Jillian Hastings Ward, Dr Karen Low and Lindsay Randall: How can parental insights transform care for rare genetic conditions?

The Genetic Rare Syndromes Observational Cohort (GenROC) study
aims to improve our understanding of how rare genetic conditions
affect the way children grow, their physical health and their
development. Through actively involving parents as experts in
their child's condition, the study seeks to gather valuable
insights and ensure that family experiences shape future research
and care strategies. You can find out more about the study and
eligibility criteria via the Bristol University website.


In this episode, Jillian Hastings Ward, patient advocate and
former Chair of the Participant Panel at Genomics England, is
joined by Dr Karen Low, a clinical geneticist leading the study
at the University of Bristol, who shares insights into its
objectives, the importance of a co-production approach with
families, and the vital data being collected in the study to
improve support for these children and their families. We'll also
hear from Lindsay Randall, a parent who discusses the journey of
receiving a rare diagnosis for her child, highlighting the
critical need for more comprehensive information and community
support.


"If you join GenROC, that data will be used to develop a growth
chart for your child essentially and their genetic condition, so
I’m really excited about it because I feel like that’s a very
concrete definite given now for all the families in GenROC, which
is just brilliant."


You can download the transcript or read it below.


Jillian: Welcome to Behind the Genes


Lindsay: Historically, there’s been a significant absence of
patient voice in rare disease research and development, and
knowing that’s changing, I think that’s really empowering for
families and to know that professionals and industry are actually
listening to our stories and unmet needs and really trying to
understand, and that offers much greater impact on the care and
treatments of patients in the future.


Jillian: My name is Jillian Hastings-Ward. On today’s episode I’m
joined by Dr Karen Low, Consultant Clinical Geneticist and Chief
Investigator for the General Cohort Study, and Lindsay Randall,
Paediatric Practice Development Nurse and founder of Arthur’s
Quest, which is a UK registered, non-profit, raising awareness
for the ultra-rare condition: SLC6A1, developmental and epileptic
encephalopathy. Welcome to you both.


Today we’ll be discussing the GenROC study, which is aiming to
understand more about the health, development and valuing the
experiences of children with neurodevelopmental conditions. If
you enjoy today’s episode we’d love your support. Please like,
share, and rate us on wherever you listen to your podcasts.


Thank you both very much for joining us today, Karen and Lindsay.
There’s a lot we want to cover, but first of all it would be
great just to put a little bit of context around the Gen-Roc
study. Karen, can you tell us a bit about what the study is
aiming to do, who is eligible and why do you want them?


Karen:  Thank you. And thank you so much for having me
today, Jillian. So, the GenROC study, first to just explain to
people what ‘GenROC’ stands for. GenROC stands for the Genetic
Rare Syndromes Observational Cohort Study. Just to give you some
context about the study, I’m a clinical geneticist and most of my
clinical work focuses on paediatrics, so I see children in my
clinics and the sort of children I see generally are children
with rare genetic syndromes. The last five to ten years we’ve got
much better at diagnosing children with these rare conditions and
that’s because testing has got so much better.


We can now do whole genome sequencing and we can do that on the
NHS, which is amazing, children can get their tests as part of
their clinical care, so it means that a lot more children are
being diagnosed with rare conditions, about 2,000 per year in the
UK. And the thing about that is, that I see these children in my
clinics and I give their families that diagnosis.


But the problem is for so many of these ultra-rare conditions,
like Lindsay’s family has, we sit there and we say to the family,
“Well, your child has got ‘X’ condition,” and we give them some
information from maybe one or two publications and linked to a
leaflet and a Facebook group. And then we say, “But really we
don’t know that much about this condition.” And they say, “But
what is it going to mean for them when they are growing up or
when they are adults? Will they be able to finish school? Will
they be able to work? What is it going to mean?” And I have to
shrug my shoulders and go, “I’m not really sure.”


And as a geneticist and as a doctor and as a mother really, I
just felt that wasn’t good enough, and I found it really
frustrating and I know that the families that I work with, that I
look after, also find it frustrating and I wanted to do better.


And I also found it frustrating that for many genes, researchers
would publish two or maybe three publications about these
conditions, and then they would move on to the next novel gene,
and actually, the journals are a bit like that as well, they like
novel things, they like new conditions, they like the next gene.
And so, it means that actually data doesn’t always carry on being
gathered in these rare conditions, and there are a lot of them.


That was another thing, I sort of felt that these conditions were
being done a disservice and that we needed to do better, so
that’s where the whole idea of the GenROC study came from was my
drive and desire to improve things for families and actually to
work with families to improve that, and that’s where so this is a
very highly co-produced study and right from the outset I’ve
involved parents in telling me what they wanted to know and I’ve
got a very, very active PPI group, full of parents of children
who have got rare genetic conditions, and also I’m really lucky
to have a young adult who has a genetic neurodevelopmental
disorder herself and they all tell me about essentially what I
should do and what I shouldn’t do. They tell me when I’m not
doing enough or when I need to do something differently, so it’s
very highly co-produced, they’re highly involved all along the
way.


So, children with a confirmed genetic diagnosis in a list of
eligible genes which people can see on our website if they Google
GenROC University of Bristol, we’ve got a very easy checker for
eligible genes, but they are essentially the most frequently
diagnosed genes in rare neurodevelopmental disorders. And if
their child is under 16, has a confirmed diagnosis and doesn’t
have any other genetic diagnoses then they can go into the GenROC
study, that’s essentially the eligibility criteria.


Jillian: That’s really interesting. It’s very helpful to hear the
background and I think as a parent of a child with a very rare
disorder hearing that the clinicians also recognise this gap and
the sort of pause that happens once you have your initial
diagnosis, is really helpful and really encouraging.


Lindsay, can we turn to you next and can you unpack a little bit
about what it meant for you to get a rare diagnosis for your
child and what point on your family journey was that compared to
where you are now?


Lindsay: I think to get a rare diagnosis for us was difficult and
challenging and I think the first kind of challenge that any
family has is actually being well-informed by a paediatrician who
is also well-informed, and that’s not always the case. That can
affect the way we acknowledge or accept a diagnosis and how we
also access support and how we understand what more we can do to
make more connections.


We did have genetic counselling offered, but I think there are
families out there who don’t get genetic counselling offered to
help them understand the child’s diagnosis, and then there’s a
heavy reliance on the internet, and as you said, there’s a lack
of information out of there. A lot of conditions are newly
diagnosed or they’re very complicated genes to work with, or as
Karen said, they’ve had a couple of papers and people have moved
on. And I think that does cause an immense feeling of isolation.


We were diagnosed in 2018, our son, our first child, and exactly
as Karen said, it was a fairly quick appointment of, “We don’t
really know much about this condition at the moment, there’s a
couple of papers. We know of 34 children in the world at the
moment with your condition. Here’s a Facebook group,” which we
did join. And it is overwhelming to be given a diagnosis that’s
delivered with such little hope I guess, finding sources of
information that’s valid and robust is challenging, not everyone
knows how to do that or has a skillset to conduct searches of
academic research and I think that clinicians could definitely do
better in also signposting the kind of umbrella charities like
Unique and Contact and Swan and patient organisations, because I
know that would have been definitely helpful for us as a family
to be able to have opportunities to connect with others.


Jillian: Thank you. Our diagnostic journey has been a bit a
similar in that we were diagnosed through the NHS, and that at
the time my son was the first person diagnosed with his disorder
in the whole of the UK so it was really a big question mark, it
was a question of our geneticist saying, “Here’s the three PDF
articles that we know exist in the world about this condition.
Can you read them and tell us whether you think that sounds like
him in order for us to be confirming our diagnosis?” I very much
hear what you’re saying there about feeling lost in the
wilderness. And we too joined a Facebook group quite shortly
after we got our diagnosis, and at the time my son was among the
older ones or certainly as time has gone by he has been among the
older children, so it can be really hard to know what might
happen next.


I think that now as Karen was saying we’re getting much better at
diagnosing people thanks to all the extra testing that’s
happening, that happens much earlier in life than it has done in
the past, but I think then it still leaves a gap in parents’
understanding because you don’t necessarily know what the next
ten years might look like for example. And so, I think making
connections with people who are in that age bracket can be really
important, but it’s very hard to do.


So Lindsay, I’m conscious that your professional training as a
nurse must have stood you in quite good stead when you were faced
with a barrage of medical literature shortly after your
diagnosis, but I think one thing that every parent shares is the
desire to do the best for their child and especially in this
world of rare disorders. There’s a huge amount of energy that
comes through the community I think, faced with the need to try
and self-start and build these networks and connections for
themselves. Is that something that you’ve seen in your community
as your experience?


Lindsay: Yes, definitely. I think we’re a growing community and
over the years of course more and more children and young adults
have been diagnosed with a few older adults coming through. It is
very much a global networking effort and parent/patient
organisations have been set up in many countries now by parents
of children with children with SLC6A1. I definitely think that
drive to become an expert in your child’s condition is a long
journey and one of continual learning and actually a lot of
families simply don’t have a capacity to take that on, I think
often the medical and scientific jargon is difficult to
understand and that makes it challenging to access.


And as you said, as a paediatric nurse, I at least have some
existing skills to understand healthcare to read the research and
speak with medical and scientific professionals with some
confidence, but in some ways, that has increased the burden I’ve
placed on myself to become an expert for my children and other
children and families who are not in the same position as me.


It does require a lot of dedication and time, and that does have
implications on families because it’s time away from our children
and from home, and from the remnants of our lives that we
desperately try to cling onto, to not lose all sense of
ourselves. It’s not often spoken about but I do see the strain it
places on the families, as well where there’s a lot of separation
and divorce sadly in the rare disease communities, and often
that’s as a result of one parent’s drive to be the expert, which
seems to cause one parent to fulfil more burden of care and that
fosters some level of resentment or sense of loneliness towards
the other one.


Jillian: There are some scary statistics out there around
familial breakdown in this context, and it is something which
there are so many factors at play, but it definitely seems to be
quite widely recognised and definitely a problem.


In terms of the time that people have to spend on liaisons with
the research community and the clinical community, that could
bring us quite nicely back into a question for you, Karen, about
what kind of information the GenROC study is looking to collect
from families, can you tell us a bit more about that, please?


Karen: Yes, absolutely. As I said before, I’ve been very
conscious of the sort of lives that our families are living, and
listening to Lindsay, her story is very reminiscent of so many
others and yours, Jillian. So I know families have about a
gazillion hospital appointments, their children are often also
very, very ill intermittently or a lot of the time, then they’ve
got school stuff to deal with or they’ve got EHC plans to try and
fight for. It’s more than a fulltime job in itself just being a
parent of a child with a rare disease and it’s hard work, so me
asking them to do anything else is asking a lot.


Luckily, I find, with the families I work with, who are
universally wonderful I should add, that they are actually just
really enthusiastic anyway about research for their child’s
condition, and that’s because there isn’t enough information out
there, so it’s relevant and important to them. But because they
have no time at all, and any time they do give is their own
personal time when they could be finally putting their feet up
and watching something on TV, I have to make it as low effort as
possible.


The questionnaire is all online, using a user-friendly and
interface as we’ve been able to develop. It’s very user-friendly,
it takes 10-15 minutes to complete; they can come and go from the
questionnaire as well. We only ask for one time point at the
beginning, which is all the sort of stuff that most parents will
be able to tell you off the top of their head as well, so they
don’t have to go looking for loads of information, apart from a
height and a weight. Then later down the line we’re going to ask
for a second questionnaire, it’s in the process of being
finalised and again that will be the same amount of time, very
easy to do, online, at their convenience. It was co-produced with
the PPI group, they’ve tested it for me, I’ve had really good
feedback and I’ve asked parents who are in the study as well for
feedback. Everyone tells me it’s not too difficult or burdensome
for them to do.


The secondary questionnaire has been very much informed by
conversations with the parents that I had as part of a nest of
qualitative interview study in GenROC, and that has driven that
secondary questionnaire quite differently to what I thought it
might be when we first set up the GenROC study. At the beginning
I thought it might just be: have things changed for your child?
Can you give us a bit more clinical data? But actually I realised
that probably I will still gather that information, but they
probably won’t have changed that much within the timespan in the
study because it will only be a year or two after they completed
the first questionnaire, and actually I realised that it would be
much more useful to look at the impact of the genetic diagnosis,
look at how they’re accessing services within the NHS, what sorts
of services they are accessing, Impact on the family and also
looking at priorities for families.


So families have talked to me about what their priorities are in
rare disease, both in service provision but also in research, and
I really am a very strong believer that we need to be given the
limited funding, we need to be doing the research that matters
the most to the families, not to the researchers. What do
families actually want us to look into? Actually, do they want us
to be looking into behaviour and what strategies work best for
example, rather than something else very medical – what matters
the most? And so that’s going to be a specific question in that
secondary questionnaire, really trying to identify what matters
to families the most and then how that can be translated into
clinical research in the future. So I’m really interested to see
what’s going to come out of that.


Lindsay: I think that sounds brilliant, Karen because I think
historically there’s been a significant kind of absence of
patient voice in rare disease research and development, and
knowing that that’s changing, I think that’s really empowering
for families and to know that professionals and industry are
actually listening to our stories and unmet needs, and really
trying to understand, and that offers a much greater impact on
the care and treatments for patients in the future and certainly
it makes endpoints more relevant to families as well.


Jillian: What kind of outputs are you going to be looking at?


Karen: The height and weight, the reason I’m asking for that is
really because we are trying to work on growth charts for
children and that’s because growth charts for children with rare
conditions don’t exist by enlarge, there are a very, very tiny
number of rare syndromes or conditions that have their own growth
chart. The problem is that most children with these sort of rare
conditions that we’re talking about are either quite small or
quite big, and the problem is that the paediatricians look at
their growth and they go, “Oh well, you’re much bigger or much
smaller than other children your own age, what shall we do about
that?” and particularly the little tiny ones it causes lots and
lots of concern, so quite often these sort of growth parameters
mean that the paediatricians do lots and lots of tests or put
feeding tubes down, or add lots of calories, so it can be quite
invasive and interventional actually that sort of growth
parameter.


But actually, sometimes that’s because of the genetic condition
and no matter how much feeding you do it’s not going to change
anything. The difficulty is we don’t know that for certain, and
actually we need good growth charts where paediatricians can make
that call, and conversely sometimes a child actually does need
investigating and the paediatrician puts it all down to their
genetic condition, and that’s why we need these growth charts. So
GenROC is aiming to gather growth data from all these children
and then we’re going to work closely with Decipher, which is a
website that was developed through the DDD study, which already
holds lots of data from that study, so we’re building on the
power of that study and we’re going to be generating growth
charts for all of these genes.


We’ve developed a new method for producing growth charts for rare
conditions where you’ve got small numbers of patients – that was
never possible before, so we’ve already proven now for four
conditions we can, so the next stage is using all the GenROC
data, putting it into Decipher and coding it in. So, if you join
GenROC, that data will be used to develop a growth chart for your
child essentially and their genetic condition, so I’m really
excited about it because I feel like that’s a very concrete
definite given now for all the families in GenROC, which is just
brilliant.


Jillian: And is that something which will be shared with the
families individually?


Karen: Really great question. I hadn’t planned on sharing the
growth charts individually with the families, but that’s
something I can also go back to my PPI group and discuss with
them about whether that’s something people would want, and also I
have a newsletter which goes out every three months to the
families, so I can certainly ask that question actually directly.
It’s going to be widely available, the growth charts, we’re going
to make sure that they’re accessible to paediatricians and
clinicians etc. but in terms of output to the study, definitely
the growth charts, we’re also hoping to have other clinically
useful outcomes depending on the different genes that come into
the study. We essentially have a cohort of children with rare
conditions, everyone puts everything down to a specific genetic
condition but we know that there must be other factors at play
that influence how children do.


And this is a really unique thing we’re trying to do with GenROC
actually, looking at aside from that genetic variant, that
alteration, what other factors are influencing how children are
doing? Because some of those might be modifiable, you know, or
some of them there could be things that could be put in place to
help improve outcomes. So I’m quite excited about that as well,
because that’s quite new and novel and not really been thought
about in this context before, so that will be an output.


And the other output is something that I’m working on with
Unique, which is the rare disease charity who has worked with us
on GenROC from the start, and they are involved in our PPI as
well and that is going to be looking at a template, calling it a
report at the moment, it’s in very early days, but something that
parents will be able to hold, it’s going to have lots of
drop-down boxes that can be tailored and modified for individual
patients and children, which will be a bit of a guide that they
can give to clinicians, professionals, education, telling them
about their condition but also telling them on an individualised
basis about what needs to be looked for in the future. Because
parents tell me they are fed up of having to tell everybody about
their child’s condition constantly, all the time, over and over
again. So what the point of this output would be is to try and
ease that burden a little bit. This is very early stages but
we’re going to involved parents all along the way.


Jillian: And is that something which builds on the hospital
passport idea that we’ve seen emerging around the world over the
last few years where parents can start off telling their child’s
story on their own behalf?


Karen: So, it’s come from my own lived personal experience of
being a mother of a child with autism and I haven’t really spoken
about that publicly before, so it’s something I’m saying for the
first time. I have a child who has autism and I have had to
navigate things like a DLA application form.


Jillian: That’s Disability Living Allowance.


Karen: Yes, exactly, which is a horrendous form, it’s the most
horrible form to complete, probably apart from an EHCP plan form
but it’s a horrible form to complete, it’s quite upsetting as a
parent and it’s also got millions of boxes that you have to fill
in. But one of the things that really, really helped me when I
was completing that was a charity who had come up with lots of
drop-downs that you could select from that might be applicable to
your child to help you complete this form. And so it made me
really think, “Well, could we do something similar for our
children with genetic conditions but come up with lots of
dropdown options that might apply to their child in all sorts of
different areas?” And that was the inspiration, it was that, and
doing the qualitative study that I’ve already done with parents
of children in GenROC who were telling me about how fed up they
were of having to constantly tell everybody about their child’s
condition over and over again.


Jillian: Yes, that’s probably very helpful to empower families to
use standard terminology across the different families because my
own son has epilepsy as part of his condition but actually trying
to describe what his seizures look like I’m not sure I’m using
the right words to fit the right boxes to fit them into the right
categories with the neurologist. So that level of standardisation
is something that we definitely need embedded into the system in
order for more people to be able to use this data more
effectively, so that sounds very helpful.


Lindsay, coming back to you, what are you hoping to get out of
this study, or what are you hoping this study will do on your
behalf for the world? What motivated you to take part?


Lindsay: I think I would like to see all of the aims of the study
realised and for the study data to be used to inform the
development of standards of care for a wide range of conditions,
those included in the study. I think it would be great if that
information, as Karen said, is available not only to the
participants but also to children diagnosed with those conditions
in the future and also it’s an opportunity to consider themes
that are identified across the disease groups as that can also
help inform future research and look at investigations into the
mechanisms of disease and where actually therapeutics could treat
maybe more than one disease at a time and increase potential for
basket trials and early access programmes – thank you to Dr Karen
Low and her team for conducting the project because it included a
comprehensive list of rare diseases, it really does give parents
and patients an opportunity to have a voice and to contribute,
which is empowering, and it gives them a little bit of autonomy
as well over their direction that science and research goes to.


Jillian: Fantastic, thank you. Karen, can you tell us a little
bit about the timeframe for the study? I realise that we haven’t
really touched on that so far.


Karen: Yes absolutely, I’m aiming to recruit 500 children as a
total. We’re open at 22 sites across the UK. Coinciding with this
podcast actually we’ve opened a second door for recruitment, so
the way we’ve recruited so far has been through clinical genetic
sites, which is the way we’ve done these sorts of studies in the
past, like the DDD study. The problem is that that relies on
clinicians identifying eligible patients and clinicians are very,
very busy in the NHS. I have worked closely with Unique who have
been doing a lot of publicity and the genetic alliance have done
publicity as well for the study, so that’s been one way of
identifying eligible participants. And also just parent power
through social media has been amazing.


The second way we’re going to recruit, and this is going to
happen very soon, is through Genomics England. So, we are going
to trial a completely novel way of recruiting to research through
Genomics England and that is for Genomics England to identify
eligible participants for GenROC and this would have been through
the 100,000 genome study and then they’re going to send them
invite letters, inviting them to take part. So that’s the next
phase of recruitment, I think if we have more than 500 then that
will be great too, we’ll be able to include those comers too, so
that’s not a problem.


But we don’t know whether this will work or not in terms of a way
of recruiting to research, this is completely new for Genomics
England and I’m a bit of a guinea pig if you like through the
GenROC study, but I was quite willing to be that guinea pig
because I thought it might increase access. So there will be some
parents who have not been told about GenROC who have not heard
about it, and who would love to take part, so I feel like this is
the way of really widening that net as wide as possible.


Jillian: I think that is a challenge isn’t it, especially in rare
disease – there’s no point doing a public broadcast about an
initiative because you’re going to hit so few of the people that
you’re interested in, so actually how you access the community is
the first challenge and I’m really pleased that Genomics England
will be able to help you there because I think that is a very
useful route through.


I think it will probably be quite reassuring to quite a lot of
families who were on the 100,000 Genomes Project who have got a
diagnosis of one of the conditions that you’re interested in, and
are now perhaps subsequently in the fallow period after you have
a diagnosis, wondering what happens next, so I can imagine it
might be quite good news for some of them at least that they are
now being invited to do something further.


And the reason that you’re building forward and you don’t want
people who are currently in the deciphering developmental
disorders study is because you’re already using their data
through another source, is that correct?


Karen: Exactly. So absolutely, I don’t want anyone to feel that I
don’t want them, that’s really not the case. I do want them but
we have their data already from Decipher, so we’re building on
the DDD data already, so they’re already contributing which is
just the beauty of it, because that’s what we should be doing in
rare disease, we should be building on previous research because
you know, you don’t want to be trying to reinvent the wheel.


Jillian: Agreed. So if someone is listening to this and has a
child with a rare developmental disorder and they are interested
in finding out more, what are the steps they need to take?


Karen: If they Google Bristol University, GenROC, they’ll come
straight to the webpage and everything is on there. There’s a
link that they can sign up, the patient information leaflet’s
there, the eligible gene list is there, all the information they
need, including our email address.


Jillian: And is there an upper age limit for recruitment?


Karen: Yes, children have to be under 16 and that’s because once
they get to 16 many of these conditions have associated learning
difficulties, and it’s just very much more complex to try and
recruit young adults, young people, with learning difficulties
and given it was a cohort study we felt it was going to be too
difficult at the moment.


Saying that, I have a huge interest actually in how these
conditions present in adulthood, and I’m actually conducting a
much smaller study at the moment in KBG syndrome, looking at
adults, and so I hope that my future research career will allow
me both to follow-up the children in GenROC, so that would be my
vision but also to be able to take this forward for other adults
with rare conditions, that’s my aim and goal in the medium to
long-term, so watch this space for that.


Jillian: That sounds very exciting, thank you.


Lindsay: I think I would like to say to Karen that I really like
the sound of the idea of following patients up into young
adulthood and adulthood, as you said, that is definitely a kind
of an unknown area in lots of the rare diseases, especially in
our condition, SLC6A1, it was mutation and the disease was only
really discovered in 2015, so it is fairly new and we have very,
very few young people and adults coming through and being
diagnosed and connecting with the rest of the community. So,
being able to understand the trajectory of conditions better and
especially conditions where actually the presentation it’s quite
a spectrum, and so the long-term outcomes for people with SLC6A1
can look quite different, so it’s good to collate more
information about that I think.


Karen: I think it’s really important, so that’s definitely where
I’m looking to for the future with GenROC and more widely, I
think it’s just something I’m really interested in and has huge
relevance for parents and families.


Jillian: Well, I think we need to wrap up there but thank you
both very much Dr Karen Low and Lindsay Randall for joining me
today as we’ve been discussing the GenROC study, and how the
study aims to improve understanding of how rare genetic syndromes
affect the way children grow, their physical health, their
development, but also how the patient and parent communities can
work more closely with researchers to end up delivering something
which is of a huge benefit to everybody.


If you would like to hear more about this, please subscribe to
‘Behind the Genes’ on your favourite podcast app. Thank you for
listening. I’ve been your host, Jillian Hastings Ward. This
podcast was edited by Bill Griffin at Ventoux Digital and
produced by Naimah Callachand.