The groundbreaking discoveries come from a study delivered through the National Institute for Health and Care Research (NIHR) Manchester 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 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 today (date), 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 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’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.

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.”

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.

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