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University of Oxford Images / John Cairns
The multicentre research, led by Queen Mary University of London and including a number of researchers supported by the NIHR Oxford Biomedical Research Centre, used 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 affect between four and six percent of people worldwide. Despite advances in genetic testing, the lack of evidence on the genetic variations that could lead to disease results in up to 80 percent of people who have a rare disease remaining undiagnosed even after genomic sequencing.
The international team of researchers developed an analytical framework for identifying the genetic causes of Mendelian diseases – diseases caused by mutations in a single gene that sometimes run in families – through rare variant gene burden analysis and applied it 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, published in Nature, identified 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 disease and anterior segment ocular abnormalities.
The analytical framework developed in this study has been made openly available for generic use beyond the study’s data, so that it can be applied to rare disease datasets across the world and so facilitate further diagnoses.
Read the full paper on the Nature website: https://www.nature.com/articles/s41586-025-08623-w