69 New Genetic Causes of Rare Diseases Identified

A landmark study has found 69 previously unidentified genetic determinants of rare disease, including uncommon forms of kidney disease and diabetes. 

The breakthrough research, involving the University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, 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 four and six per cent of people worldwide. Despite advances in genetic testing, most genetic variants that lead to disease remain unknown resulting in around 80 per cent of people with a rare disease being undiagnosed even after genomic sequencing. 

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

The team then applied this 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, published in Nature, identified genetic variants in 69 genes not previously known to be associated with any 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 newly discovered genetic variants for rare forms of kidney disease, diabetes, schizophrenia, epilepsy, Charcot-Marie-Tooth (CMT) disease, and anterior segment ocular abnormalities (developmental defects or structural issues within the front part of the eye).

Professor Albert Ong, Professor of Renal Medicine at the University of Sheffield and Consultant Nephrologist and Clinical Lead for Kidney Genetics at Sheffield Teaching Hospitals NHS Foundation Trust, said: “Sheffield has a long and proud history of kidney disease research. This paper highlights the power of unlocking genetics through the 100,000 Genomes Project to provide hope to millions of people suffering with undiagnosed rare diseases by discovering many new genes for diseases ranging from epilepsy, diabetes, brain disorders to cystic kidney disease.”

Professor Ong, who gave his expert opinion on the 22 genes linked to rare kidney diseases found in the study, added: “Gene discovery is the first step towards diagnosis, a clearer understanding and the eventual development of new treatments to cure or slow disease. This is great news for patients and their families as it will provide them with an opportunity to be given a clear diagnosis. I am also proud that many patients from Sheffield contributed to this important UK project.” 

Reference: Cipriani V, Vestito L, Magavern EF, et al. Rare disease gene association discovery in the 100,000 Genomes Project. Nature. 2025. doi: 10.1038/s41586-025-08623-w

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