Dr Gavin Arno, Kate Arkell, Bhavini Makwana and Naimah Callachand: Can genomic research close the diagnostic gap in inherited sight loss?

In this episode, our guests explore the impact of genetic
discoveries on inherited retinal dystrophies, in particular
retinitis pigmentosa (RP). The discussion highlights a recent
study that identified two non-coding genetic variants linked to
RP, predominantly in individuals of South Asian and African
ancestry.


The conversation highlights how advances in whole genome
sequencing are uncovering previously hidden causes of genetic
disease, improving diagnostic rates, and shaping the future of
patient care. It also addresses the challenges faced by
individuals from diverse backgrounds in accessing genetic
testing, including cultural barriers, awareness gaps, and
historical underrepresentation in genomic research.


Our host Naimah Callachand is joined by researcher Dr Gavin Arno,
Associate Director for Research at Greenwood Genetic Centre in
South Carolina, Kate Arkell, Research Development Manager at
Retina UK, and Bhavini Makwana, a patient representative
diagnosed with retinitis pigmentosa and Founder and Chair of BAME
Vision. We also hear from Martin Hills, an individual diagnosed
with autosomal dominant retinitis pigmentosa.


To access resources mentioned in this episode:


Access the Unlock Genetics resource on the Retina UK website

Visit the BAME vision website for more information and
support

Find out more about the groundbreaking discovery of the
RNU4-2 genetic variant in the non-coding region which has been
linked to neurodevelopmental conditions in our podcast episode



 


"Discoveries like this lead to better clinical management. We
understand better the progression of the disease when we can
study this in many individuals from a wide spectrum of ages and
different backgrounds. We can provide counselling as Bhavini was
talking about. We can provide patients with a better idea of what
the future may hold for their eye disease, and potentially, you
know, we are all aiming towards being able to develop therapies
for particular genes and particular diseases."


 


You can download the transcript or read it below.


Naimah: Welcome to Behind the Genes.  


Bhavini: The few common themes that always come out is that
people don’t really understand what genetic testing and
counselling is. They hear the word counselling, and they think it
is the therapy that you receive counselling for your mental
health or wellbeing. There is already a taboo around the
terminology. Then it is lack of understanding and awareness or
where to get that information from, and also sometimes in
different cultures, if you have been diagnosed with sight loss,
you know blindness is one of the worst sensory things that people
can be diagnosed with. So, they try and hide it. They try and
keep that individual at home because they think they are going to
have an outcast in the community, in the wider family, and it
would be frowned upon). 


Naimah: My name is Naimah Callachand and I am Head of Product
Engagement and Growth at Genomics England.  I am also one of
the hosts of Behind the Genes. On today’s episode I am joined by
Gavin Arno, Associate Director for Research at Greenwood Genetic
Centre in South Carolina, Kate Arkell, Research Development
Manager at Retina UK, and Bhavini Makwana, patient
representative.  Today we will be discussing findings from a
recently published study in the American Society of Human
Genetics Journal which identified two non-coding variants as a
cause of retinal dystrophy in people commonly of South Asian and
African ancestry. If you enjoy today’s episode, we’d love your
support. Please like, share, and rate us on wherever you listen
to your podcasts. 


Okay, so first of all I would like to ask each of the three of
you to introduce yourselves. Bhavini, maybe we’ll start with
you. 


Bhavini: Hi, I’m Bhavini Makwana, patient representative, and
also Chair of BAME Vision. I have other roles where I volunteer
for Retina UK, and I work for Thomas Pocklington Trust. 


Naimah: Thanks Bhavini. Gavin. 


Gavin: Hi, my name is Gavin Arno, I am Associate Director for
Research at the Greenwood Genetic Centre in South Carolina, and I
am Honorary Associate Professor at the UCL Institute of
Ophthalmology in London. 


Naimah: Thanks Gavin. And Kate.  


Kate: Hi, I’m Kate Arkell, Research Development Manager at Retina
UK.  


Naimah: Lovely to have you all today. So, let’s get into the
conversation then. So Gavin, let’s come to you first. First of
all, what is retinitis pigmentosa and what does it mean to have
an inherited retinal dystrophy? 


Gavin: So, retinitis pigmentosa is a disorder that affects the
retina at the back of the eye. It is a disease that starts in the
rod photoreceptor cells. So, these cells are dysfunctional and
then degenerate causing loss of peripheral and night vision
initially, and that progresses to include central vision and
often patients will go completely blind with this disease. So,
retinal dystrophies are diseases that affect the retina. There
are over 300 genes known to cause retail dystrophy so far, and
these affect different cells at the back of the eye, like
retinitis pigmentosa that affects the rods. There are cone rod
dystrophies, ones that start in the cone photoreceptors, macular
dystrophies that start in the central retina, and other types of
retinal dystrophies as well. 


Naimah: Thanks Gavin. And Bhavini, just to come next to you. So,
you received a diagnosis of retinitis pigmentosa at the age of 17
after a genetic change was found in the RP26 CERKL gene. At this
time only ten other families in the UK had been identified with
this type of genetic alteration. Would you mind sharing a bit
more about your journey to your diagnosis? 


Bhavini: Yeah. So, at the age of 17 is when I got officially
diagnosed with retinitis pigmentosa, but leading up to that I was
experiencing symptoms such as night blindness. So, I struggled
really badly to see in the dark, or just in dim lighting, like
this time of the year in winter when it gets dark quite easily,
all my friends from college could easily walk across the
pavement, but I struggled. I was bumping into a lot of things.
Like things that I wouldn’t really see now that I know my
peripheral vision, I was losing that, so like lamp posts or trees
or bollards, I would completely miss or bump into them. I was
missing steps, and had a really, really bad gaze to the sun.
Like, everything was really hazy. That continued and I just put
it down to stress of exams. You know, just given that age and
where I was at the time of my life. But then it kind of
continued. So, I went to the see the optician who then referred
me, and after months of testing I got diagnosed with retinitis
pigmentosa. Back in the late 90s when I was diagnosed there
wasn’t really anything about genetic testing, or cures., or
treatments. I was basically just told to get on with it, and that
was it.  


It was only until about 15/16 years later I came across Retina
UK, started understanding what retinitis pigmentosa is, and what
it means, and then when I was offered genetic testing and
counselling at one of my annual Moorfields appointments, they
explained to me what it involved, what it could mean, what kind
of answers I would get, and I agreed to take part. It was a
simple blood test that myself and both my parents took part
in.     


Naimah: Thanks for sharing that Bhavini. So, I know you were able
to receive a diagnosis through whole genome sequencing in the
100,000 Genomes Project after the alteration in the gene was
found, and this was found in the coding region of the genome. But
in this study that we are talking about in this podcast, we know
that the two genetic changes that were found, they were in the
non-coding region of the genome. Gavin, could you tell me in
simple terms what the difference is between the coding and
non-coding region of the genomes and why these findings are
significant in this case?  


Gavin: Yes, sure. So, the human genome is made up of about 3
billion letters or nucleotides which are the instructions for
life essentially. Now, within that human genome there are the
instructions for roughly 20,000-25,000 proteins. This is what we
call the coding genome. These are the bits of DNA that directly
give the instructions to make a protein. Now, we know that that
part of the genome is only roughly 2% of the entire genome, and
the remaining 98% is called the non-coding genome. Now, we
understand that far less well. We have a far poorer understanding
of what the function of the non-coding genome is versus the
coding genome. So, typically molecular diagnostic testing or
genetic testing is focused on the coding genome, and historically
that has been the fact. Now with advances in genome technologies
like whole genome sequencing and the 100,000 Genomes Project, we
are able to start to look at the non-coding genome and tease out
the previously poorly understood causes of genetic diseases that
may lie within those regions of the genes.  


Naimah: Thanks Gavin, I think you have just really highlighted
the possibilities available with looking at the non-coding region
of the genome.  Kate, coming to you next. I wanted to talk
about the importance of uncovering and understanding genetic
causes of inherited retinal dystrophies, and how do discoveries
like these change the landscape of care for patients with
inherited retinal dystrophies? 


Kate: So, getting a genetic diagnosis can really help families
affected by inherited retinal dystrophy. It helps them and their
ophthalmologists to better understand their condition, and in
some cases gain some insight into possible prognosis, which helps
people feel a lot more in control. It can also potentially inform
family planning decisions and even open up options around access
to reproductive technologies for example, not only for the
individual, but sometimes also for their close relatives. Of
course, researchers are making great strides towards therapies,
some of which have reached clinical trials. But a lot of these
approaches are gene specific, so for people who know their
genetic diagnosis, they are more able to recognise research that
is most relevant to them and quickly pick out potential
opportunities to take part. At the moment it is still the case
that around 30% of our community who have a genetic test will not
receive a clear result, and that can feel very frustrating. So,
the more discoveries like this that are made, the
better.  


Naimah: Thanks Kate.  So, now we are going to hear a clip
from Martin Hills, our Retina UK patient representative who has
been diagnosed with autosomal dominant retinitis pigmentosa.
Martin has undergone genetic testing and shares more about his
experience. 


Martin: My name is Martin Hills, and I was officially diagnosed
with autosomal dominant retinitis pigmentosa in 2001, and because
of that I immediately had to stop driving which made a huge
impact both on myself and my family.  My eyesight has slowly
deteriorated over the years. It first started with difficulty
seeing at night, and also playing some types of sport, which I
think probably was in my 20s. My peripheral vision has been lost
slowly and now has completely gone. Fortunately, I still have
some reasonable central vision left which is a great help. I am
registered as severely sight impaired, and I am also a symbol
cane user. My father and aunt were both diagnosed with this
condition, and my daughter has been relatively recently, as has
altogether eight members of our wider family, and that also
includes two younger generations. In 2015 I went for genetic
counselling and testing and at that time it was for 176 genes
known to be associated with retinal dystrophies. I believe that
has now gone up to about 300, but at the time they couldn’t
recognise what my faulty gene was, and that has still been the
case to my knowledge to date.  


I have also been part of the 100,000 Genome Project along with
several others of my wider family, and I am also a participant in
the UK Inherited Retinal Dystrophy Consortium RP Genome Project,
which has been sponsored by Retina UK. The impact of not having a
positive genetic test result is quite interesting and has really
been a rollercoaster. I guess it is all about hope, and to start
with when I knew I was going to be genetically tested, I think my
first reaction was optimism, and I think if you have a positive
test result, that is a real hope for the future. I think that is
quite exciting particularly as things seem to be progressing so
rapidly. But because I didn’t get a positive result, the next
reaction I had really was disappointment because I felt one step
behind people with a positive result. Of course the natural
reactions are one of frustration, and then I guess followed by
realisation of the situation, and heading towards trying to
adjust and making coping strategies for the future.  I still
feel that genetic testing for all forms of medical conditions is
so important and has a huge future in understanding and then
potential treatments for so many medical issues. I guess it might
be a bit too late for me, but if I can contribute to finding a
restorative treatment for the younger generations of my family,
and for that matter other people, then I think that is good
enough for me.  


Naimah: So, we have just heard from Martin that although he has
not been able to have a positive genetic test result, his
involvement in various studies may have benefits in helping
others find treatment. So, I guess on that point Bhavini, maybe
you could comment, or ask you how you felt whenever you were
about to get a diagnosis through whole genome sequencing? 


Bhavini: Yes. When I got called in almost three and a half years
after the testing that took place was a massive, massive relief
because not only did I get genetic counselling before the testing
period, but I got called in and I spoke to a genetic counsellor
who explained what they had been able to find and what kind of RP
it was, how it would progress, and just answer so many questions.
I am the mother of two daughters and even having two children, I
lost a lot of sight after my first daughter, but at that time
there wasn’t any evidence or there wasn’t any … you know, there
was nothing I even knew about what questions to ask or anything,
so I did go on to have a second child and drastically lost more
sight. I had always been told, because the lack of awareness and
understanding of RP in my family, and I am one of four children,
and I am the only one that has it, so there is no other family
history. Now I know it could have skipped generations, but I was
always told things like it was karma. I must have done something
in my past life. I was told to kind of have these herbs or these
remedies to cure my sight loss, you know my RP. I was even
desperate enough to kind of …  all these bogues treatments
that you find online. You know, anything. I was so desperate to
find anything that would help me.  


When I received that testing and the counselling, it explained so
much about how my daughters may or may not be affected, how they
are carriers, and that was explained to me, how it would
progress. So many questions and worries that I had for almost a
decade and a half, they were answered. And not only for me, for
my family, and all those people that told me all these sorts of
things that I used to worry about that could have caused my RP. I
was able to explain it to them and they understood that it was
nothing to do with me being bad in my past life. It was actually
you know, there is something scientific about it. So, it kind of
gave me lots and lots of answers, and actually I then created a
private Facebook page just with my RP26 CERKL genetic that I have
been diagnosed with, just to see if there is anybody else out
there, because when I was diagnosed, I think at the time I was
told there was only myself and nine other families in the UK
diagnosed with this particular gene. Now, I haven’t been that
active on it, but you know there are people across the world who
found my post and joined the group, and we share experiences
about the age that we were kind of diagnosed, the kind of rate
the symptoms have developed. It is so fascinating because we have
got such similar experiences.  


There is parents on there who are there on behalf of their
children, and it is just so nice to see … I know it is RP, but
the specific gene and the rate of which we have experienced all
the symptoms, it is quite similar. So, it has been quite
supportive and helpful and reassuring to my family including my
daughters. 


Naimah: That’s incredible Bhavini and it’s really nice that you
have created that group and created kind of like a support
network for all the other families that have been affected by the
same genetic condition as well. Yeah, that’s incredible. Gavin, I
know the findings in the study show that the genetic changes in
this study are more common in people of African and South Asian
ancestry. So, so I want to understand why is this an impactful
finding in the study? 


Gavin: Yes, so Kate mentioned that around 30% of people with
inherited retinal dystrophies who have genetic testing don’t get
a molecular diagnosis and we are working in my research lab and
many other research labs to improve that. Now, that figure is
very much higher in patients of for example African ancestry in
the UK, and this is partly due to the fact that historically and
even now genetic studies have been focused on European
individuals and taken place in the US, and the UK, and Europe,
and wealthy countries across the world. This means that people of
African ancestry are poorly represented in genetic studies, not
just genetic studies of genetic disease, but population studies
as well. So, we have less of an understanding of the genetic
variants found in the genomes of individuals of African ancestry.
So, that means we solve less of the genetic cases, particularly
at Moorfields we published a paper on this several years ago with
the diagnostic rates in European patients versus those of African
ancestry, and it was very, very much lower. So, we need to do
better for those patients, and this study identified a cause of
retinitis pigmentosa in 18 families of African ancestry who were
recruited to the 100,000 Genomes Project.  


This is a fairly large proportion of the patients with RP of
African ancestry seen at Moorfields Eye Hospital, and when we
contacted collaborators around the world many more families were
identified, and I think we ended up publishing around about 40
families who were affected by this particular mutation. So, we
can look at that variant, we can look at the DNA sequence around
that variant, and we found there is a chunk of DNA around the
mutation in the gene that was coinherited by all of those
different individuals. So, this is what we call an ancestral
haplotype. It’s an ancient variant that goes back many, many
generations and it has a fairly high carrier frequency in genomes
of African ancestry. So, we think this will be a fairly
significant cause of retinitis pigmentosa across the continent of
Africa. And so, identifying it will enable us to provide a
molecular diagnosis for those families. Potentially there will be
many more families out there who don’t know they have this cause
of disease yet. They may be affected but they haven’t yet
received genetic testing.  


But discoveries like this lead to better clinical management. We
understand better the progression of the disease when we can
study this in many individuals from a wide spectrum of ages and
different backgrounds. We can provide counselling as Bhavini was
talking about. We can provide patients with a better idea of what
the future may hold for their eye disease, and potentially you
know we are all aiming towards being able to develop therapies
for particular genes and particular diseases. As Kate mentioned
many of the gene therapies are gene specific, so if we identify a
cause of disease that is predominant like this and affects many,
many people, then of course there is more interest from the
pharmaceutical industry to develop a therapy for that specific
gene. 


Naimah: Thanks Gavin. I think that really does showcase how
impactful these findings really are. Kate, can I come to you. So,
Gavin touched on it there that people with African and Asian
ancestry are significantly less likely to get diagnosed, but why
is it important to ensure that these groups are represented in
the genomic datasets? 


Kate: So, we need to ensure that genetic testing and diagnostic
accuracy works for everyone, and not just those of European
ancestry. So, as Gavin said if the datasets don’t reflect the
genetic variations seen in African or Asian populations, then the
tests based on those data are more likely to give incomplete
results for those groups of people. We really need a diverse
range of genetic information for researchers to work on. As it is
clear from this study’s results, populations from African
backgrounds for example may have unique genetic mutations linked
to retinal dystrophy. So, if those are really underrepresented in
datasets based on European populations, that is obviously going
to present a problem. Gavin mentioned access to treatment. We
need to overcome some of these disparities in healthcare access,
and   inclusion of broad spectrum of genetic data is
actually a foundation for that.  


Naimah: Thanks Kate. 


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Naimah: So underrepresented groups are often less likely to know
about genetic testing due to a combination of social economic and
systemic factors that create barriers to access information.
Cultural taboos can also play a significant role in shaping
attitudes towards genetic testing, and I think Bhavini you kind
of touched on this slightly with some of your experiences. I
wonder, did you experience any of these cultural taboos? 


Bhavini: Yes, some of them, but I think by the time I was
informed about what genetic testing and counselling is I had come
across Retina UK and I had already started having that background
knowledge, so when that was offered to me, I actually had a basic
understanding. But as Chair of BAME Vision I work with a lot of
ethnic communities, and when I speak about my own personal
experience about receiving genetic testing and counselling, I
kind of break it down into my own language, and the few common
themes that always come out is people don’t really understand
what genetic testing and counselling is. They hear the word
counselling, and they think it is the therapy that you receive
counselling for your mental health or wellbeing.  So, again
there is already a taboo around the terminology. Then it is lack
of understanding and awareness, or where to get that information
from. Also sometimes in different cultures, if you have been
diagnosed with sight loss, you know blindness is one of the worst
sensory things that people can be diagnosed with, so they try and
hide it. They try and keep that individual at home, because they
think they are going to have an outcaste in the community and the
wider family, and you will be frowned upon, people will talk
really bad.  


So, it is not really common knowledge, so they don’t even talk
about it. So, there is a lot of layers to unpick there. That is
one of the priority areas in 2025 that we at BAME Vision are
going to be working on to try and raise that awareness in
different communities about what genetic testing is, what it
could mean, how to get genetic testing if it is not offered to
you at your own clinic. There is a lot of work I know Retina UK
have done, so working with them, and how we can reach different
communities to raise that awareness. 


Naimah: That’s great. You have touched on how important the
education piece is. I wonder, do you have any other examples of
how healthcare providers and genetic counsellors might better
engage communities to ensure that they are receiving the care
that they need? 


Bhavini: Yeah, absolutely. So, I think having information in
different languages is essential, and I don’t expect to have lots
and lots of leaflets in different languages. Whether it is audio
form or whether there is different professionals within that
setting that speak different languages that can communicate to
those patients, or even their family or friends that could
translate. I think language is definitely something. And having
representation, so like different people who have accessed this
and sharing their story and going out into community groups and
sort of sharing those messages, is definitely what has been
working for us, and we have been doing that on other topics that
we have used. 


Naimah: Yes, they all sound like really important ways to try and
engage with different communities. You have already mentioned how
amazing that Retina UK have been and the support that you have
received from them. So, I wonder Kate, if you could tell us a bit
more about the support that is available for those with inherited
sight loss, and how these resources can support people from
underrepresented groups as well. 


Kate: So, we have a range of support services at Retina UK most
of which involve our fantastic team of volunteers, one of whom is
Bhavini, who are all personally affected by inherited retinal
dystrophy themselves. So, they are all experts by experience so
to speak. The team also does include members of the Asian
community as well. So, if somebody makes a call to our helpline,
they will be able to speak to somebody who genuinely understands
what they are going through, which can be a lifeline for those
who are feeling isolated and especially I think as Bhavini
mentioned, if they feel unable to talk openly with their own
family and certainly within their community. We have a talk and
support service that offers ongoing more regular telephone
support as well as in-person and online peer support groups where
people can make social connections with others in similar
situations. I think Bhavini has mentioned that she herself runs
our London and Southeast local group.  We also have an
information resource called Unlock Genetics. That explains
genetics in understandable language and clearly explains how
people can access testing and what that will involve. So, we have
stories on there from people who have gone through the process
and talk about that. So, that is available on our website, and we
can provide it in audio format as well. 


Naimah: So Gavin, looking to the future, what does this research
mean for patients with sight loss and their families? What does
this mean in the future? 


Gavin: So, I think now that we have access to whole genome
sequencing through projects like the 100,000 Genomes Project, we
are able to start the process of understanding new causes of
disease that are found outside of the coded region.  So, we
can now look for non-coding variants that cause disease which was
previously not possible because genetic testing was focused on 2%
of the genome. As we make discoveries like this these will inform
future studies. So, the more we identify this type of variant and
are able to functionally test the effect on the gene or the
protein, we are able to use that information to lead future
tests. What this needs is large population datasets to be able to
analyse these sorts of variants at scale. The more genomes we
have the better our understanding will be of our population
frequencies, and the key thing is here for inherited retinal
dystrophies, all of these variants that we are identifying are
very, very rare. So, we only find them in a very small number of
individuals affected with disease, and an infinitely smaller
number of individuals in the unaffected general population. So,
the larger that population dataset is that we can study, the
better we can understand the rarity of these variants and pick
those out from the many, many millions of non-pathogenic or
harmless variants that we find in the genomes of all the
individuals. 


Naimah: Do you think the paper will help lead the way for
diagnosis of other conditions in African and South Asian
communities?   


Gavin: Yes. The better we understand causes like this, and we are
now at the point where most of the genes that cause retinal
dystrophy have been identified already, so the remaining causes
to be identified will be these more difficult to find cases,
non-coding variants, structural variants, which we haven’t
touched on today which are larger rearrangements of the genome.
These things are harder to find, harder to interpret, so the more
that we find like this, the better our ability will be to
interpret those sorts of variants. There are many similar
findings coming out of genome studies like 100,000 Genomes
Project. For example, there was a significant finding recently
published on a non-coding RNU gene which causes a significant
proportion of neurological disorders in the 100,000 Genomes
Project. You need these studies to be able to drive forward the
research in areas like this.  


Naimah: Thanks Gavin, and the discovery that you are mentioning
is the RNU4-2 gene that was discovered earlier this year. You can
hear more about that on our other podcast on our website which is
‘How has groundbreaking genome work discovery impacted thousands
far and wide’ to learn more about that as well. But yeah, I agree
it is another really great example of how impactful these
findings can be.


Okay, we’ll wrap up there. Thank you to our guests Gavin Arno,
Kate Arkell, and Bhavini Makwana for joining me today as we
discussed the findings from a recent study which has identified
genetic changes responsible for retinal dystrophy, and people
commonly of South Asian and African ancestry. 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 have been your
host and producer, Naimah Callachand, and this podcast was edited
by Bill Griffin of Ventoux Digital.