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The groundbreaking discoveries come from a study delivered through the National Institute for Health and Care Research (NIHR) 91直播 Biomedical Research Centre (BRC) and , and The University of Manchester and could provide answers for several thousands of people with neurodevelopmental conditions around the world.

Since the breakthrough, 18-year-old Rose Anderson from Stretford in 91直播 has received a diagnosis of one of the newly discovered conditions.

Rose has been known to the team at the 91直播 Centre for Genomic Medicine at 91直播 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 91直播 research team last year, Rose鈥檚 mum Lyn said: 鈥淲e felt excited and relieved to finally receive Rose鈥檚 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.鈥�

The study was supported by the MFT-hosted NIHR 91直播 BRC, as part of its which aims to improve diagnosis of rare conditions.

Researchers from the NIHR 91直播 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 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 鈥榙ark matter鈥� because they were not understood, or 鈥榡unk DNA鈥� because it was thought they were not essential.

Published in Nature Genetics today (date), 91直播 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 鈥� disorders that affect brain development 鈥� 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 identified in 2024 which has an impact on learning, behaviour, speech and movement) 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, 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, dad Joe and younger sister, Lily.

At Lyn鈥檚 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鈥檚 symptoms.

Lyn said: 鈥淵ou wonder if it鈥檚 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 鈥� 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.

鈥淲hen 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.

鈥淭his 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.鈥�

Rose and her family are working with the 91直播 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.

91直播 lead and first author of the paper Dr Adam Jackson, Academic Clinical Fellow at the 91直播 Centre for Genomic Medicine at MFT and The University of Manchester and early career researcher in the NIHR 91直播 BRC鈥檚 Rare Conditions Theme, said: 鈥淏y proving that non-protein coding genes play a key role in human health, this study challenges long-held assumptions about 鈥榡unk DNA鈥� and brings hope to many families searching for answers.鈥�

Dr Jackson, who is also part of the (MRCC), a virtual centre based at MFT which aims to improve the lives of people with rare conditions, explained: 鈥淚dentifying these genetic mutations was a one-year process. They are difficult to understand because they are in the 鈥榙ark matter鈥�, so we didn鈥檛 know what their effect would be when they don鈥檛 produce a protein. It was thought that one of the genes didn鈥檛 do anything at all, but our method of looking at R-loop forming regions has highlighted this region to be active.鈥�

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: 鈥淲e 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.鈥�

Noah鈥檚 diagnostic journey began at around 15 months old when his family noticed he wasn鈥檛 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 91直播 team鈥檚 discovery.

Maria said: 鈥淲e took part in the 100,000 Genomes Project because as a family we thought, what鈥檚 there to lose? If it can help your child or other children with disabilities in the community, why wouldn鈥檛 you? We didn鈥檛 expect to hear anything from it until we got the phone call.

鈥淣avigating early years as a parent can be difficult, it鈥檚 full of emotion and your brain blocks things out. You can feel self-blame and guilt, wondering if it鈥檚 something you did. It can also be a hard time for siblings 鈥� Noah鈥檚 sister was seven at the time of his autism diagnosis. It鈥檚 important to have a network of professionals around families to support them and put the children at the centre of conversations.鈥�

This study was supported by the , 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 91直播 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 91直播 BRC and Co-Lead for the EpiGenRare Node, said: 鈥淲e 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 鈥� 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.鈥�

The 91直播-based team鈥檚 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 with RNU2-2-related disorder after a decade-long diagnostic journey.

Gitty鈥檚 mum, Miriam, said: 鈥淲e felt very relieved when we found out. The diagnosis didn鈥檛 change anything because Gitty was 10 years old at this stage and we鈥檝e lived through all these symptoms. But knowing that it won鈥檛 affect our other children and can鈥檛 be passed down by them was a big relief. Uncertainty can be very unnerving, so having a diagnosis gives us peace of mind.鈥�

Professor Marian Knight, Scientific Director for NIHR Infrastructure, said: 鈥淔or 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."

Dr Sarah Wynn, CEO of Unique, a charity which supports families affected by rare genetic disorders, said: 鈥淭his 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鈥檚 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.鈥�