8th April, 2025: The groundbreaking study, which was published in Nature and involved Newcastle University, used a novel analytical technique to pinpoint the genetic foundation of uncommon diseases, potentially leading to more patient diagnoses and the creation of novel therapeutic interventions. Globally, between 4% and 6% of people suffer from rare diseases. Even after genome sequencing, up to 80% of persons with uncommon diseases go undetected due to a lack of knowledge about the genetic variants that could cause the condition, despite advancements in genetic testing.
An international team of researchers has created rare variant gene burden analysis, an analytical framework for determining the genetic aetiology of Mendelian disorders (mutations in a single gene), to address the problem. The framework was then applied to 34,851 individuals and their family members’ genomic records (a total of 72,690 genomes) from Genomics England’s 100,000 Genomes Project.
The study found genetic variations in 69 genes that were previously thought to be linked to rare diseases. In 30 of these instances, the innovative approach’s accuracy was confirmed by the new genetic discoveries being corroborated by pre-existing experimental data. The newly identified genetic variations for rare forms of diabetes, schizophrenia, epilepsy, Charcot-Marie-Tooth (CMT) illness, and anterior segment ocular abnormalities were, crucially, backed by the strongest overall genetic and experimental data.
John Sayer, Clinical Professor of Renal Medicine at Newcastle University and Consultant Nephrologist at The Newcastle upon Tyne Hospitals NHS Foundation Trust, stated: “Newcastle has established itself as a global leader in rare disease research, continually advancing genomic medicine to identify new genetic causes and enhance diagnostic and treatment strategies for rare conditions. Our study demonstrates how we are harnessing the power of genetics to improve patient outcomes.”
Recruitment of patients for the rare disease component of the Genomics England 100,000 Genomes Project was greatly aided by Newcastle University and Newcastle Hospitals.
Neil Rajan, Professor of Dermatogenetics at Newcastle University and Consultant Dermatologist at Newcastle Hospitals, said: “For patients with rare diseases lacking a known genetic cause, this research highlights how large-scale national genome sequencing projects can provide crucial answers. The ‘diagnostic odyssey’ remains a significant challenge for the rare disease community, and identifying new genes is an essential step toward improving diagnosis and outcomes for these patients.”
To find individuals who would benefit from the trial, Newcastle University’s established Rare Diseases Centre and expertise in genetics and clinical genomics were essential. The project team recruited patients and gathered a lot of clinical data by working directly with patients and their families.
The study’s principal author, Damian Smedley, a professor of computational genomics at Queen Mary University of London, commented, “The 100,000 Genomes Project data has provided a singular chance to illustrate the clinical utility of extensive statistical techniques in rare illness research. Finding novel genetic connections and ending the diagnostic journey that many patients with rare diseases and their families must endure are made possible by this strategy.”