New Frontier in Understanding Brain Development and Rare Diseases

Researchers at the NIHR Manchester Biomedical Research Centre (BRC) and the University of Manchester have identified a group of previously unknown genetic disorders linked to neurodevelopmental conditions.

Their study, published in Nature Genetics, reveals that mutations in overlooked regions of DNA, once thought to be non-functional, play a role in brain development. This work has already led to new diagnoses for patients, including 18-year-old Rose Anderson, and may improve how rare neurological conditions are identified in the future.

Since the study, Rose Anderson from Stretford, Manchester, has received a diagnosis for one of the newly identified conditions. Rose has been known to specialists at the Manchester Centre for Genomic Medicine at Manchester University NHS Foundation Trust (MFT) for most of her life. However, a clear explanation for her seizures and developmental delay had remained elusive.

Upon receiving Rose’s diagnosis from the research team last year, her mother, 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 funded by the MFT-hosted NIHR Manchester BRC under its Rare Conditions Theme, which focuses on improving the diagnosis of rare diseases.

Researchers from NIHR Manchester BRC, MFT, and the University of Manchester worked with international scientists to analyze genetic data from thousands of individuals. This included participants in the 100,000 Genomes Project, a Genomics England initiative aimed at understanding the role of genes in health and disease.

Genes are sections of DNA that carry instructions for producing proteins, which are needed for cell growth and repair.

Previously, parts of DNA that do not produce proteins were considered unimportant. They were often referred to as "dark matter" or "junk DNA."

In their study, Manchester researchers challenged this view. They showed that changes in these regions can significantly affect brain development.

The team found that mutations in genome regions that form R-loops—DNA-RNA structures that influence gene activity—are more common than previously thought.

This discovery led to the identification of two previously unknown neurodevelopmental conditions.

• RNU2-2-related disease is associated with developmental delays, intellectual disability, small head size (microcephaly), autism, and seizures.
• RNU5B-1-related disease is linked to developmental delays, low muscle tone (hypotonia), large head size (macrocephaly), and poor growth.

Neurodevelopmental conditions, which affect how the brain develops, impact an estimated 2–5% of the global population.

For many families, these conditions remain undiagnosed, as standard genetic testing often fails to identify a cause.

The two newly identified conditions, along with ReNU syndrome (a condition described in 2024 that affects learning, behavior, speech, and mobility), now account for over 1% of previously unresolved developmental cases.

This research may help provide a genetic explanation for many of these cases worldwide.

Rose, who was diagnosed with RNU2-2-related disease in October 2024, enjoys music, walking, swimming, going to cafés, and riding tandem bikes. She lives with her mother, Lyn, father, Joe, and younger sister, Lily.

Concerns about Rose’s health first arose during a 20-week pregnancy scan. Although she later underwent extensive genetic testing at MFT and took part in research studies, a clear diagnosis was not found until this recent discovery.

Lyn remarked: “You wonder if it is 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.”

Lyn continued: “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.”

Lyn said, “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 better understand RNU2-2-related disorder. Since her diagnosis, Rose has taken part in additional research at MFT. This includes donating skin cells to help researchers generate brain stem cells for epilepsy studies.

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. Adam Jackson, Study Lead and First Author, The University of Manchester

Dr. Jackson, who is also affiliated with the Manchester Rare Conditions Centre (MRCC), a virtual center at MFT aimed at improving the lives of individuals with rare conditions, elaborated: “Identifying these genetic mutations was a one-year process. They are difficult to understand because they are in the ‘dark matter’, so we did not know what their effect would be when they do not produce a protein. It was thought that one of the genes did not do anything at all, but our method of looking at R-loop forming regions has highlighted this region to be active.”

Fifteen-year-old Noah, from the Isle of Wight, was diagnosed this year with RNU5B-1-related disorder. The diagnosis was made by a team at University Hospital Southampton NHS Foundation Trust, more than seven years after he donated his DNA to the 100,000 Genomes Project.

His mother, Maria Villa Vine, shared: “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 around 15 months old, when his family noticed he was not meeting expected developmental milestones. At age four, he was identified as having autistic traits. After a reassessment at age 12, he received an autism diagnosis.

Clinicians in Southampton conducted several rounds of genetic testing, but these did not produce a clear diagnosis. Noah later joined the 100,000 Genomes Project. Although it did not immediately lead to answers, his data remained in the research database and ultimately contributed to the Manchester team’s discovery.

Maria remarked: “We took part in the 100,000 Genomes Project because as a family we thought, what is there to lose? If it can help your child or other children with disabilities in the community, why would not you? We did not expect to hear anything from it until we got the phone call.”

“Navigating early years as a parent can be difficult; it is full of emotion, and your brain blocks things out. You can feel self-blame and guilt, wondering if it is 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 is important to have a network of professionals around families to support them and put the children at the center of conversations,” she added.

The study was supported by the EpiGenRare Node, which focuses on research into the epigenomics of rare diseases. It is part of the Rare Diseases UK Platform, funded by the Medical Research Council and NIHR.

Professor Siddharth Banka, the study’s senior author, led the research. He is a Professor of Genomic Medicine and Rare Diseases at the University of Manchester, a Consultant Clinical Geneticist at the Manchester Centre for Genomic Medicine at MFT, and the Clinical Director of the MRC Clinical Sciences Centre.

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.”

Siddharth Banka, Professor, The University of Manchester

Banka is also a Rare Conditions Co-Theme Lead at the NIHR Manchester BRC and Co-Lead for the EpiGenRare Node.

The Manchester team’s findings have helped patients and families beyond the UK.

In Australia, the research enabled clinicians to diagnose 11-year-old Gitty with RNU2-2-related disorder, ending a diagnostic search that had lasted over ten years.

Gitty’s mother, Miriam, expressed: “We felt very relieved when we found out. The diagnosis did not change anything because Gitty was 10 years old at this stage and we have lived through all these symptoms. But knowing that it would not affect our other children and cannot be passed down by them was a big relief. Uncertainty can be very unnerving, so having a diagnosis gives us peace of mind.”

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.”

Marian Knight, Professor and Scientific Director, NIHR Infrastructure

Dr. Sarah Wynn, CEO of Unique, a charity that supports families affected by rare genetic disorders, stated: “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.”

Wynn said, “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.”