The breakthrough research, involving Newcastle University and published today in Nature, uses a new analytical approach for identifying the genetic basis of rare diseases, which could diagnose more cases and help develop new treatments for patients.

Rare diseases collectively affect between 4% and 6% of individuals worldwide. Despite advances in genetic testing, the lack of evidence on the genetic variations that could lead to disease results in up to 80% of people who have a rare disease remaining undiagnosed even after genomic sequencing.  

‘Analytical framework’

To address the issue, an international team of researchers has developed an analytical framework for identifying the genetic causes of Mendelian diseases (mutations in one gene), known as rare variant gene burden analysis.

The experts then applied the framework to the genetic records of 34,851 people and their family members (72,690 genomes in total) from Genomics England’s 100,000 Genomes Project. 

The study identified genetic variants in 69 genes previously unknown to be associated with rare disease. In 30 of these cases, the new genetic findings were supported by existing experimental evidence, thereby confirming the accuracy of the novel approach.

Importantly, the strongest overall genetic and experimental evidence supported the newly discovered genetic variants for rare forms of diabetes, schizophrenia, epilepsy, Charcot-Marie-Tooth (CMT) disease, and anterior segment ocular abnormalities.

John Sayer, Clinical Professor of Renal Medicine at Newcastle University and Consultant Nephrologist at Newcastle Hospitals, said: “Newcastle is a world-leader in rare disease research, consistently pushing the boundaries of genomic medicine to uncover new genetic causes and improve diagnostic and therapeutic approaches for rare conditions.

“Our study shows how we continue to use the power of genetics to improve the lives of our patients.”

Newcastle University, together with The Newcastle upon Tyne Hospitals NHS Foundation Trust, contributed significantly to recruitment of patients to the rare disease arm of the Genomics England 100,000 Genomes Project.

Neil Rajan, Professor of Dermatogenetics at Newcastle University and Consultant Dermatologist at Newcastle Hospitals, said: “For patients living with rare diseases, where there is no known genetic basis, this work shows how the scale of national genome sequencing projects can provide answers.

“The ‘diagnostic odyssey’ is a challenge that is faced by the rare disease community, and the discovery of new genes is a key step towards improving this for patients.” 

‘Expertise in genetics’

Newcastle University’s expertise in genetics and clinical genomics, and its established Rare Diseases Centre, was crucial in identifying patients who would benefit from the study.

In the project, the team worked directly with patients and families for recruitment and the collection of extensive clinical data.  

Damian Smedley, Professor of Computational Genomics at Queen Mary University of London and senior author of the study, said: “The 100,000 Genomes Project data has provided a unique opportunity to showcase the clinical impact of large-scale statistical approaches in rare diseases for discovering new associations and to end the diagnostic odyssey for many rare disease patients and their families.”

Reference: Cipriani V, Vestito L, et al. “Rare disease gene association discovery in the 100,000 Genomes Project.” Nature. DOI: 10.1038/s41586-025-08623-w