Researcher on the rise: Alfredo Dueñas Rey
A look into rare causes of sight loss
By Florence Cornish on
Researcher Alfredo Dueñas Rey shares how data from the National Genomic Research Library helped him to find genetic causes of rare inherited eye conditions.
My focus is inherited retinal conditions
I'm originally from Spain, but I did my Bachelor’s degree in Stockholm, Sweden. I then moved to Lund where I studied a Master’s program in molecular genetics.
Following this, I began a PhD under a Marie Curie Innovative Training Network fellowship, and since then I have been a PhD student at the Center for Medical Genetics in Ghent, Belgium.
My research focuses on inherited retinal conditions, specifically looking for rare genetic causes. Initially I focussed on a specific type of blindness caused by a specific gene, before expanding to study retinal diseases more broadly.
This is when I first started using larger datasets such as the National Genomic Research Library (NGRL).
A difficult task at hand
The field is very complicated, it was all new to me before I began my PhD. I think there can be a misconception that there is only one type of inherited retinal disease, but actually there are so many.
The genetics behind these conditions is very complex. There are thousands of genetic changes across hundreds of genes that are known to be linked with inherited retinal disease. Often, different genetic changes can result in similar symptoms, so it’s hard for doctors to know exactly what they’re looking at.
Finding the genetic cause is really like looking for a needle in a haystack, which sounds like a cliché, but it is really true.
A deeper dive into my research
Genes are small sections of DNA that carry the information we need to build a particular protein.
Within each gene, there are regions that regulate whether the gene is turned on or off, similar to a light switch. One of these regions is called the 5’UTR.
The information carried in 5’UTRs does not get turned into a protein. Instead, it fine tunes the level of protein being made.
In routine genetic testing, 5’UTRs are rarely looked at. This is because interpreting genetic changes within these regions can be very challenging
For my research, we wanted to better understand how genetic changes in 5’UTRs can cause inherited retinal conditions in patients.
We started by defining how to categorise these genetic changes, and how we could interpret them. We then applied this to a group of patients who had inherited retinal eye conditions.
Finding the genetic cause is really like looking for a needle in a haystack, which sounds like a cliché, but it is really true."
Alfredo Dueñas Rey
Interesting findings on sight loss
We found 11 different genetic changes in 5’UTRs that were likely to be linked to inherited retinal disease. We then confirmed these with additional experiments.
A particularly interesting finding we made was from a family in the 100,000 Genomes Project, who had already received a genetic diagnosis. The problem was, researchers and clinicians couldn’t fully understand how the identified gene was actually causing their retinal condition.
From our research, we discovered that the identified gene carried a disease-causing genetic change in its 5’UTR. We looked at 10 other families who had all received the same genetic diagnosis as the first family, and found that all of them had the same genetic change in the 5’UTR as well.
Many standard tests don’t look at 5’UTRs, which is why previous testing didn’t pick it up. However, it is most likely that the faulty 5’UTR was affecting normal protein production, in turn causing problems with vision.
The aim of my research is to bring answers to patients
The ultimate aim of this research is for 5’UTRs to not be overlooked in routine diagnostic testing. I believe this would increase the number of patients receiving a genetic diagnosis for their condition.
From our observations, these variants are very rare. They appear to be a rare cause of rare a condition, but that's not a reason why they should be neglected.
We want to add more ways in which genetic variation can be looked at, and improve the number of diagnoses we can deliver. Especially in the inherited retinal disease field, where we are at the forefront of genetic therapy.
The impact of a diagnosis
Having a diagnosis opens so many doors for potential treatment. To be eligible for genetic therapies, you most often need a very accurate molecular diagnosis.
An example of this is gene augmentation therapy. This is when a functioning version of the faulty gene is added back into the cells. But of course to get this therapy, we must be absolutely sure which gene has to be replaced.
Not only is it important for treatment, but a diagnosis or a name for a condition is a big milestone for patients in other ways. It helps with acceptance, but also the community aspect, finding other patients with the condition and becoming a part of support networks.
It is also helpful to know whether the condition is likely to re-occur in the family. This gives people the option of genetic counselling and lets them plan ahead for the future.
Though using data from the 100,000 Genomes Project wasn’t in my initial research plan, it became absolutely essential. Not only the genomic data, but also the clinical information that was linked with it all."
Alfredo Dueñas Rey
The value of the 100,000 Genomes Project
Data from the 100,000 Genomes Project was critical for our research.
We initially began our project using in-house data generated from routine testing. However, this data only covered a fraction of the genome, and the regions I wanted to evaluate had not been included.
This is when I knew I needed to use data from whole genome sequencing.
Though using data from the 100,000 Genomes Project wasn’t in my initial research plan, it became absolutely essential. Not only the genomic data, but also the clinical information that was linked with it all.
What’s up next for me?
For now I’m just focussed on finishing my PhD, and then I will consider the possibilities. What I know for sure is that I would like keep working with genetic conditions, genetic data, and in particular for rare conditions, regardless of whether it's in academia or industry.
The work I have done with genetic data and data analysis has really been what I am most interested in, and what I really hope to continue with.
My message to other researchers
I am constantly recommending Genomics England. I talk to my colleagues about it all the time, saying they should get access to data from the 100,000 Genomes Project.
There are so many possibilities, not only for rare diseases, but also the cancer dataset is so remarkable for research.
I would like to continue working with data in the NGRL in the future.
And finally…
I would like to thank the main funding body supporting my PhD, the EU-funded Marie Curie Skłodowska-Curie Actions Doctoral Network, more specifically StarT.
To read about the research in more detail, check out the full paper on 5’UTR variation in inherited retinal diseases.
To stay up to date with the Genomics England Research Community, take a look at our other blogs, or check out the support available for early career researchers.
