by Kirk, Edwin;
There’s a twist to this tale. If the repeated section is 27 repeats or longer, it’s too much to cope with for the machinery in the cell that’s responsible for copying DNA while making an egg or sperm. Mistakes can be made. In this case, it’s a very specific type of mistake: the DNA copying mechanism has a risk of slipping — like a stuck record. CAG CAG CAG skip CAG CAG where was I? CAG CAG CAG … This means there’s a chance that the child will inherit a larger (or, sometimes, smaller) repeat than their parent.
For reasons we don’t understand, it makes a difference whether a man or a woman passes the expansion on. On the whole, it’s worse to inherit the HD repeat expansion from your father2 than from your mother. The chance of a reduction in size is much less, and the chance of an expansion much more. Since larger repeat sizes lead to earlier development of symptoms, one of the consequences of all of this is that HD can actually get worse through the generations in a family — with earlier onset and quicker progression. There are a number of conditions that do this; the phenomenon is called ‘anticipation’, despite the fact that early onset Huntington disease is hardly something to look forward to. It took a while to figure out this generational worsening, because the phenomenon is kind of weird and unexpected, and also because it’s quite easy for family trees to give the appearance of anticipation just by chance. This is in part because the first person in a family who gets the diagnosis of a rare inherited condition is often a child with severe problems; that child’s affected parent is probably more mildly affected. That looks like anticipation, and, although it isn’t, you may need to see a fair few families before you can rule the possibility out.
[2 You might think this is an example of the process for making an egg being superior to the process for making a sperm, but it seems like it’s not that simple. For some other triplet repeat disorders, such as fragile X syndrome and myotonic dystrophy, it’s the other way round — expansions mainly happen when the repeat is passed on by a woman.]
You can probably see where things are headed here. If anticipation in Huntington disease means earlier and earlier onset through the generations, eventually it might get to a point when it starts very early — and it can. ‘Juvenile’ HD starts before the age of 20,3 and children sometimes show symptoms when they are as young as five. The diagnosis of HD in such a young child is a double blow: almost certainly, his or her father has a smaller expansion, but one that means he, too, will develop the disease in time.
[3 People with juvenile HD have at least 50 repeats; the youngest affected children can have more than 60.]
One more thing before you put yourself in Jason’s shoes. For now, at least, Huntington disease has no cure. There are treatments that can lessen the symptoms, to be sure, but once the symptoms start, the condition is relentless, a slow-moving juggernaut that has only one destination.
Now … let’s say there is a 1 in 2 chance that this is your fate. We can do a test and give you an answer. Think you’d like to take the test?
For most people, it turns out, the answer is a very definite NO. Nearly nine out of ten people who know they are at risk choose not to find out. Their reasons vary. Many figure that, since there’s nothing they could do about the information that will change the outcome, there’s no real benefit to having the information. Some prefer uncertainty, and the possibility of a long and healthy life, over certainty that could be of a bad outcome. It’s not knowledge you can un-know once you have it.
This means that the people who come to see a geneticist about testing are something of a select group. Reading this, you may think that you know what you would do, and that you are part of that select group, but it’s quite possible that you are wrong. When people are asked whether, in principle, they would choose to be tested, about 80 per cent say yes — almost the reverse of what actually happens. This gap between what people say they would do and what they actually do when given a real-world choice has a name. It’s called the intention–behaviour gap, and it applies well beyond the deeply personal and life-changing decision to have testing for HD. If you’ve ever signed up for a gym membership and then found yourself not, in fact, going to the gym — there’s the gap.
Having said that, the group of people who do choose to be tested are generally very sure about that decision. Sometimes, like Jason, people wait for years before taking positive steps to have the test. But once you make it into my clinic room, it’s very likely you’ll go ahead — I can count on the fingers of one hand those I’ve seen who have reversed the decision at or after that point. When that does happen, it can be at the very last minute. Our department’s files hold a sealed envelope containing the HD result of a man who had the test done but, when he was called with the news that his result was available, changed his mind about receiving it. For more than 15 years, that envelope has sat waiting, unopened. He has probably lived out the answer — developing symptoms, or not — by now.
From time to time, I do see people who come for testing but don’t really want to know the answer. Mostly, they are in a situation that is similar to Jason’s: they are planning a family and don’t want to pass the condition on to their children. This opens up an unusual option: an exclusion test.
The gene we are interested in here, HTT, sits on chromosome 4. The idea of exclusion testing for HD is to identify if an embryo has inherited its copy of chromosome 4 from Jason’s mother, not his father. Remember that Jason has two copies of chromosome 4, one inherited from his father and one from his mother, and Jason’s father had HD, but his mother did not. Jason will pass on either his father’s chromosome 4 or his mother’s, to each of his children.4 If the embryo has its grandmother’s chromosome 4, it’s in the clear. The laboratory would make no effort to work out which of Jason’s father’s two copies of chromosome 4 harbours the faulty gene, because the information isn’t needed to achieve the desired result. That way, we could be certain the baby won’t have HD without revealing Jason’s status.
[4 It’s actually a little more complex than that, because of recombination — a process of creating a new, mix-and-match chromosome containing parts of each of a person’s two copies of every chromosome. So really we are looking to identify an embryo with the grandmaternal chunk of chromosome 4 that contains the HTT gene, not the whole thing.]
Jason and Lauren considered this option, but Jason had already decided that he needed to know what would happen to him before making plans for the future. When I met him, it was his second visit — he’d already met with Lisa Bristowe, the genetic counsellor with whom I work. They had talked through the issues, the reasons to be tested or not to be, the possible implications for insurance,5 and how Jason might deal with either of the possible results. Lisa had been sensitive to red flags: Is this someone for whom a bad result might be a truly devastating blow? Would he need extra psychological support around the time of the result? We had arranged for Jason to meet with a neurologist, who had found no signs of HD; this meant that, if the result were positive, it would not mean that Jason had HD, but that he was destined to develop it later. We’d offered an appointment with a psychologist as well, but Jason had declined this.
[5 As you can imagine, life-insurance companies are not big fans of Huntington disease. As I write, in Australia there is a moratorium on insurance companies discriminating against people on the basis of genetic test results, for life-insurance policies of up to $500,000 as well as some other types of insurance. This is voluntary, and we don’t know if it will be permanent.]
At the second meeting, we ran over some of the same ground, discussed medical issues, and arranged the test. Two tests, in fact: we always do predictive tests in duplicate, because of the consequences of getting things wrong, and because the biggest single cause of laboratory error is testing the wrong sample. Rare though it is for two individuals’ blood tubes to be mixed up, sending two separate samples, which are tested independently, makes it nearly impossible for this to happen.
Six
weeks later, we met the couple again. Walking to the outpatients clinic that morning, I carried a sealed envelope containing Jason’s result; just before the appointment, when I knew that he had arrived at the hospital and was waiting to see us, I opened it.
I don’t believe in luck, not really. But Jason had come to see me part way through a freakish two year period during which nobody that I tested for HD received bad news — and he did not break the run.
For Lisa and me — although not, of course, for Jason and Lauren — this was a pretty routine, straightforward scenario. But the ability to do ‘predictive’ testing can throw up situations that are not straightforward at all. Consider identical twins who have a 1 in 2 risk of developing HD. One wishes to be tested, the other does not. By testing one, you have tested the other. We would not communicate the information to the other twin, of course … but what are the chances that she will inadvertently find out, or, to put it another way, how likely is it that the secret will be kept from her?
If, somehow, she is not told, how will she live with the knowledge that her twin knows the answer for both of them? Imagine being the twin who does not know, having an ordinary conversation with your twin and knowing all the time that she knows your shared fate — and could tell you the answer in a second, with as little as a nod or a shake of the head?
I’ve never encountered this situation, but from time to time we see people like Kim, a young man whose maternal grandmother had recently died of HD. His mother did not wish to be tested, but he did. Good news for him would tell us nothing about his mother6 — but if he had inherited the faulty gene, then so had she. In that case, she accepted his decision to be tested, and it turned out that his 1 in 4 chance (1 in 2 chance his mother had inherited the faulty gene, times 1 in 2 chance she had then passed it to him) did not come up, leaving his mother where she had started.
[6 Almost nothing. There’s a branch of mathematics called Bayesian probability, which is something of a favourite of geneticists. It allows us to combine different types of information to modify our assessment of the likelihood that something will happen. Without digging too much into the details, in this case, the finding that the man did not inherit an HD expansion shifts the probability that his mother had inherited an expansion from 1 in 2 to 1 in 3.]
What about testing children? It’s natural for parents to be deeply concerned about the possibility that their children may develop a condition such as HD in the future, and to have a desire to find out — driven mostly, perhaps, by the hope of receiving good news. Very soon after predictive testing became possible, the genetics community decided that we should say no to such requests. There are various reasons for this: concerns of genetic discrimination, and of stigmatisation; worries that children will be treated differently, in a way that will harm them. The most compelling reason, for me, is that by testing them we take away their option not to be tested. Knowing that most adults, given the choice, do not have testing, is it fair to a child to take that future possibility off the table?
All of this hinges on the fact that we have no treatments yet that change the outcome in HD, although there is a great deal of research directed at developing such a treatment. If we knew that there was a medication that could prevent the disease from taking hold, and that you needed to start taking it when you were a child in order for it to work, the rules would change immediately. There are other conditions in which the stakes, and, as a result, the rules, are different in this way. Take familial adenomatous polyposis (FAP), for instance. This is a condition in which hundreds to thousands of growths, called polyps, form in the colon. Left alone, colon cancer is inevitable; surgery to remove the colon is needed once the polyps are present. Screening with colonoscopies is needed to see if that has happened yet, starting from around 10–12 years of age. Polyps tend to start showing up in the mid-teens, but they can appear even earlier.
Because of this, genetic testing in a child who is at risk of having FAP is completely uncontroversial, although not taken lightly. There are important differences between FAP and HD. The age at which problems develop is generally much earlier in FAP — genetic testing in a child would not usually be happening decades before the first symptoms might appear. And you can do something about it, using screening and surgery … and the something that you can do is relatively burdensome,7 adding an incentive to do testing, so that you can spare half of the at-risk kids from having to go through it.
[7 I can attest from personal experience that having a colonoscopy is no big deal, thanks to the wonders of anaesthesia — but preparing for one (bowel washout) is not fun at all.]
Falling somewhere in between these extremes is a group of conditions that affect the heart. A cardiomyopathy is a disease of the heart muscle. Most commonly, the muscle becomes thickened,8 which can block the flow of blood through the heart; or it becomes weak and floppy.9 Either type can lead to problems with the flow of electricity through the heart, with potentially fatal results. Other conditions, such as long QT syndrome, affect that flow of electricity without changing the heart muscle.
[8 Hypertrophic cardiomyopathy.]
[9 Dilated cardiomyopathy. There are several other types of cardiomyopathy that are much less common than these two.]
These are mainly dominant conditions, like HD and FAP, and they vary enormously within and between families affected by them. I once saw a 14-year-old boy who popped into a fast-food restaurant on his way home from school. It happened that the woman standing in line behind him was a nurse. This was fortunate because, when the boy’s heart suddenly stopped, the nurse performed CPR until the ambulance arrived. Remarkably, the boy suffered no ill effects, but it turned out that he had quite a severe cardiomyopathy that had caused his cardiac arrest. We were able to identify the genetic cause of his condition and track it through the family. There were several people in the family who turned out to have relatively mild heart problems — including the boy’s mother. But her father, who was in his 70s, carried the same genetic change as his grandson, and had done so all his life, yet his heart remained healthy.
For adults, at least, deciding to be tested for conditions like this is generally much more straightforward than the decision to be tested for Huntington disease. The implications are worrying, to be sure, and it might be distressing to find out that you are at risk of developing a serious heart condition. But there are treatments that can change the likelihood that you’ll die from the condition, and there’s that chance that you might never develop symptoms. Still, though — should we test children in families like this, to see if they have inherited the at-risk version of the gene? What would the result mean? It’s not ‘predictive’ if you can live your whole life without ever developing a problem. On the other hand, these are not always adult-onset conditions — quite young children can be affected sometimes. There are treatments that can reduce the risks … but you could also just screen for problems using non-genetic tests such as echocardiography (an ultrasound of the heart), which are not invasive or burdensome, and then treat any problems as they arise.
It’s not at all clear what we should do about this,10 and different geneticists have come to different conclusions. My own position has shifted over the years; now, I explain all the issues to parents who want to have their children tested, I make sure they understand the implications, and then, if they still want to go ahead, I do the test. If the child is old enough, they get to have a voice in the decision-making process. Teenagers often say no.
[10 It’s not clear to geneticists. Cardiologists are generally very clear-cut about the issue: they want us to just get on with it, so that they don’t have to screen people who don’t need to be screened.]
The implications of the results are potentially a bit different for a heart condition than for a brain condition or cancer. Probably the risk of stigma isn’t there, but there are some extra concerns. Want to be an airline pilot when you grow up? How sympathetic is the company doctor
likely to be to the idea that you have a genetic test result that says your heart might suddenly stop one day? Never mind that you might also live a long and healthy life and never show effects — aviation is a risk-averse business, and it wouldn’t be at all surprising if this type of information turned out to be career-limiting.
*
In HD, FAP, and inherited heart conditions, the uncertainty is often about whether to have a test. But sometimes, uncertainty follows from the result, rather than preceding the test.
Lee-Ann and Derek had been trying for a baby for what seemed like a long, long time. Test after test had not found a cause for their infertility, beyond one that had been obvious from the beginning: time was not on their side. When they first went to see a doctor about their difficulties conceiving, Lee-Ann was 37 and Derek was 40; by the time I met them, she was 41, and pregnant at last, a naturally conceived pregnancy after several years of unsuccessful IVF. They told me that they had been overjoyed by the pregnancy, but worried about the possibility of a chromosome problem in the baby. Then, an early ultrasound scan showed an excess of fluid at the back of the baby’s neck. Chromosomal conditions are among the possible causes for this finding,11 so they chose to have chorionic villus sampling (CVS) done. This test takes a tiny piece of the placenta for use in genetic testing, with the idea being that, since the placenta shares its genetic make-up with the baby, if the baby has a chromosomal problem, it will be present in the placenta as well.12
[11 There’s a long list of other possible causes, but if the chromosomes and 18-to-20-week ultrasound are normal, the outcome is usually a healthy baby.]
[12 Sometimes, there can be changes that are present in the placenta but not in the baby. More on this in chapter 11.]