The research, published in Nature and led by Queen Mary University of London, 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.

To address this issue, an international team of researchers developed an analytical framework for identifying the genetic causes of Mendelian diseases (genetic disorders caused by a single gene mutation) through rare variant gene burden analysis.

This method finds common genetic changes in groups of patients with specific genetic disorders compared to a control group.

Leveraging the extensive data from Genomics England’s 100,000 Genomes Project, the team applied this framework to the genetic data of 34,851 individuals and their family members, totalling 72,690 genomes.

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 (developmental defects or structural issues within the front part of the eye).

Co-author Professor Henry Houlden (UCL Queen Square Institute of Neurology) said: “This is an excellent example of collaboration in analysing a wide spectrum of ethnically diverse patients within the UK populations.
“Such initiatives are essential to continue, along with continued funding for research on rare disorders, to help end the diagnostic odyssey for rare disease patients.”
Co-author Dr Heba Morsy (UCL Queen Square Institute of Neurology) added: “As a geneticist and bioinformatician, I find this study particularly exciting because it highlights the power or large-scale genomic analysis in uncovering previously unknown genetic causes of rare diseases.

“This research brings us one step closer to bridging the gap between genomic discovery and clinical diagnosis, ultimately helping more patients find answers and access tailored care.”

The 100,000 Genomes Project was Genomics England’s first initiative and involved sequencing 100,000 genomes from around 85,000 NHS patients affected by rare diseases or cancer – with the goal of understanding the role genomics can play in healthcare.

The research was funded by Aligning Science Across Parkinson’s, the Michael J. Fox Foundation for Parkinson’s Research, the Health Research Board and the National Institute for Health and Care Research (NIHR) Barts Biomedical Research Centre (BRC), alongside support from the National Institute of Child Health and Human Development and the UCLH NIHR Health BRC, Wellcome, and the Medical Research Council.

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