Manchester discovery of two new genetic disorders improves diagnoses for patients with neurodevelopmental conditions
Two previously unknown highly frequent genetic disorders have been discovered by researchers in Manchester, paving the way for improved diagnosis of neurodevelopmental conditions and opening new doors for future treatments.
The groundbreaking discoveries come from a study delivered through the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (BRC) and could provide answers for several thousands of people with neurodevelopmental conditions around the world.
Since the breakthrough, 18-year-old Rose Anderson (pictured right) from Stretford in Manchester has received a diagnosis of one of the newly discovered conditions.
Rose has been known to the team at the Manchester Centre for Genomic Medicine at Manchester University NHS Foundation Trust (MFT) for nearly her whole life, although a precise diagnosis for her seizures and developmental delay has proved difficult to find.
On receiving the news from the Manchester research team last year, Rose’s mum Lyn said: “We felt excited and relieved to finally receive Rose’s diagnosis. Rose is a very happy person, and with any diagnosis, she will always be Rose to us. This has helped us pinpoint what has caused her to be the way she is.”
The study was supported by the MFT-hosted NIHR Manchester BRC, as part of its Rare Conditions Theme which aims to improve diagnosis of rare conditions.
Researchers from the NIHR Manchester BRC, MFT, and The University of Manchester (UoM) collaborated with scientists globally to analyse the genetic data of thousands of individuals including those who took part in the 100,000 Genomes Project, a Genomics England initiative to sequence and study the role genes play in health and disease.
Genes are sections of our DNA and contain the instructions for building proteins, which are needed by the body for cell growth and repair.
Parts of our genes that do not make proteins have previously been dismissed as ‘dark matter’ because they were not understood, or ‘junk DNA’ because it was thought they were not essential.
Published in Nature Genetics, Manchester researchers have challenged these assumptions, showing that changes in these regions play a crucial role in brain development.
The team found that mutations in regions of the genome that form R-loops (special DNA-RNA structures that can influence genetic activity) are more common than previously thought.
This insight led them to uncover two new neurodevelopmental conditions:
- RNU2-2-related disorder, which is linked to developmental delays, intellectual disability, small head size (microcephaly), autistic traits and seizures.
- RNU5B-1-related disorder, associated with developmental delays, weak muscle tone (hypotonia), larger-than-average head size (macrocephaly), and poor growth.
Neurodevelopmental conditions – disorders that affect brain development – impact 2-5% of people worldwide.
For many families, these conditions remain a mystery, as current genetic tests often fail to find a cause.
The two new conditions, along with ReNU syndrome (a condition which has an impact on learning, behaviour, speech and movement, identified in 2024 using data from Genomics England’s National Genomic Research Library) account for more than 1% of all unsolved developmental cases.
This means the breakthrough could provide a genetic explanation for several thousands of people globally with these conditions.
Rose’s story
Rose, who was diagnosed with RNU2-2-related disorder in October 2024, loves music, walking, swimming, visiting cafes and riding a tandem bike. She lives with her mum Lyn (pictured below right with Rose), dad Joe and younger sister, Lily.
At Lyn’s 20-week pregnancy scan, it was first suspected that Rose may have a rare genetic condition. Despite undergoing extensive genetic testing at MFT and taking part in research, the team had been previously unable to find a specific cause for Rose’s symptoms.
Lyn said: “You wonder if it’s just a random thing that has happened or parents sometimes look to themselves for the cause. Rose first started experiencing seizures when she was a baby – she would become flushed, very vacant and would loll her head to one side. After a bad seizure when she was 2 and a half years old, Rose was diagnosed with epilepsy. She occasionally has seizures now, but these are better managed with medication.
“When Rose went to nursery, younger children began overtaking her with early developmental milestones. Rose is non-verbal and is great at communicating using objects and symbols. She experiences hyperventilation (rapid breathing), can struggle with spatial awareness and needs support with eating and personal care.
This breakthrough is fantastic, and we hope it will lead to more families receiving a diagnosis now and when early symptoms first appear. This could help improve quality of life for other children and young people and find out what it is that makes them unique.
Rose and her family are working with the Manchester team to help them better understand RNU2-2 related disorder. Rose has also taken part in more research at MFT since receiving her diagnosis, including donating skin cells to help the team produce brain stem cells for epilepsy research.
Thanks to this research, Rose Anderson was able to receive a diagnosis of RNU2-2-related disorder last year.
Study lead and first author of the paper Dr Adam Jackson, Academic Clinical Fellow at the Manchester Centre for Genomic Medicine at MFT and The University of Manchester and early career researcher in the NIHR Manchester BRC’s Rare Conditions Theme, said: “By proving that non-protein coding genes play a key role in human health, this study challenges long-held assumptions about ‘junk DNA’ and brings hope to many families searching for answers.”
Dr Jackson, who is also part of the Manchester Rare Conditions Centre (MRCC), a virtual centre based at MFT which aims to improve the lives of people with rare conditions, explained: “Identifying these genetic mutations was a one-year process. They are difficult to understand because they are in the ‘dark matter’, so we didn’t know what their effect would be when they don’t produce a protein. It was thought that one of the genes didn’t do anything at all, but our method of looking at R-loop forming regions has highlighted this region to be active.”
Noah’s story
15-year-old Noah from the Isle of Wight was diagnosed with RNU5B-1-related disorder by the team at University Hospital Southampton NHS Foundation Trust this year, more than seven years after donating his DNA for the 100,000 Genomes Project.
His mum, Maria Villa Vine, said:
We were blown away when we received the diagnosis and to find out it was rare. I always knew my boy was special, but this confirmed it! Having a diagnosis can help you understand yourself, so this will support Noah being able to do that.
Noah’s diagnostic journey began at around 15 months old when his family noticed he wasn’t reaching some milestones that are typically displayed at that age. At four years old, Noah was diagnosed with autistic traits and following a reassessment when he was 12, Noah was diagnosed as autistic.
Following extensive initial genetic investigations by clinicians in Southampton, Noah took part in the 100,000 Genomes Project. This did not find a diagnosis, but his data was entered into the research environment which resulted in the Manchester team’s discovery.
Maria said: “We took part in the 100,000 Genomes Project because as a family we thought, what’s there to lose? If it can help your child or other children with disabilities in the community, why wouldn’t you? We didn’t expect to hear anything from it until we got the phone call.
“Navigating early years as a parent can be difficult, it’s full of emotion and your brain blocks things out. You can feel self-blame and guilt, wondering if it’s something you did. It can also be a hard time for siblings – Noah’s sister was seven at the time of his autism diagnosis. It’s important to have a network of professionals around families to support them and put the children at the centre of conversations.”
This study was supported by the EpiGenRare Node, which facilitates research into the epigenomics of rare diseases and is part of the Medical Research Council and NIHR-funded Rare Diseases UK Platform.
Professor Siddharth Banka, senior author of the study who oversaw the research, is a Professor of Genomic Medicine and Rare Diseases at UoM, Consultant Clinical Geneticist at the Manchester Centre for Genomic Medicine at MFT, and Clinical Director of the MRCC.
Discussing the next steps for the research, Professor Banka, who is also the Rare Conditions Co-Theme Lead at the NIHR Manchester BRC and Co-Lead for the EpiGenRare Node, said: “We now want to understand these conditions better, such as how do their symptoms evolve over time, are there any associated complications and discover potential treatment options. We also need to understand the mechanism of the disease better – how exactly are these genetic mutations causing neurodevelopmental conditions? With this information, we hope to identify treatments and therapies, and make these available for patients.”
The Manchester-based team’s findings have also had a positive impact on patients and families worldwide.
In Australia, the breakthrough has meant that clinicians there were able to diagnose 11-year-old Gitty with RNU2-2-related disorder after a decade-long diagnostic journey.
Gitty’s mum, Miriam, said: “We felt very relieved when we found out. The diagnosis didn’t change anything because Gitty was 10 years old at this stage and we’ve lived through all these symptoms. But knowing that it won’t affect our other children and can’t be passed down by them was a big relief. Uncertainty can be very unnerving, so having a diagnosis gives us peace of mind.”
Professor Marian Knight, Scientific Director for NIHR Infrastructure, said: “For parents of children with neurodevelopmental conditions, understanding the cause of symptoms is an essential first step to getting the best help for their child. The experimental medicine championed by our NIHR Biomedical Research Centres which leads to important discoveries like this provides real benefits for real people like Rose. This exciting work has the potential to change the care of patients not only in the UK but around the world.”
Professor Matt Brown, Chief Scientific Officer at Genomics England, said: “This is an exciting discovery, made possible through Genomics England’s National Genomic Research Library, that’s transforming lives for families across the globe.
“For potentially thousands of families, this means long-awaited answers — and the identification of new molecular targets that could lead to innovative treatments.
“Advances like this show how understanding our genes and DNA is revolutionising the way we diagnose and treat disease. None of it would be possible without the incredible contribution of participants in the 100,000 Genomes Project and the NHS Genomic Medicine Service, who have generously shared their clinical and genomic data to power research.”
Dr Sarah Wynn, CEO of Unique, a charity which supports families affected by rare genetic disorders, said: “This research study which has discovered two new frequent causes of neurodevelopmental conditions is incredibly important and valuable to patients and families, who have often been searching for a long time for the answer to their child’s developmental delays.
“Receiving a diagnosis like this can be life-changing for families, not only by providing the explanation they have been looking for but enabling them to connect to others and learn more about the condition resulting in improved care and support for their child. We are enormously grateful to research teams such as this, who work tirelessly to discover new gene associations and understand more about rare genetic conditions bringing benefit to people and families all over the world.”