Sarah Wynn, Emma Baple, Lindsay Pearse and Naimah Callachand: How has a groundbreaking genomic discovery impacted thousands worldwide?

In this episode, we delve into the impact of the new
groundbreaking research uncovering the RNU4-2 genetic variant
linked to neurodevelopmental conditions. The discovery, made
possible through whole genome sequencing, highlights a genetic
change in the RNU4-2 gene that affects about 1 in 200 undiagnosed
children with neurodevelopmental conditions, making it more
prevalent than previously thought. This discovery represents one
of the most common single-gene genetic causes of such conditions.


Our host, Naimah Callachand, Head of Product Engagement and
Growth at Genomics England, is joined by Lindsay Pearse who
shares her journey through the diagnosis of her son Lars. They
are also joined by Sarah Wynn, CEO of Unique, and Emma Baple,
Clinical Genetics Doctor and Professor of Genomic Medicine in the
University of Exeter and the Medical Director of the Southwest
NHS Genomic Laboratory Hub.


We also hear from the 2 research groups who independently
discovered the findings:


Dr Andrew Mumford, Professor of Haematology at the University
of Bristol

Link to the research paper: Mutations in the U4 snRNA
gene RNU4-2 cause one of the most prevalent monogenic
neurodevelopmental disorders 



Assistant Professor Nicky Whiffin, Big Data Institute and
Centre for Human Genetics at the University of Oxford

Link to the research paper: De novo variants in the
RNU4-2 snRNA cause a frequent neurodevelopmental syndrome





To access resources mentioned in this podcast: 


Unique provides support, information and networking to
families affected by rare chromosome and gene disorders - for
more information and support visit Unique's website.

Connect with other parents of children carrying a variation
in RNU4-2 on the RNU4-2 Facebook group.



 


"I think one of the things we really hope will come out of
diagnoses like this is that we will then be able to build up more
of that picture about how families are affected. So, that we can
give families more information about not only how their child is
affected but how they might be affected in the future."


 


You can download the transcript or read it below.


Naimah: Welcome to Behind the Genes.


Lindsay: So, this feeling that like we’ve been on this deserted
island for eight years and now all of a sudden, you’re sort of
looking around through the branches of the trees. It’s like, wait
a minute, there are other people on this island and in this case
actually there's a lot more people on this island. Yeah, it’s
very exciting, it’s validating. It gives us a lot of hope and,
you know, it has been quite emotional too and also a bit of an
identity shift. Being undiagnosed had become quite a big part of
our identity, and so now that’s kind of shifting a little bit
that we have this new diagnosis and are part of a new community.


Naimah: My name is Naimah Callachand and I’m Head of Product
Engagement and Growth at Genomics England. On today’s episode,
I’m joined by Lindsay Pearse whose son Lars recently received a
genetic diagnosis, made possible by research using data from the
National Genomic Research Library, Sarah Wynn CEO of Unique, and
Emma Baple, a clinical genetics doctor. Today we’ll be discussing
the impact of recent research findings which have found a genetic
change in the non-coding RNU4-2 gene, to be linked to
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.


Naimah: And first of all, I would like everyone to introduce
themselves. So, Lindsay, maybe if we could come to you first.


Lindsay: Great, thank you. So, thank you for having me. I’m
Lindsay Pearse, I live outside of Washington DC and I’m a mum to
3 boys. My oldest son Lars who is 8, he was recently diagnosed
with the de novo variant in the RNU4-2 gene.


Naimah: Thank you. And Emma?


Emma: My name is Emma Baple. I’m a Clinical Genetics Doctor which
means I look after children and adults with genetic conditions.
I’m also a Professor of Genomic Medicine in the University of
Exeter and the Medical Director of the Southwest NHS Genomic
Laboratory Hub.


Naimah: And Sarah?


Sarah: Hi, thank you for having me. I’m Sarah Wynn, I’m the CEO
of a patient organisation called Unique, and we provide support
and information to all those affected by rare genetic conditions.


Naimah: Great, thank you. It’s so great to have you all here
today. So, first of all Lindsay, I wonder if we could come to
you. So, you mentioned in your introduction your son Lars has
recently been diagnosed with the de novo variant. I wondered if
you could tell us a bit about your story, and what it’s been like
up until the diagnosis.


Lindsay: Sure, yeah. So, Lars is, he’s a wonderful 8 year-old
boy. With his condition, his main symptoms he experiences global
developmental delays, he’s non-verbal. He’s had hypertonia pretty
much since birth and wears AFO’s to support his walking. He has a
feeding disorder and is fed by a G-Tube. Cortical vision
impairments, a history of seizures and slow growth, amongst other
things.


So, that's just a bit of a picture of what he deals with day to
day. But he’s my oldest child, so first baby. When I was
pregnant, we were given an IUGR diagnosis. He was breech, he had
a hernia soon after birth, wouldn’t breastfeed. But all of these
things aren’t terribly uncommon, you know. But once he was about
3 or 4 months old, we noticed that he wasn’t really able to push
up like he should, and we were put in touch with early
intervention services for an assessment. So, we went ahead and
did that when he was about 4 or 5 months old. And as parents, we
could just kind of tell that something was off from the
assessors. And, you know, they were very gentle with us, but we
could just get that sense that okay, something is off, and
they’re worried here.


So, that kind of kickstarted me into making appointments left,
right and centre with specialists. The first specialist that we
saw was a neurologist. And yeah, again, that's another
appointment that I’ll never forget. She referred us to genetics
and to get an MRI and some lab work but at the end of the
appointment, she said to us, ‘Just remember to love your child.’
And, you know, that was quite shocking to us at the time because
it wasn’t something that had ever crossed our mind that we
wouldn't do or felt like we needed to be told to do this. But on
the other hand, it certainly set off a lot of worry and anxiety
of okay, well, what exactly are we dealing with here?


So, fast forward, we saw genetics and that was about when Lars
was about 8 months old. We went through a variety of genetic
testing, a chromosomal micro-array, a single gene testing, then
the whole exome testing. Everything came back negative, but it
was explained to us that what was going on was likely an
overarching genetic diagnosis that would explain his like,
multi-system symptoms.


And so meanwhile as he was getting older his global delays were
becoming more pronounced and we were also in and out of the
hospital a lot at this time. At first, he was in day care and,
you know, any sort of cold virus would always turn into like a
pneumonia for him. So, we were just in and out of hospital seeing
a myriad of specialists, trying to put together this puzzle of
what's going on and it was really hard to accept that nobody
could figure it out. That was just, you know, sort of
mind-blowing to us I guess. So, we applied for and were accepted
into the Undiagnosed Diseases Programme at the National Institute
of Health over here. The NIH as it’s commonly referred to. So, we
first went there when Lars was 2. He was one of their youngest
patients at the time. But that was a really great experience for
us because we felt like they were looking at him holistically and
across a bunch of all of his systems, and not just seeing a
specialist for sort of each system. So, we really appreciated
that.


We also did the whole genome sequencing through this research
study. Although that also came back negative and so at that
point, we were told to kind of keep following up symptomatically.
Keep seeing the specialists and eventually maybe one day we’ll
find an overarching diagnosis, but that science just hadn’t quite
caught up to Lars. It was hard for me again to believe that and
to sort of wrap my head around that. But certainly, it was an
education from all of the doctors and geneticists and everyone we
saw at NIH, to realise like how far there still was to go in
terms of genetic research. How it wasn’t also that uncommon to be
undiagnosed in the rare disease community. I would say that being
undiagnosed sort of became part of our identity. And it’s, you
know, it was something that, you know, you had to explain to like
insurance companies and to his school, and it became part of our
advocacy around him. Because without being able to say oh, it’s
this specific thing and if it was someone who hadn’t met Lars
before, trying to explain to them that, you know, yeah, within
the range of this community you can be undiagnosed, and they just
haven’t found it yet, but I promise you there is something going
on here.


And I’d say the other thing too without a diagnosis you have no
prognosis, right? And so, trying to figure out what the future
would look like. Also, family planning. We waited 5 and a half
years before we had another child and, you know, it was certainly
an anxiety ridden decision. Ultimately after seeing as many
specialists as we possibly could, we still were left with the
same answer of well, we just don’t really know if it will happen
again. So, that was a big decision to make. But again, it just
kind of became part of our identity and something that you did
eventually accept. But I would say in my experience I feel like
the acceptance part also of Lars’ disabilities perhaps took me a
little bit longer. Because again, I didn’t have a prognosis, so I
didn’t exactly know what we were dealing with. Only as he has
become older and, you know, you’re sort of getting a better sense
of what his abilities might be than being able to understand,
okay, this is what I’m dealing with. I need to accept that and do
what I can to care for him and our family in the best way that we
can.


Naimah: Thanks so much for sharing that, Lindsay. I feel like
you’ve touched on a lot of really, you know, a lot of
complications and difficulties for your family. Especially, you
know, with regards to keeping hopeful and things about the
prognosis as well, I’m sure it was really difficult. You’ve
mentioned that Lars was able to be diagnosed recently due to
recent research efforts. So, Sarah, I wonder if you can tell us a
bit more about these and what the findings have meant for
patients with neurodevelopmental conditions.


Sarah: Yes. So, I think we know that there are lots of families
that are in Lindsay and Lars’ position where they know that there
is almost certainly an underlying genetic condition, and it just
hasn’t been found yet. And so, I think we know that lots of
researchers are working really hard to try and find those causes.
I think over time we know that as time goes on and research goes
on, we’ll find more of these new genetic causes for
neurodevelopmental conditions. I think particularly as we start
to look at regions of the genome that we haven’t looked at so
much so far. But I think one of the things that's really
extraordinary about this one is that actually it turns out to be
much more common than we might have expected, for one of these
new conditions that we haven’t found before. But I think it’s
about one in 200 of those undiagnosed children with
neurodevelopmental conditions, have this diagnosis so that's not
a small number. That's not a rare finding at all actually, that's
much more common than we could ever have anticipated.


But I think one of the things that we do know is that as we look
further and deeper into that genomic sequence, so, we’ve started
off looking at the bits of the sequence that are genes that code
for proteins. This changes in a gene that actually doesn’t code
for protein, so it’s less obvious that it would be important but
clearly it is important in development because we know when it
has a spelling mistake in it, it causes this neurodevelopmental
condition. But there will be as researchers look more and more at
these kinds of genes, and also the other part of the genome that
is not genes at all, we’ll find out more and more the underlying
genetic causes of these neurodevelopmental conditions.


I think it’s also really important to stress why this is so
important to find these genetic changes and it’s because families
really need a diagnosis. Lindsay talked quite eloquently and a
lot about that knowing something was off and really wanting to
know the reason why. Getting these diagnoses might change care
management or treatment, but actually really importantly it just
gives an answer to families who have often been looking for an
answer for a really long time.


Naimah: I just wanted to go back to the point that Sarah made
that actually this genetic change is relatively common. Emma, I
wondered if you could tell us a bit more about maybe why it took
us so long to discover it?


Emma: That's an interesting question actually. I suppose the sort
of slightly simplified answer to that question is we haven’t been
able to sequence the whole of a person’s genetic information for
that long. And so, children like Lars would have had, as Lindsay
described lots and lots of genetic tests up until they had a
whole genome sequencing which is what Sarah was talking about.
The types of tests that we had up until the whole genome
sequencing wouldn't have allowed us to look at that bit of the
genetic code where this RNU4-2 gene can be found. So, we can only
really find that using whole genome sequencing. So, before that
existed, we wouldn't have been able to find this cause of
developmental condition.


Naimah: Okay, thanks Emma.


Naimah: Now we’re going to hear from one of the two research
groups who are responsible for these research findings. First of
all, let’s hear from Nicky Whiffin.


(Clip - Nicky Whiffin)


Naimah: How were the findings possible using the Genomics England
dataset?


Nicky: So, most previous studies have only looked at genetic
variants that, in genes that make proteins, but only a subset of
our genes actually do makes proteins. The Genomics England
dataset we have sequencing information on the entire genome, not
just on these protein coding genes and that means we can also
look at variants in other genes. So, those that make molecules
other than proteins. And RNU4-2 for example, makes an RNA
molecule.


Naimah: These findings translated to direct patient benefit for
patients like Lars who were able to receive support from Unique.
How does this demonstrate the value of the dataset?


Nicky: Yes. So, it was incredible that we could find so many
patients with RNU4-2 variants so quickly. This was enabled by
access to Genomics England data but also to other large
sequencing datasets around the world. So, we worked with people
in the US, in Australia and also in mainland Europe. These large
datasets enabled us to spot consistent patterns in the data and
by looking across multiple datasets we can also make sure that
our findings are robust. When we realised how significant this
was and how many families would be impacted, we very quickly
contacted Sarah at Unique to see if we could direct patients to
them for support.


(End of clip)


Emma: There's one thing I wanted to raise. It’s important to
recognise the way that was discovered was through the National
Genomic Research Library that Genomics England hosts. To
highlight the value of that, and the value of having this
centralised resource where families have been kind enough really
to allow their data to be shared with some limited clinical
information that allowed these researchers to be able to pull
this out. And I think it highlights the power of the National
Health Service in that we were able to create such a resource.
It’s really quite astounding that we’ve found such a common cause
of a rare genetic condition, and it wouldn't have happened in the
same timescale or in this way without that resource. And then to
just say that as Sarah talked about the fact that we’ve been able
to get that information out there, also the researchers were able
to get out there and contact the NIH and all of these other
programmes worldwide. In Australia, America, everywhere in the
world and quickly identify new patients who had this condition
and get those diagnoses out really rapidly to people.


But all that came from that power of sharing data and being able
to have that all in one place and making it accessible to very
clever people who could do this work and find these answers. It’s
so important for families like Lindsay’s, and all the families in
England and around the world that have got these answers. So, I
guess it’s a big plug for the value of data sharing and having a
secure place where people feel that it’s trusted and safe, that
enables these diagnoses to be made.


Lindsay: If I could just echo that, we’re so grateful that that
exists in the UK. Just acknowledging like the privilege here that
we have had to be able to, I mean for our family in the US, that
we’ve been able to, you know, get ourselves into the NIH study
and into the study at Children’s National. That takes a lot of
work. I feel like not everybody has that opportunity to be able
to spend the time to do these applications and to go to all the
appointments and get the testing done and have the insurance to
cover it. So, very grateful that the system exists in a way in
the UK that made this sort of research possible. I just hope that
that can be replicated in other places, and also to what Emma was
saying earlier, come up with a lower cost test as well for this
to further the growth of the community and of course then the
corresponding research.


Sarah: I think firstly we have to sort of thank all of those
families that took part and do share their data, because I think
it’s not always clear why you might want to do that as a family.
I think this is really a powerful example of the benefit of that.
I also think the data sharing goes one stage further. So, it’s
partly about getting the diagnosis, but the data sharing going
forward about how this condition impacts families, both
clinically and sort of day to day lived experience, is how we’ll
be able to learn more about these conditions. And so, when
families get this diagnosis next week or next year, not only will
they get a diagnosis, but they’ll get a really good idea about
what the condition is and how it might impact their child.


Naimah: And Lindsay, coming back to you. So, we’ve talked about,
you know, what it meant for your family before the diagnosis, but
what has it meant to have a diagnosis and how did you feel? And
what happened whenever you received the diagnosis?


Lindsay: Sure. Lars was again part of the NIH Undiagnosed
Diseases Research study. So, once you attend this programme and
if you are not diagnosed like at the end of your stay, they keep
your details on file and you’re part of this database at the NIH
Undiagnosed Diseases Programme. So, if you’re undiagnosed after
your sort of week-long work up, your samples stay within the
research programme. We were also part of a research programme at
Children's National Medical Centre, the Rare Disease Institute.
So, our samples were sort of on file there in their database as
well.


And so, at the end of March I was really quite shocked to receive
a call from our long time and trusted geneticist at Children’s
National that they had found a diagnosis. It was quite emotional.
I really kind of didn’t believe it. I just kept asking, you know,
‘Are you sure? Is this it?’ you know, ‘How confident are we?’
Because I think in my head, I sort of always thought that we
would eventually find a diagnosis, but I thought that Lars would
be, you know, a 30- or 40-year-old adult. I thought it would be
decades from now. Like I felt like for whatever reason we had to
wait decades for the science to sort of catch up to him.


So, we were very, very grateful. It felt very validating, I
guess. I had always kind of had this intuition feeling that we
were sort of missing something and it’s more that the science
just hadn’t quite caught up yet. But, you know, it was validating
to know that okay, Lars is not the only person in the entire
world with this, it is something that is relatively common in
fact within the rare disease community. That is also very
exciting to me personally because I’m hopeful that that will lead
more researchers to be interesting in this, given how, quote on
quote, common it is. I’ve sort of been describing it as like a
mass diagnosis event but also more so this feeling that like
we’ve been on this deserted island for eight years and now all of
a sudden, you’re sort of like looking around through the branches
of the trees. It’s like, wait a minute, there are other people on
this island ad in this case, there's actually a lot more people
on this island.


Yeah, it’s very exciting, it’s validating. It gives us a lot of
hope. And, you know, it has been quite emotional too and also a
bit of an identity shift. Because I spoke earlier about how like
being undiagnosed had become quite a big part of our identity.
So, now that's kind of shifting a little bit that we have this
new diagnosis and are part of a new community. But yeah, we’re
just very grateful that the research had continued. And, you
know, I think sometimes you sort of have this feeling of okay,
our files are up on a shelf somewhere, you know, collecting dust
and are people really looking at them? And actually, it turns out
that the research was ongoing and yeah, we’re just very grateful
for that.


Naimah: Thanks so much for sharing, Lindsay. It sounds like it’s
been a real rollercoaster of emotions for your family and I’m
glad to hear that, you know, you’ve got some hope now that you’ve
got a diagnosis as well. So, moving onto the next question. Emma,
I wanted to ask you then, how will these findings improve
clinical diagnostic services for those for neurodevelopmental
conditions?


Emma: So, you asked me earlier about why it had taken so long to
find this particular cause of neurodevelopmental condition, and I
gave you a relatively simple answer. The reality is one of the
other reasons is that almost eight out of ten children and adults
who have RNU4-2 related neurodevelopmental condition have exactly
the same single letter spelling change in that gene. So, actually
that in itself means that when researchers are looking at that
information, they might think that it’s actually a mistake.
Because we know that when we sequence genetic information, we can
see mistakes in that sequencing information that are just because
the machine has, and the way that we process that data, it’s not
perfect. So, sometimes we find these little mistakes and they’re
not actually the cause of a person’s problems, they’re just what
we call an artefact or an issue with the way that that happens.


So, that is part of the reason for why it was tricky for us to
know whether this was, or rather the researchers to know whether
this was or was not the cause of this particular condition. But
that in itself is quite helpful when we think about how we might
identify more people who have this going forwards. Because unlike
in Lars’ case where we didn’t know what the cause was and so we
were still searching, and we didn’t know where to look in the
billions of letters that make up the genetic code to find that
answer, we now know that this is really very common. It’s
unbelievably common. I think we didn’t think we would be finding
a cause of a rare genetic condition that was this commonly
occurring at this stage. But the fact that it’s just a single,
it’s commonly this one single change in the gene means that we
can set up pretty cheap diagnostic testing. Which means that if
you were somewhere where you wouldn't necessarily have access to
whole genome sequencing, or a more comprehensive testing in that
way, we could still be able to pick up this condition. And it’s
common enough that even if you didn’t necessarily recognise that
a person had it, you could still have this as part of your
diagnostic tool kit for patients who have a neurodevelopmental
condition. It’s common enough that just doing a very simple test
that could be done in any diagnostic lab anywhere in the world,
you would be able to identify the majority of people who have
this.


Naimah: Now let’s hear from the other research group who are
responsible for these findings. Here is Dr Andrew Mumford.


(Clip - Dr Andrew Mumford)


Naimah: Why are these research findings significant?


Andrew: It offers genetic diagnosis not just for a handful of
families but potentially for many hundreds of families, who we
all know have been searching often for many, many years for a
genetic diagnosis. But actually, there are other gains from
understanding how this gene causes neurodevelopmental disorder.
We know that there's GRNU4-2 in codes, not a protein actually,
but a small nuclear RNA which is unusual for rare, inherited
disorders. It’s a component of a very complicated molecule called
the spliceosome which in turn regulates how thousands of other
genes are regulated, how they’re made into proteins. So,
fundamentally this discovery tells us a lot about the biology of
how the spliceosome works. We already know that some other
components of the spliceosome can go wrong, and result in
diseases like neurodevelopmental disorders. This gives us an
extra insight and actually opens the door to, I hope, a whole
load of more discoveries of genetic diagnosis possible from other
components of this complicated molecule.


Naimah: Your research group used a mathematical modelling
approach. Can you tell me a bit about this, and what this means
for other rare conditions, Andrew?


Andrew: So, identifying relationships between changes in
individual genes and different kinds of rare, inherited disease
is notoriously difficult because of the volume of data that's
involved and the need to be absolutely certain that observed
genetic changes are actually the cause of different rare,
inherited disease. So, applying statistics to that kind of
problem isn’t new. But what my collaboration group have achieved
here, is to develop, actually developed some years ago a
completely new approach to applying statistics to genetic data.
We call that BeviMed and we’ve been working for many years on the
genes in code that make individual proteins. Most rare disorders
are caused by genetic changes in genes that make proteins.


What this discovery comes from is actually we’ve applied the
BeviMed statistical technique to genes that don’t make proteins,
they’re non-coding genes. For example, genes that make small
nuclear RNA, it’s just like RNU4-2. What's unusual about the
BeviMed approach is that it’s very sensitive to detecting links
between genetic changes and rare diseases, and it can detect
statistical associations really driven by very, very small
numbers of families.


So, we apply it to datasets like the 100,00 Genomes dataset and
identify associations using statistics that have got a very high
probability of association. Other members of the team then seek
to corroborate that finding by looking at if we can see the
association in other datasets, and we certainly achieve that with
RNU4-2. But also, assessing biological plausibility by
investigating what we understand already about in this case, a
small nuclear RNA, and how it can possibly result in a disease.
And we normally try and employ other independent evidence such as
experimental investigation. Or going back to our families and
asking for additional data to help really test this sort of
theory that changes in this particular gene have resulted in a
problem with neurodevelopment.


(End of clip)


Naimah: Emma, are there any other ways that we can identify these
conditions based on their clinical presentation?


Emma: So, Lindsay and I were talking with you just yesterday,
wasn’t it? And I asked Lindsay about what sorts of things Lars
had in common with other children and adults who have been
diagnosed with this condition? I actually think Lindsay probably
gives a better summary than I would, so I might ask you to maybe
repeat what you said to me yesterday. But the bit of it that
really stood out to me was when you said to us that a lot of
parents have said, ‘I'm not sure how we weren’t all put together
in the first place because you notice so many things that were in
common.’ So, maybe if you can give that summary and then I can
translate that back into medical terms, if that’s okay Lindsay.


Lindsay: Sure, of course. Yeah, it been again, kind of mind
blowing, some of the similarities. Especially as we’ve exchanged
pictures and such, and baby pictures especially where some of the
children like look like siblings. So, definitely some
similarities in facial features, you know, everyone seems to
experience some of the slow growth, so a short stature or quite
skinny. There's feeding issues also that seem to be quite common.
Also, you know, things like the global developmental delays,
that's certainly across the board and histories of seizures,
that's also quite common. Some people have experienced also some,
like, bone density issues, that's not something that we’ve
experienced so far, but that also seems to be quite common.


But then also, behaviourally, there's a lot of similarities which
has been, I think, quite exciting to a lot of us because you’ve
always thought okay, so this is just my child. And of course,
some of that is true but it’s also interesting to find out some
of these other things that are, you know, are quite similar. So,
a lot of people have mentioned their child having, like, an
interesting sense of humour. Kind of like a very slapstick sense
of humour which is quite interesting. Or everyone seems to love
water, everybody loves swimming pools and bathtime, and all of
that. Lars loves a windy day. Something about the wind, he just
loves it and plane noises and things like that have also come up
with other people. So, yeah, it’s been really interesting and
cool to see.


Emma: So, I guess Lindsay’s sort of very beautifully summed up
what is written in the research publication. So, there's only two
research publications so far on this condition, it’s all really
new. And I am definitely not claim to be a clinical expert on
this condition, and I don't think there are any yet. It will take
people time to see lots of children and adults who have this
particular condition. But ultimately what Lindsay summarised was
the common clinical features that have been described by parents.
In my job as a clinical genetics doctor, part of what we look at
is a person’s appearance. So, Lindsay described the photographs
of children particularly when they were little, looked very
similar. In the photographs that I’ve seen, I would agree with
that. And so obviously those children look like their mum and
dad, but they have other features that are in common. They have a
characteristic appearance and that helps doctors like me to have
an idea as to whether a child or an adult might have a particular
condition.


Then put together with the sorts of information that Lindsay gave
us around the low tone, so being a little bit floppier
particularly when they’re little. The slow growth and growth
problems, problems with eating, also with seizures. Those are all
common things that were pulled out of both of the two research
publications on this condition and putting that all together into
one picture helps doctors to have an idea whether somebody may
have a particular condition. That would help us in this case to
potentially request that simple test I was talking about, if
maybe we were practicing in a part of the world where we wouldn't
have the resources that we thankfully do have in the United
Kingdom, and in the USA.


Naimah: So, Sarah, just coming to you next. How does this
research spread awareness and help other patients with these
conditions?


Sarah: So, I think one of the things that's been really great
about research now is that we are able to, you know, social media
and things like that mean that we can spread this information
really quickly across the world basically. I think what that does
is that as well as helping bring people together that they’ve got
this diagnosis, what it does is I think it provides hope for all
of those people that Lindsay was talking about at the beginning
who don't have a diagnosis. So, that piece around people are
still looking, the researchers are working hard and that even if
you don't have a diagnosis today you might get one in the future.
Lindsay talked about your sample being dusty and not being looked
at. I think it gives lots of families, not just those that get
this diagnosis but all of those that haven’t got a diagnosis,
hope, that hopefully in the future they will get a diagnosis.


I think one of the things we really hope will come out of
diagnoses like this is that we will then be able to build up more
of that picture about how families are affected. So, that we can
give families more information about not only how their child is
affected but how they might be affected in the future. That
prognosis information that Linsday said is really missing when
you don't have a diagnosis. And I think the other thing that
hopefully is the next stage in this journey with this discovery
is that those two science publications that Emma talked about,
what we will want to do here at Unique working with the
researchers and those families that have got a diagnosis, is to
produce a patient family friendly information leaflet about this
condition.


One of the things we know is really important about those patient
leaflets is including the photos. Because as both Emma and
Lindsay have said that idea that they have facial features in
common. And so, if you look at a leaflet and you can recognise
your child in it, and you can see others that look like it, that
can be a really sort of quite heartwarming experience in what
often is a lonely experience with a rare condition.


Naimah: And I think kind of on that point about it being a lonely
experience, I wondered Lindsay if you could talk a bit more if
this research has allowed you to connect with other parents and
families who have received a diagnosis, and what impact that's
had on your family?


Lindsay: Yeah. I mean, and I think everything that Sarah has said
was spot on. It’s wonderful to have resources like Unique to
connect families and have those diagnoses on the platform, so
other clinicians can look for it and sort of grow this group. I
think that has definitely been the highlight of getting this
diagnosis at this stage, right. Because there's not much more you
can do with it, with someone so brand new so being able to
connect with the other families has been wonderful. One amazing
mum who with this diagnosis set up a Facebook group, RNU4-2
Family Connect. And, you know, it’s just been amazing to see
people from all over the world joining this as they receive this
diagnosis, you know, sharing their stories. We’ve spent countless
hours on the weekends over the past couple of months on Zoom
calls with total strangers, but just you find that you can just
talk for hours and hours because you have so much in common.


It’s great to see what has worked well for other families and,
you know, what has not worked. Sharing resources, just kind of
all learning together. Also seeing the spectrum of this
diagnosis, I think most genetic disorders have a spectrum and
this seems to be the same here. So, that's been very interesting.
And of course, our son is 8, Lars is 8. There's now a 33-year-old
and a 29-year-old in the Facebook group. Speaking for me
personally it’s just amazing to see them and like it’s very cool
to see where they’re at. That sort of helps you answer some of
those questions about that before were quite unknown when you
were thinking about the future. Obviously, everybody’s
development whether you have a genetic disorder or not, it is
going to be what it’s going to be, and everybody is going to do
their own thing. But being able to see what a path might look
like is just so helpful. And, you know, we all want community and
connection, and so this has been really, really great to have
that now.


Sarah: I don't think there's much more that I can add because
Lindsay articulated so well. But it’s really heartwarming for us
to hear the benefits of those connections because that's really
why Unique and other support groups exist. Is to provide, partly
to provide information, but I think predominantly to put families
in touch with other families so that they can find a new home and
connect and share experiences. And, you know, stop feeling as
alone as they might have done before.


Naimah: Okay, we’ll wrap up there. Thank you to our guests,
Lindsay Pearce, Sarah Wynn and Emma Baple for joining me today as
we discussed the research findings which found a genetic change
in the RNU4-2 gene which has been linked to neurodevelopmental
conditions. If you’d like to hear more like this, please
subscribe to Behind the Genes on your favourite podcast app.
Thank you for listening. I’ve been your host and producer, Naimah
Callachand, and this podcast was edited by Bill Griffin of
Ventoux Digital.