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Professor Frances Flinter

Brief Outline: Professor Frances Flinter has conducted research to identify the gene for Alport Syndrome.
Background: Frances Flinter is Professor in clinical genetics and consultant geneticist at Guy’s Hospital. She was trained in paediatrics and completed her specialist training in genetics. She has also conducted research to identify the gene for Alport Syndrome.

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Frances developed an interest in Alport Syndrome while working as a junior doctor in paediatrics, where she encountered a family with children affected by Alport Syndrome. Subsequently, in her doctoral research she focused on identifying the genes linked to the syndrome. She was appointed as a consultant geneticist at Guy’s Hospital in 1994. Her specialist interests include inherited kidney diseases and preimplantation genetic diagnosis. She is also interested in the regulation of genetic testing.
Frances is also medical adviser to the national charity and support group Alport UK, and has organised several charity initiatives. As consultant geneticists, Frances consults patients of all ages about the genetic background and the hereditary aspects of Alport Syndrome. However, she emphasises that that there are no single sources of information for Alport Syndrome patients. Therefore, it is essential that GPs, kidney doctors and geneticists work together to provide comprehensive care.
 

Professor Frances Flinter explains why there is debate about the label of ‘carrier’.

Professor Frances Flinter explains why there is debate about the label of ‘carrier’.

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The terminology is controversial. And certainly, there's quite strong pressure from American colleagues and from some in Europe to label everybody who has a mutation in an Alport gene as having Alports, regardless of whether or not they've just got a bit of blood in their urine, or they've got full blown clinical features and kidney failure. And the reason they do that is that they want to make sure that carriers get the right sort of follow-up, that they also have their blood pressure and their urine tested once a year, with a low threshold for prescribing an ACE inhibitor if they get high blood pressure or protein in their urine. But I've found that for many parents whose children just have a little bit of blood in their urine, and perhaps a biopsy that shows thin basement membranes, with a single mutation in the Alport gene - if you refer to them as having Alports, they go away and they read up all about Alport syndrome and fear quite unnecessarily, in most cases, that their child is going to develop kidney failure, hearing problems and so on. And I've seen the use of that language cause a lot of distress in families, and it's taken quite a while to unpick all of that. So I would prefer at a genetic level to describe people who have a single mutation as being carriers of Alports. And then qualify that if they develop symptoms to describe them as manifesting carriers. And I would only refer to them as being affected with Alports for, if they are carriers of X-linked Alports and go on to develop renal impairment and hearing problems, and so on. And that's a problem that affects probably only five or ten percent of carriers, female carriers, of X-linked Alports. And particularly because we now know that early treatment of high blood pressure and proteinuria with ACE inhibitors can protect their kidney function, we really should in the future be able to prevent the vast majority of carriers from having significant problems.
 

Professor Frances Flinter explains the genetic causes of Alport Syndrome.

Professor Frances Flinter explains the genetic causes of Alport Syndrome.

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So we think all people with Alport syndrome have the condition as a result of a mutation in one or two genes. The majority of cases of Alports are what we call X-linked. They're caused by an alteration in the gene on the X chromosome. And that therefore affects males much more significantly than females, because men only have one X chromosome whereas women have two X chromosomes. So women have two copies of the gene for X-linked Alports, and men only have one copy. And if they have a mutation in that one and only copy, then they will inevitably be affected by the condition. Whereas women who inherit a mutation in one of their two copies of that gene are usually much more mildly affected. A smaller proportion of patients with Alport syndrome have what we call autosomal recessive Alports, because they inherit a mutation in both copies of the gene that's on one of the autosomes. So a gene that we all have two copies of, men and women. So, for patients with autosomal recessive Alports, sex doesn't play a role in that, it's simply a question of a child having parents who are both carriers of recessive Alports and then being unlucky and inheriting the mutated gene from both parents. Now we know that carriers of recessive Alports, like carriers of X-linked Alports, have usually much more mild features. And they can be passed down for several generations through a family. And sometimes that's led people to suggest that we should call carriers of Alports, or refer to them as having dominantly inherited Alports. But I don't actually think dominantly inherited Alports exists, because people who are carriers of Alports don't have the full range of features that would be enough for us to refer them- to them, as having Alport syndrome. They don't usually have the hearing problems, they don't have the eye problems, and the majority of them will retain normal kidney function. So I don't use the term autosomal dominant Alports, I talk about people who are carriers of recessive or X-linked Alports as being manifesting carriers if they develop some symptoms.
 

Professor Frances Flinter, Consultant Geneticist explains what usually happens when people are referred to her for an appointment.

Professor Frances Flinter, Consultant Geneticist explains what usually happens when people are referred to her for an appointment.

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So, most families who are referred to me are referred to me by a kidney doctor. Occasionally I get referrals direct from GPs. I will see the family, take a very detailed family history on both sides. Obviously what I'm particularly interested in is whether anybody else in the family has had kidney problems, is known to have blood in the urine. Particularly if they're also known to have had hearing problems associated with that. And then I will identify the person that is most likely to give us an answer if we arrange genetic testing. And that's not necessarily the youngest person in the family. It may be that there's an uncle somewhere who's definitely had significant kidney problems, perhaps a kidney transplant. And it may make most sense to test him first, because we're most likely to find the answer there. And then once we've discovered his mutation, we can test other relatives, in what we describe as a cascade fashion, step by step, to see whether they've inherited the same alteration as has been identified in the first person we’ve studied. And in genetics we've referred to that person as the proband, it's the person at the heart of the family, where we initiate our genetic testing and get the information that we need to be able to test other people and find out whether they have inherited Alports or are carriers of the type of Alports that's in their family.

So we just take a small blood sample, three or four mils of blood. And we put it in what's called an EDTA bottle, it's a little pink or purple capped- topped bottle. And that goes to the laboratory where they extract the DNA. And they then sequence the type 4 collagen genes. Or more specifically, three particular sub groups of type 4 collagen genes. It's the genes that code for the alpha 3, alpha 4, and alpha 5 chains of type 4 collagen. Now the alpha 5 chain of type 4 collagen is coded for by the gene on the X chromosomes. So if there's a mutation in that gene, we now know that the proband has X-linked Alports. The alpha 3 and the alpha 4 chains both are involved in autosomal recessive forms of Alports. So if we find mutations in one or other of those genes, we know we're dealing with recessive Alports.
 

Professor Frances Flinter explains prenatal diagnosis and pre-implantation genetic diagnosis (PGD) for people with Alport Syndrome.

Professor Frances Flinter explains prenatal diagnosis and pre-implantation genetic diagnosis (PGD) for people with Alport Syndrome.

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I think it's very important to emphasise that genetics departments will never be directive in terms of the counselling they offer. So they will never tell a couple what they should do, because we don't know - each couple must make their own individual choice. But some couples may prefer to choose one of the options that's available to them that mean that they can avoid passing Alports on to a child of theirs. 

And I suppose the most common thing that couples would consider is prenatal diagnosis. That means having a test done once they're already pregnant, at about eleven or twelve weeks of pregnancy, to see whether or not the baby has inherited the mutation. And some people might do that because they would consider terminating a pregnancy that is known to be affected. That's obviously a very difficult decision for any couple to make, these are couples who want to be pregnant, who want to have children. And it's very hard deciding whether or not to have prenatal diagnosis with a view to terminating an affected pregnancy. But if the mutation is known in the family, then that is something that's available to them. Of course, for some couples there's a very strong desire to avoid having affected children. But prenatal diagnosis and termination of pregnancy are not something that they could consider. And it's for those couples that pre-implantation genetic diagnosis may be an acceptable alternative. So pre-implantation genetic diagnosis - or PGD for short - uses fertility treatment to obtain eggs and sperm from the couple that are fertilised in the laboratory. So that the embryos created as a result can be tested for Alports before an unaffected one is selected to be put into the womb in the hope that it will implant and lead to a pregnancy. And there are a small number of couples every year who choose to have pre-implantation genetic diagnosis in order to try and maximise the chance of having a baby that is not affected with Alport syndrome.
 

Professor Frances Flinter talks about the process and timescale involved with PGD.

Professor Frances Flinter talks about the process and timescale involved with PGD.

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There are many couples now who've had healthy babies following PGD. But it's a complicated process to go through. And I think of course couples find it quite stressful, because at any stage they may come to a halt. They may not - the eggs may not fertilise, the fertilised eggs may not grow to the stage at which they can be biopsied, the biopsied embryos may not survive the process of being biopsied, or we may have one or two and then we test them they're all affected. So there can be huge disappointment at any stage.

So PGD has quite a protracted timescale. When patients get pregnant naturally and have prenatal diagnosis, as long as we already know the mutation to look for, we can actually test for it as soon as they get to twelve weeks of pregnancy. With PGD we only have a really tiny amount of DNA taken from the biopsied embryo to test, and so for technical reasons what the laboratory does has to be very different. And because we want to be absolutely sure that we have a robust and reliable test that will work on the tiniest amount of DNA, the laboratory has to do a lot of preparatory work beforehand, before we're ready to start putting a couple through IVF. And we need DNA from both members, both members of the couple who are considering PGD, and usually also a DNA sample from at least one other relative who carries the mutation, in order to be able to develop a tailor-made test for that couple that we are confident will work with a tiny amount of DNA. And that laboratory work-up, as we call it, takes about three months once we have DNA samples from all the relevant people. Only then can we refer them to the assisted conception unit where there's all sorts of screening tests that need to be done, and consent forms to be signed, before they are then scheduled to start the ovarian stimulation that is required for IVF. So there's usually at least six months run-in before they get ready to start their treatment. And so for couples who are in a great hurry to get pregnant, it's unlikely that PGD is going to be the best option for them.

And so then from six months onwards, what sort of timescale? What would that potentially-

It's very difficult to generalise. After one cycle of ovarian stimulation, there may be no embryos, and therefore they need to go through the whole ovarian stimulation process all over again. And of course that will take several more weeks. On the other hand, they may go through one cycle of ovarian stimulation and have two embryos that are predicted to be unaffected. We will put one back a month after biopsying and testing it. If the woman doesn't become pregnant she can come back a few weeks later, and have her next frozen embryo put back, to see if that will implant. So people may be able to have two or three goes at becoming pregnant after just one cycle of ovarian stimulation, particularly if they're younger and they've produced plenty of eggs, and those eggs have fertilised successfully and survived the process of being biopsied and tested.
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