but just going back to absolute basics in the last episode. Uh, I asked the question the difference between genetics and genomics. I think what was explained was when you're speaking about individual genes, that's genetics. Whereas genomes includes the whole thing. The whole, and genetics is a, is a sort of subset of genomics. 

[00:09:54] Dr Angela Brady: So genomics is really the study of an organisms complete set of genetic information. So the genome's got, uh, coding and also non-coding, DNA. So the whole genome is looking at the complete. Uh, amount of, uh, genetic information, uh, within an organism.

[00:10:13] So not just the coding region, but also the non coding region. Whereas when we think of genetics, it's more the study of heredity and the study, uh, say of a particular single gene and the, the function of that particular gene and how that gene, uh, you know, can regulate the onset of the, uh, particular, why, why a change in that gene might cause a, a disease.

[00:10:34] So the whole genome is like 3x109 base pairs, and the majority of the genome is, in fact, non coding, it's only about 2 percent of the genome that codes for the actual genes. So and so overall, we've got 20, 000 genes on our genome. We used to think it was about 30, 000. Now it's thought to be about 20, 000 genes, but that only actually makes up about 2 percent of the DNA.

[00:11:07] DNA. And then the non coding DNA is the remainder of 98 percent of the DNA, and that's thought to contain important aspects like regulatory elements, you know, switching on and switching off of genes, and our understanding of that is starting to increase. Whereas today, often, if we're trying to investigate a diagnosis, then probably we're still generally looking at the coding region, You got it.

[00:11:37] Uh, particular genes whereas actually we're, we're starting to do whole genome sequencing much more routinely now and getting the genetic code for the whole uh, individual for all the, uh, genetic information for an individual and then, uh, starting to try and work out how the, the non coding DNA is also important for the development of certain diagnoses.

[00:12:00] Dr Munir Adam: Wow, that is so interesting because from when I was taught, I, I knew all along that The coding part of DNA is a very, very small part, and then you've got the rest of it. But I always thought the rest of it was irrelevant, immaterial, didn't matter. But actually, what you're saying is that that 98%, as you say, which is non coding, might be important and have a regulated function.

[00:12:21] Which, of course, could prove to be extremely important. So, moving from genetics to genomics then, I guess, when we're doing tests, we're not just looking at single gene tests, we're looking at lots of genes together. Is that what we're 

[00:12:36] Dr Faye Dannhauser: So I think, Milly, you're probably touching on polygenic risk. So complex common conditions are conditions that we see commonly in general practice and largely they're not inherited by an abnormal copy in one gene.

[00:12:49] Um, so you can look at lots of different Polygenic markers that might individually not have much of an impact, but if you put them all together, they may increase that individual's risk of a certain condition like cardiovascular disease or diabetes. 

[00:13:04] Dr Munir Adam: Oh, I see. So, 

[00:13:05] Dr Faye Dannhauser: polygenic when, when, it's more in research at the moment, but looking at polygenic risk.

[00:13:10] It gives you a bit more of a a risk score. You can develop pontogenic risk scores that give you some idea if that individual might be at increased risk of a condition compared to the general population. But it's, it's not really ready yet for clinical use, but it is being used a lot within research.

Why testing is so important

[00:13:27] Dr Munir Adam: But, but if I could play devil's advocate and say that Okay, fair enough, you can do some tests and increase, check your risk and so on. If you have a test and it shows that you've got a particular gene and you're at high risk, I mean, you're damned, isn't it? You can't change your genes. So, what's the point of making a diagnosis?

[00:13:44] What's the point of having that test? 

[00:13:47] Dr Angela Brady: So, so you're right. If you do make a particular diagnosis, then it's extremely unlikely you're going to be able to offer gene therapy and, uh, it's not going to be possible to, uh, amend the way the gene works. However often just the actual having a definite diagnosis made can be enormously helpful for a family.

[00:14:06] So say if, if a couple have a child with unexplained developmental delay and you make a particular, uh, diagnosis, then that can give really important information about the child's prognosis and also let, uh, parents know if the child's going to be at risk of developing other particular problems, say like a, a heart defect, so then you can put in place certain screening.

[00:14:28] And, uh, obviously you know, screen for other abnormalities as needed. Also it can help determine the couple's chance of having a further affected child and give them options for when they're say, planning to extend their family or for their relatives to know whether they're likely to be at risk of having a child with, uh, similar problems and potentially options available for them as well.

[00:14:53] So if you sort of think of another example, say, um, like BRCA1, the Angelina Jolie gene, if, um, you, you've had a diagnosis of cancer and then you're diagnosed as having that particular gene, then that can be really important for yourself, but also for other family members. So for yourself that would explain why you've developed breast cancer, but also.

[00:15:14] It would, uh, give you information that you also increase risk of developing ovarian cancer. So, there'd be, uh, and also a higher risk of developing a further breast cancer, further, uh, second primary breast cancer. So, therefore, you've got options. You can have screening for further breast cancer, but, uh, or some individuals choose to have risk reducing mastectomies.

[00:15:34] And, uh, there isn't screening for ovarian cancer, so the, the management is risk reducing surgery to remove the ovaries and fallopian tubes once somebody's, uh, finished their family. Also if you have a BRCA gene change, then you are, um, you can respond better to certain drugs such as PARP inhibitors and also, so not just the benefits for the individual, but also for the family members.

[00:15:55] So if they know there's a particular gene in the family predisposing to, uh, breast cancer, say, then, then they can also have a test to work out have they inherited that gene and are they at increased risk? And if so, they can go on and have the screening or the management or the risk reducing surgery.

[00:16:12] And, and also potentially options for them, uh, when they're planning their family. So, yes, you're right it's really unlikely you're going to be able to interfere or affect the way the gene works, but the power of making a diagnosis and then knowing what you're dealing with can be extremely helpful.

[00:16:31] Dr Faye Dannhauser: And, and, and carrying on from that example, um, I believe that if you've got other environmental factors that can also affect that risk. So it's not pointless to actually give lifestyle advice. So we know that there are traditional risk factors that increase your risk of breast cancer. So looking at their body mass index and uh, contraceptive pill use and HRT.

[00:16:55] So you would take that information into account when you're dealing with your patients day to day in general practice. 

[00:17:01] Dr Munir Adam: Right, got that. Okay, so you can focus your general advice about environmental factors and lifestyle factors, particularly for those who may have a higher risk based on their genomic makeup.

[00:17:12] On that note, I vaguely remember something about genes not always expressing themselves fully. I can't remember about that now, uh, in terms of what the terminology is. It's not always a yes or no affair, is it? 

[00:17:26] Dr Angela Brady: So, uh, penetrance really refers to the proportion of people with a particular genetic variance or gene mutation who actually show signs of that particular genetic disorder.

[00:17:40] So if we think about the BRCA1 gene, the Angelina Jolie gene, then females who have a disease causing variant in the BRCA1 gene have about a 70 percent lifetime risk of developing breast cancer and about a 40 percent lifetime risk of developing ovarian cancer. So not everybody who has a BRCA1 gene variant will definitely develop breast cancer or ovarian cancer.

[00:18:02] So that's really referring to the variable penetrance. So that's why sometimes in the family it can look as though the genetic, the gene sort of skipped generations, but actually it hasn't. The gene is present, but certain members of the family aren't actually showing signs of the diagnosis. Whereas, um, there's the term variable expression is really used when, uh, the condition Fully penetrant so for example neurofibromatosis type one usually if an individual has a disease causing variant in the NF1 gene then they'll show signs of the conditional that can be quite subtle and the variable expression can be that even within the same family, although the affected members of the family, they've all got the same change in the NF1 gene then, uh, sometimes some individuals tend to be more severely affected and others less severely affected.

[00:18:54] So that, that's what we sort of mean by variable expression. So I, I hope that helps clarify that a bit. 

The genes isn't the whole picture

[00:19:02] Dr Munir Adam: Oh, I see. Right. Yeah, I get that. So so variable penetrance is the proportion of people where the gene seems to express itself. Whereas variable expression is how much it expresses itself. So some might have it mild, some might have it more severe.

[00:19:20] Okay, 

[00:19:22] Dr Faye Dannhauser: I think the whole thing about genomics is genomics looks at not just at the genes, but the genes interaction with each other and with the environment. So I think there's been studies that have looked at polygenic risk for breast cancer. And if you've got the BRCA and other polygenic risk factors, your overall risk might be a bit higher.

[00:19:39] Um, and then again, if the environment is unfavorable, and that's interacting with that gene, that might further increase your risk. 

[00:19:47] Dr Munir Adam: There we are then, that's very primary care, isn't it? It's about being holistic and what you're saying is that the genomics is part of that being holistic bit. That perhaps we don't sometimes think about.

[00:20:00] Dr Faye Dannhauser: I could give you another example, because you asked, that might be relevant for primary care, what's the point of doing genetic tests? So a common condition that we might more commonly see in primary care is familial hypercholesterolemia. And it's thought that the background risk is about 1 in 250 patients.

[00:20:18] And most of these patients are undiagnosed. And it's really important that we get these patients diagnosed because 50 percent of men that have this condition that are untreated are at risk of having a heart attack or stroke by the age of 50. And we've got, we've got effective treatments that we use frequently in primary care statins that we can give from the age of 10 that significantly reduce this risk and extend life in some studies, um, add another 15 years of life to that individual.

[00:20:46] So I think that's a prime example where genetics You know, having that knowledge, having that information can really help to improve the, the care of our patients and I think it's really important that we embrace that. 

[00:20:58] Dr Munir Adam: Okay. 

[00:20:59] Claire Green: So, um, obviously if we have someone come into the surgery that has, you know, concerns around something that they believe might be inherited from a line Perhaps mother, father, grandparent.

[00:21:09] What do we do? Where do we go? And what are the first steps we need to be sort of considering really? 

[00:21:16] Dr Faye Dannhauser: So the first thing we need to do is try and find out what particular disease risk they're concerned about and delve a little bit into the family history. And I think family history is not done particularly well in general practice.

[00:21:30] In part, that's because We are limited by the electronic medical record and the IT systems that we use. But patients often don't really know in detail their family history. But, you know, sometimes it can be useful. I've, I've had patients come to me requesting HRT and they've had, I routinely ask about breast cancer history and that sometimes reveals, uh, information.

[00:21:54] Um, that we should be alert to, and red flags for thinking about an underlying diagnosis, uh, genetic diagnosis include having a patient or a family member with disease onset a much younger age than we would expect. So, for example, that case that you listed earlier, Muneer about dementia, so if you had, if he had a first degree relative that had dementia diagnosed under 55, that would send alarm bells ringing.

[00:22:22] Yeah. If the condition is unusual for the sex of that patient, so if you've got a male breast cancer in the family, that might also send alarm bells. If there is a patient develops a condition that doesn't have any typical risk factors for that condition. So, for example, alpha 1 antitrypsin deficiency, if you have that in a younger individual that had never smoked, that might alert you to the possibility.

[00:22:46] And individuals with strong family histories are best, especially those that have cancers that might be associated with, with each other. And I guess we've already touched on BRCA today, but, um, another More common, uh, hereditary type of cancer syndrome would be Lynch syndrome. Um, so if you've got lots of family members that have, uh, endometrial cancer, colorectal cancer, and that might alert you to that as a possibility.

[00:23:13] Dr Munir Adam: Right. Okay. That makes sense. And then I think the point you were making was that when you want to actually test for these things, it isn't a gene you're testing, but a combination, like it's, it's multiple genes that you test in order to determine the risk genetically. 

[00:23:28] Dr Angela Brady: I think maybe when we're talking about, the thing is I don't want GPs to think polygenics is, is the norm because it isn't at all.

[00:23:36] No. I would just quite like to talk a bit like breast cancer. So I think probably in the future, we will have a whole panel where we look at not just the high risk genes, but all the polygenic risk scores as well. So variants within the genome, which we know can be associated with a higher risk or a lower risk of breast cancer.

[00:23:53] And then ideally, if we get all that information, we won't necessarily need to arrange a mammogram for all ladies over the age of 50 at the minute every three years. You know, we'll only need to screen those women who've got a mammogram. say high risk genes plus the higher risk factors with the polygenic markers plus lifestyle factors.

[00:24:12] So I think that's the way we're kind of trying to go. Incorporating genomics into practice. Uh, we're certainly not there yet. 

Genomics testing & Referrals: When, what and when not!

[00:24:20] Dr Angela Brady: And there's, there's quite a bit of controversy. 

[00:24:23] People go and have these polygenic risk scores and we know they haven't got a high risk gene. But their polygenic risk score on this sort of SNP array comes out really high.

[00:24:32] And that's just not utilized. I don't think we really understand it well enough to be utilizing that information as yet on the NHS, whereas at the minute, the testing is very much confined on the NHS to sort of seven high risk genes. There are some more. if there's a stronger family history that might suggest other diagnoses.

[00:24:51] But at the minute, the, the standard gene panel test for high risk breast cancer is, is seven genes that we look at. 

[00:24:59] Dr Munir Adam: Well, everything you're saying here resonates with the feelings I've had about testing as well, because don't just test for something just because you can. There's a whole process of actually evaluating whether it's suitable to have a test program for something.

[00:25:10] And what we're seeing here is direct to consumer testing, which Pretty much anybody can just go and pay a bit of money, do it. And then we get lumbered in primary care with having to interpret those. 

[00:25:20] Dr Angela Brady: So, direct to consumer genetic testing. Well, there are some advantages, but also some cons, and I think one of the advantages is that somebody's taking an interest in their health, and they're trying to find out if they're at risk of certain things, and if they're found to be at risk, then potentially they might modify their lifestyle to try and minimize the risk of getting problems.

[00:25:43] But, uh, my concern is that Often an individual might get false reassurance. They might think they've had a complete genetic test for something, for a particular diagnosis, whereas actually what's included in the test is only a sort of fraction of the genetic changes that can cause the condition. So they might be falsely reassured or potentially they might be found to have a variant in a particular gene and then think there are, they are at high risk when actually they're, they're not because it's only a risk factor and it's not a definite diagnosis.

[00:26:13] So I think there's pros and cons but I think actually the cons outweigh the pros. 

[00:26:18] Dr Munir Adam: So I would very much be in favor of testing being the sort of thing which, you know, a specialist is advising or supervising and determining if that's actually going to be helpful, if it's going to cause unnecessary anxiety.

[00:26:31] But just while we're on the topic of testing then, Are there, are there any tests that we can do in primary care? Is there anything that we have access to? Or would we be referring to yourselves? And if we do refer, how do we refer and where do we refer? 

[00:26:44] Dr Angela Brady: So there are some, uh, genetic tests which can now be, uh, requested by primary care.

[00:26:51] There's just three at the moment. That's, I, I think, slightly to increase. So at the moment, in terms of who's in the UK, in England, who's eligible for genetic testing, we use the, um, National Genomic Test Directory. So if you just Google test directory, it comes up, you scroll down to the second thing which shows eligibility, and then within that you can screen and you can put in primary care and it will come up with these three conditions.

[00:27:16] So now you can do carrier testing for cystic fibrosis and testing for alpha 1 antitrypsin and also for haemochromatosis. So for other genetic conditions, you can look to see who might be eligible. So you can look to see, uh, you know, who's eligible to get hereditary breast ovarian cancer testing, which is the R2 O8 test.

[00:27:38] And you can see, so all women under the age of 40 are eligible now, who have breast cancer, are eligible now for this, uh, gene panel test. Also, all males with breast cancer, or if there's a significant family history, individuals of Ashkenazi Jewish ancestry with, with breast cancer. So, the, the, and the criteria have become lower and lower.

[00:27:58] Prostate genetic testing, that, that's now become into the test directory for, as an example. 

[00:28:03] So, for gPs, there's those three current conditions often we get referrals and, you know, there's somebody coming to see the GP to say, Oh I, uh, there was a implication that I might've had a chromosome change or something like that.

[00:28:17] So sometimes I might say, You can arrange that chromosome test if it's, if it confirms that, we can please refer back. So sometimes we liaise like that. So in terms of making referrals from primary care to, uh, genetic services, it's electronic referral system. And we've recently been working with, uh, Primary care teams to try to create two forms, a rare disease and a cancer form, and within that to give clear guidance as to the information that we need.

[00:28:46] And Faye, it's right, isn't it, you know, sometimes a patient comes to you and says, oh, I've got a family history of this, and so and so has had a genetic test. So what we would ask is that actually we need that, the information about the affected relative's genetic test in order to see that individual in the genetic clinic.

[00:29:02] Dr Faye Dannhauser: The additional thing is, as primary care physicians, is that we will get patients that maybe don't need to go to the genetics clinic, but they may be eligible for genetic testing through a specialist clinic. So examples of this might be in our region, the inherited cardiac conditions clinic, we'll see patients that might have a cardiac condition that's genetic.

[00:29:23] So there are other clinics. And even if, um, Your patient doesn't look like a high risk for BRCA, but they've still got a significant family history for breast cancer You might refer them to the family history clinic 

[00:29:34] Dr Munir Adam: And is it the case that if it's they've got two family members that have had breast cancer That's my I can recall that being the sort of criteria for referrals to the breast clinic Is that, is that correct?

[00:29:44] Dr Angela Brady: Yes, depending upon the age of diagnosis and things, then yes, and the age of your patient. So yes, they might be eligible to have what we call B1 or B2 screening. B1 is sort of extra mammograms, an annual mammogram from 40 to 50 or B2, annual mammogram from 40 to 60. 59, depending upon the number of people affected, the age of diagnosis.

[00:30:05] We used to see patients in genetics where there was just a family history. Now we generally only see patients where we can actually offer a genetic test. So if we get a referral of somebody with a family history, we might, may say, complete the cancer questionnaire and we'd refer that onto the family, uh, history clinic.

[00:30:22] We'll write back to the GP to say this is the screening that we would recommend for your patient and ideally their sister or their mother should have the genetic testing since they're the ones who are affected. 

[00:30:35] Claire Green: What, what happens, just a quick question, what happens if, obviously you've got that family history, so there's a strong link there, but what if those family members are no longer with us and they hadn't had the genetic testing, what would happen?

[00:30:46] Dr Angela Brady: So, in clinical genetics, we would ask for a detailed family history questionnaire, and then we can obtain confirmation of diagnoses from the cancer registry if people have passed away. And if there's a first degree relative, say, who's died recently, what we might do is get the tumor tissue, and clinical genetics can arrange genetic testing on that tumor tissue, uh, to So we can dissect, the lab can dissect out, uh, unaffected tissue from a tumor and look for genetic changes in that, and then see if there's a, a genetic change which, at risk, relatives might be at risk of inheriting.

[00:31:24] If you've got a deceased relative, you can get a tumor, you can try and do some testing on that, say, but if you can't, then we sometimes do do unaffected genetic testing. Right. Okay. So if there's a really strong family history, everyone's deceased, you can do unaffected genetic testing. Because you've got to have a significant family.

[00:31:43] The criteria for offering that has to be quite high. You have to have sort of significant score. And we use something called a Manchester score and to sort of work that out. And we have to have a confirmation of an affected family member. It can't just be the individual saying, oh, so and so have this and so have this.

[00:31:59] And, and that's really important because sometimes somebody says, oh, it's a bearing, but actually it was cervical or endometrial, which You know, totally changes what the, like, the genetic cause in the family might be. 

[00:32:10] Dr Munir Adam: In primary care, we do tend to have a lot of patients that come along who, whose history, family history is, I think my so and so relative had some sort of gynecological cancer.

[00:32:20] We often do find ourselves with very vague sort of, but concerning histories, and they're like, I need to be tested for everything. But the other way around, related question to that is, what if somebody is found to be positive in something, which means that their family members are at risk? And you can't, they don't necessarily live with the person or locally or might not even be contactable.

[00:32:41] Does anybody have a responsibility to inform them? 

[00:32:45] Dr Angela Brady: So, when we make a definitive diagnosis in somebody, then we talk very much, when we're counselling about doing the test, you know, it's going to have implications for you and potentially at risk family members. And then, uh, we would give a letter to pass, for them to pass on to at risk family members with the details you know.

[00:33:04] Often about the gene that's involved, what the implications of the gene might be, and so they would hopefully hand that on to their at risk relatives. But we can't approach their at risk relatives directly. I mean, sometimes I might have a consultation and they'll say, can you talk to my mum? She wants to test too.

[00:33:21] So sometimes we do. The patient might ring their mother and we might have a discussion and say, we will arrange a separate appointment, say, for you. But ideally we give a letter, they pass it on to the GP, the GP refers into the local genetics unit. 

[00:33:36] Dr Munir Adam: So you're, you're very much relying on that particular relative being concerned for their family members.

[00:33:41] Well, that's a lot of useful information for me. And I think we should probably wrap up now. What do you think, Claire? 

Our reflections and take-home points

[00:33:48] Claire Green: Okay, yeah. So I think today's been incredibly valuable. Again, sort of linking genes, um, and genomics into primary care. Essentially something that I'd not really previously considered, but something that actually is vitally important.

[00:34:03] You know, significant conditions that could, if we get there soon enough, be treatable and reduce risk, which could improve outcomes for patients, really, and make a real difference to quality of life. So, for me, learning has been vast, encouraging patients to take control of their own health and how that direct consumer testing does have positives, but we've got a long way to go with it.

[00:34:22] So, perhaps, We aren't at a point where we should be encouraging those to go for, for that sort of thing, but essentially being aware of it and having some understanding around it. So we know what to do when the results come to us, who to refer to, um, and that family history is vitally important. That's, you know, where I come in, I see a lot of patients and I get that time to get that history that could then go on to help the, um, myself and, you know, colleagues form a decision for that patient moving forward.

[00:34:47] But I'll certainly take the time to think about family history and, um, inherited conditions and. You know, all the big terms that have been used today. I might have to listen again. 

[00:34:57] Dr Munir Adam: Yes. Good. I'm not the only one then.

[00:35:02] So for me, as well as being a good revision for me in terms of basic terms and concepts, and a lot of it is coming back. What I also heard is that, first of all, we can actually refer directly for tests in a few limited conditions in those three conditions that you mentioned. And we have a pathway using ERS to refer to both genetic services to get tests done.

[00:35:21] And the breast cancer one you mentioned is a good example of that. And as well as that, as Faye mentioned, we can refer to Um, sort of specialty specific services that might also provide some kind of, uh, genetic testing depending on what the specialty is like cardiology or breast, clinics, et cetera.

[00:35:37] I'm really beginning to feel more and more that there's a lot more that we should be doing in primary care. You mentioned a couple of. Places on websites and things and we'll make sure we include a link to those resources in the show notes I've shared a little bit about what I've gained out of this and I think listeners should be thinking about what am I going to do differently from tomorrow and I know what I am going to do differently I'm going to be a bit more careful and a bit more specific about taking an accurate family history and like Claire said, I think I'm going to have listened to it a couple of times and reinforce those concepts so that they become very well embedded. 

[00:36:09] We will, um, we'll continue learning about genetics and genomics and all things related. Thank you so much for joining. Thank you. 

[00:36:18] Dr Angela Brady: Thank you.

[00:36:19] Mhm.

[00:36:23] Dr Munir Adam: And we have covered a variety of topics and definitions in today's episode. We will be revisiting and building on those in subsequent episodes and revising on them. But if you want to find out more, to brush up your knowledge about these, and really internalize the fundamentals, then you can do that using the Genomics Education Program, and a link to that is provided in the show notes.