Understanding genetics in inherited MND

We spoke to people about their understanding of genetics in inherited MND. This section covers:

  • Finding information on the genetics of MND
  • Understanding genetics in inherited MND
  • Key definitions

Finding information on the genetics of MND

Inherited MND is complex, and research is ongoing to help improve understanding of the condition. Making sense of the genetics of MND may be confusing for families. People had different approaches to how much they wanted to know about gene variants associated with inherited MND and how they are passed on (inheritance), the likelihood of developing the disease if carrying a particular genetic variant (penetrance), gene repeat sequences in the context of genes like C9orf72, and factors that could influence the age where symptoms develop and contribute to the development of MND. The terms mentioned here can be found in the ‘key definitions’ section below.

Understanding these details was important and interesting for some people.

Finding out about the C9orf72 genetic variant in her family enabled Lillian to search for scientific papers. Learning as much as possible is “the way my mind works”.

I’ve been all over the internet, I’m that kind of person that immediately you can just Google C9orf72 and find out rafts of scientific papers about the age of onset, the number of repetitions and whether that’s got an effect on onset, whether you’re likely to get it younger than your parents or not. And I immediately became, I got myself as far knowledgeable about it as I possibly could, because I’m like that. I know a lot of people wouldn’t do that but it’s the way my mind works.

So that was a massive time of activity, and I think I must’ve sat at my computer for months researching familial motor neurone disease and obviously the dementia side of it as well, and everything that they’d found out about this gene so far.

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For people who had a scientific background, reading scientific information and journal articles was a good way to get informed, and others spent time learning about these areas and becoming familiar with scientific jargon so they could understand. However, not everyone felt knowing this was necessary, or that it would change their experience of living with inherited MND in the family. Harriet said, “it’s not that important to me to know that detail. It doesn’t enhance my experience of all of this”. Some of the people we spoke to felt complex genetic information went “over my head”, and it was enough to know that other people understood it and were doing research on it.

People had different experiences of seeking information on inherited MND. People had sometimes been given information by healthcare professionals (including through genetic counselling), other family members, or had looked for reliable information online. Some families had been given misinformation in the past, such as being told that MND couldn’t be inherited, but this message had generally changed over the years. The information people want may evolve over time and with changing circumstances, along with people’s understandings and awareness.

Understanding genetics in inherited MND

People we spoke to generally understood that if a parent carries a dominant gene variant linked to inherited MND, each child has a 50% (or 1 in 2) chance of inheriting it. However, it could be difficult for people to make sense of the chance they could be affected.

For Kirsty, who didn’t know if her mum carried the C9orf72 genetic variant or not, understanding her own risk was more complicated.

So yeah, I didn’t really have a lot of factual information. It was just there is this gene and we knew that it came from my grandmother so in that sense… well I knew it was a 50/50 chance of having it or not, and this was always something I found really confusing was when they talked about the percentage chances of, you know. So, it was a 25% chance for me, but that didn’t necessarily make sense because I thought, “Well mum either has it or she doesn’t”, so therefore it seemed more like it was 50/50 for me as well if that makes any sense. But I mean maths is really not my strong suit. But those percentages never really made any sense to me, because it seemed based on whether you found out or didn’t find out, and I was like, “Well, whether you find out or not, the chance of you having it is still the same”.
 
Then, but I think because there’s three uncles who have all tested positive, I think we were all getting to the stage where we were starting to think, “It can’t be 50/50, it seems like it’s a much higher chance than that”, like somehow – and this is where, no scientific reasoning for this – I think in my head I started to just think of it as an extra strong gene, that it was somehow, there was a higher chance of getting it somehow because it was extra powerful or something [laughs]. Which is I think why we were all so sure that my mum would have it as well, because once you have three people, three out of six with it, you start to think, “Hmm okay”. It didn’t seem likely that she wouldn’t.

 

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Most were aware that there are different gene variants associated with inherited MND, though not everyone realised this at first; in other neurological conditions, like Huntington’s disease, there is just one gene linked to the disease.

Helen had never considered that there might be multiple genes which could cause MND. Finding out that her mother-in-law had the C9orf72 genetic variant “opened a whole world of questions”.

(Text edited by Helen)

It sounds so bizarre, but it just didn’t like… It just, whether we’d like just subconsciously put that to the back of our mind to not think about it, I don’t know. I think maybe we just thought there was one gene, one genetic mutation, and his mum had that gene and that’s what it was, and whatever that one gene was is the one that he was at risk of having.

It just never really crossed our minds to look into it at that point in that much depth to even get to the stage of thinking, “Oh, there’s like lots of different genes and…” and when we realised, it was like, “Whoa, we really need to be looking into this” you know. There’s like five main genes out there. Which one is ours? Like there’s a whole world out there. There’s, you know, Facebook forums and groups and research things and trials and we’d been oblivious to all of this. It had sort of passed us by and once, but once we knew that, it was, you know, there was no stopping us then, I think. It was like, it opened a whole world of questions for us and our family that have sort of been answered then the past couple of years.

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There was also some awareness that not all of the genes associated with inherited MND have been identified. Hugh had genetic testing after his MND diagnosis, which came back negative. He said, “I was one of the, whatever it is, 30%, 40% of people with familial MND who don’t have a known gene”. Where genetic testing came back positive, finding out the name of the gene variant in the family was significant new information for some people.

People highlighted that the same gene could cause such different symptoms, even within a family, which was hard to understand for some individuals. Learning that certain genetic variants, including C9orf72, can also cause other neurological symptoms like frontotemporal dementia (FTD) could be a lot to take on board. Karen said, “every case is different… In my family they both had limb onset… but that doesn’t necessarily mean that’s how it would impact on me if I was to get it… there is no way of knowing”.

David points out that there are many factors that influence how people are affected by MND, and it is important to treat everyone as an individual, with their own unique disease.

And I would say one of the best things you can say to people – I was saying this to my wife last night – it’d be better to say, “You have a unique disease that is in the motor neurone disease field, but yours is unique, and how you respond and how you progress and what happens to you is you, it’s just you, and so we need to work with you as an individual.” I would say too, it’s a bit like, and I was saying this last night, we used to say people had autism, we now say people are on the autistic spectrum and each person is different, and I’ve worked with people on the autistic spectrum and they were all different.

We have a tendency to say, “You’ve got motor neurone disease”. Well no, what have you got? SMA, ALS, FALS, sporadic ALS, what have you got?  Well even if you’ve FALS and its C9orf72 ALS or SOD1 ALS, it’s still your disease, it’s, it’s, it’s your disease, it’s not anybody else’s. It’s not my, I don’t have my mum’s disease; I’m not my mum you know. She got it within her 40s, she wasn’t as physically fit as I am, she hadn’t done the things I have done, her diet was totally different from my diet, there are so many factors affecting.

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Several people talked about the issue of genetic variants of inherited MND seeming to ‘skip a generation’. This can appear to happen when a person passes on a gene variant to their child but doesn’t develop symptoms in their own natural lifetime, particularly if they die at a relatively young age.

This is also linked to the issue of penetrance (the terms mentioned here can be found in the ‘key definitions’ section below), as incomplete penetrance is another reason why the disease can appear to skip a generation. People we talked to generally understood that having the gene variant does not mean an individual will necessarily go on to develop MND, but people had been told or read different statistics about the chances. Although scientists generally agree that the chance of developing symptoms increases with age, and that different gene variants may have different penetrance, it is hard to give an exact figure on the increased likelihood that an individual who has inherited a gene variant associated with inherited MND will develop the disease in their lifetime. This is partly because there are other factors involved which are not completely understood (including protective genes), and other ‘triggering’ events that might have to happen during a person’s life. Adam asked his genetic counsellor for a figure on the chance he would be affected, which is where things got “cloudy”. Some people found these uncertainties gave them hope, but others found it hard to deal with, like Calum who said, “you could go your entire life thinking you have something when you might not get it, it’s just horrible not knowing”.

Hugh’s consultant told him that not everyone who carries a gene variant associated with MND will develop symptoms. This could be one reason why more family members haven’t been affected.

My consultant did make it plain that you know, you could be carrying it but not exhibit the symptoms, which is one of the… what’s the term? Penetrance, the penetrance of the disease was very variable. I guess what I concluded from that is that in this particular case, while there might be quite a number of members of our family carrying the genetic variation, it must have pretty low penetrance or else an awful lot more of us would be affected than has proved to be the case so far.

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People were often interested in what may influence the age at which symptoms develop in people with inherited MND. Again, this is something that is not easy to predict for an individual. Some had been told that age of onset can follow a pattern in families, though it can also vary significantly between relatives. People generally imagined they would be affected at a similar age to parents and other family members. A few individuals were interested in how the number of ‘repeats’ in C9orf72 could influence the age symptoms develop. Lillian asked this question to researchers. She recalled, “there’s been papers saying in people with lower numbers of repeats, the onset is later in life… they just said that’s not absolutely proven”. Calum also had unanswered questions about the significance of the number of repeats. This is a subject of ongoing research.

Receiving his pre-symptomatic genetic test results, Calum had almost expected to be told “you’ve got it… we can see it in the microscope”, but he found the way the results were presented unclear.

I think one of the things I would say to you is how the result is presented to you is ambiguous because they test you and say you have it, but they do it on a marker of repeats in your gene, so do you have ‘X’ amount of repeats in that gene, and if it’s over a certain mark the NHS classes you as “has it”, whereas in other countries the mark is lower.

So when you’re researching about these sort of things you don’t really know where you stand against other tests, and there’s no like great international testing standard that says people have got it if they’ve got ten repeats, whereas Calum’s got 40, so it’ll go over. And that was really, really difficult to comprehend that yeah, so science is all great and whatnot but actually we can’t test properly to know what the result is.

So, I asked the genetic counsellor in my result’s appointment to request a detailed breakdown of my results. So instead of just saying I’ve got 40, and I think I asked for a breakdown of my father’s results and my results to see how many repeats there were, and I can’t remember what the other thing I asked for. Basically I wanted to know how many I had, because basically the test is “have you got more than 40, if you’ve got more than 40 you’ve got it”, but I didn’t know how many I had. So I said, “Well how many did my father have and how many have I got? Have I got 41?” because if I’ve got 41 my opinion is going to be, “Well what’s the difference between 40 and 41, am I just at a lower risk?” whereas you could have 39 and 40 and I’m thinking, “Well, am I in that category that I’m at risk if I was tested in a different country?” you know, so I wanted to know.

So in February, the counsellor came back to me with the results. She’d sent the tests to [hospital] to do a detailed breakdown and they came back and said that they couldn’t identify how many I had because different parts of the body have different amounts, so the repeats in one section that they took the blood from in my arm could be 40 bloods, but I could have less in my neck or wherever.

So, they did test but they couldn’t count every repeat because it just goes on forever, so I have no idea how many repeats I’ve got. I don’t know if it makes a difference like Huntington’s disease where you have a different stage. They say it doesn’t, but some research says you’ve got it at different rates. So, I felt in worse space for knowing that I had it and don’t know the results, which was a bit annoying.

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People talked about other factors which could influence the development of MND. They sometimes questioned whether other genes, including from an unaffected parent, could have an influence. Others talked about potential lifestyle or environmental factors.

Family experiences can contribute to people’s understandings of how they or other relatives may be affected by inherited MND. Sometimes experiences of inherited MND in the family didn’t match what people knew about the disease. Robyn knew that men and women could be affected, but in her immediate family it was only males who had developed MND. Dani knew that the SOD1 gene could be passed on, but none of the next generation in her family had developed the disease to date. Sometimes, it was more or less than 50% of a generation who were affected, though people often realised there were more complex reasons behind this. Each child of a gene-carrier has a 50% chance of inheriting the genetic variant, in spite of how many siblings they have, but not everyone who carries a gene related to inherited MND will develop symptoms, although they can still pass this on to their own children.

Dani is one of sixteen siblings, and five have developed MND. She knows there is a 50% chance each sibling could be affected, and wonders if other siblings could be gene carriers.

So because we’re such a large family, we’ve sort of distorted the figures, really. Because if my mother had of had five brothers and sisters, there’d be more people with it. Whereas she went on to have so many kids, you know, and so many of us have got it. When I look at statistics, five out of sixteen really, you know, it’s quite a high percentage of people… it’s meant to, it’s a dominant gene so it’s meant to be 50%, isn’t it? So there could be others that had it and didn’t die of it, or haven’t died of it. A few of my brothers and sisters have died of other diseases like cancer and heart attacks and things,  but no… it wouldn’t solve anything really, it’s just interesting, I suppose, to know where it came from.

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Inheriting a genetic variant linked to inherited MND was seen as a matter of ‘luck’ or chance (the toss of a coin or roll of the dice) and individuals often pointed out that there was an equal chance of not inheriting the gene variant. Although some people emphasised that there was no way to know who would be affected, others talked about having a sense, hunch, or ‘gut feeling’ about whether they, or other relatives, would develop the disease. Such feelings were often based on physical and personality traits (being ‘like’ an affected parent or relative). These feelings and fears sometimes influenced people’s decisions to have pre-symptomatic genetic testing, or not to find out if they carried the gene variant in the family. Even though there was no “scientific reasoning” behind such feelings, they could be hard to put aside, an experience that has also been seen in research with families affected by Huntington’s disease.

Mary has always thought that she might develop MND, because she takes after her father and grandma in other ways.

I’ve always had… maybe a feeling deep inside, that I probably will get it, only because I was really close to him and I just feel that we were somehow alike, more alike than what my sister was to him. And then my grandma, when he was really ill, his sisters and brothers were saying that I had my grandma’s eyes, like, I was the spitting image. And I was thinking, ‘I don’t want to have my grandma’s eyes,’ because I thought if I’ve got her eyes – I know it sounds bizarre, but I thought then it might be passed down because I had some gene because of her eyes. Just silly stuff like that. I also used to wish that my mum had probably had an affair and he wasn’t really my dad [laughs], just so that I didn’t have the gene. But I think we’re too much alike for it, for him not to be my dad, so yeah.

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Although research around inherited MND has developed rapidly, there is a lot that has yet to be discovered. People we spoke to had questions that had not been answered. Some individuals wondered whether other neurological conditions that had affected their family could be linked to inherited MND, or why gene variants like C9orf72 can cause FTD and MND. In other families, genetic testing had failed to identify a genetic cause of MND, in spite of multiple relatives being affected.

Key definitions

Gene variants linked to inherited MND

Scientists have discovered many genes associated with MND. The most studied genes are linked to inherited MND and significantly increase a person’s risk of developing the disease. These include C9orf72, SOD1, FUS and TARDBP. In people from a white European background, C9orf72 gene variants account for approximately 40% of cases of inherited MND, SOD1 for 20% and FUS and TARDBP for less than 5% each. In continental Asian populations, a higher proportion of inherited MND is caused by SOD1 gene variants and a much lower proportion is caused by C9orf72 gene variants. Scientists are continually discovering new genes associated with inherited MND and genes with changes that might increase an individual’s risk of developing MND. Other ‘variants of unknown significance’ (VUSs) may occur in genes associated with MND, which may or may not cause disease. Research in the future may help scientists to better understand their significance.

Inheritance

Inheritance refers to the way genetic characteristics are passed between parents and their children. We all carry two copies of each of the approximately 20,000 genes, one inherited from each parent. Most of the gene variants associated with inherited MND, including the most common variants mentioned above, are inherited in what is called a ‘dominant’ pattern. This means that only one changed copy of the gene is required to cause disease. An affected parent would have one normal copy of the gene and one copy with a change that could increase the risk of MND (pathogenic gene variant). Each of their children has a 50% chance of inheriting the gene variant that increases the risk of MND, and a 50% chance of inheriting the normal copy of the gene. Only one parent needs to carry one copy of a dominant gene variant linked to inherited MND for it to be potentially passed on to their children.

Penetrance

Penetrance refers to the proportion of people who carry a particular genetic variant who will develop symptoms of the associated condition in their lifetime. Where a gene variant is described as having incomplete penetrance, not everyone who carries this gene variant will develop the disease. This depends on a combination of environmental and other genetic factors. It is not currently possible to define exactly what these are and what they mean in terms of an individual’s risk.

Gene repeat sequences

The normal structure of the C9orf72 gene consists of a sequence of six bases (see ‘genes and gene variants’ above) with the code ‘CCGGGG’, repeated over and over again. Many other genes also contain repeat sequences, and repeating sequences may have important roles in how genes work. The number of repeats that each individual has on each of their copies of the gene can be variable, but when a repeat sequence expands beyond a certain size, it can then be associated with an increased risk of developing a disease like MND. Scientists study unaffected individuals to understand the range of repeat sizes which are ‘normal’. If a person has a higher than normal number of repeats, they are said to have a ‘repeat expansion’ which increases the chance of developing a certain disease, and they may pass this gene variant to their own children. In genes linked to inherited MND, like C9orf72, it is not completely understood how the number of repeats in the gene impacts a person’s chance of developing symptoms (including, for example, how the number of repeats could be linked to the age of onset). It is not always possible for a person to find out exactly how many repeats they carry. Sequences can be very long, and it is likely that the number of repeats can vary in different cells of the body and might change over time.

Please see the glossary section for more key terms.

Seeking information on inherited MND

People have different approaches to and experiences of seeking information around inherited MND. We spoke to people about: Approaches to seeking information: from wanting to...