Personalising WGS doubles diagnosis of rare diseases 

A new study led by Medical Research Council-funded researchers from UCL has found that tailoring the analysis of whole genome sequencing to individual patients could double the diagnostic rates of rare diseases. 


In 2018, the UK’s department of health announced an NHS Genomic Medicine Service, which allows patients with rare diseases to have their entire genetic code read in the hope of providing a much-needed diagnosis. However, the interpretation of this data can be extremely challenging and many people with complex, rare genetic diseases still do not receive a molecular answer to the cause of their problems. 

The study  

In the study, published in Nature Communications, researchers at The London Mitochondrial Centre at UCL Queen Square Institute of Neurology and UCL Great Ormond Street Institute of Child Health sought to offer such patients an improved chance of receiving a genetic diagnosis. 

To do so, they tested how using a genomic medicine team of specialist doctors, bioinformaticians, and scientists could boost the capabilities of NHS diagnostic laboratories beyond the standard semi-automated analysis of data.  

The UCL team re-evaluated undiagnosed cases to identify clues that might help direct further, more personalised analysis. They subsequently applied additional bioinformatic approaches, using advanced computer technologies to identify genetic alterations in a patients’ DNA which may be causing disease but had been overlooked during routine testing. 

The work included 102 undiagnosed patients, suspected of having a primary mitochondrial disease (a large group of incurable genetic disorders that affect children and adults, associated with a broad spectrum of medical problems, severe disabilities, and reduced lifespan), who had undergone whole genome sequencing via the NHS’s 100,000 Genomes Project. 

This personalised approach increased the diagnostic rate from 16.7% to 31.4%. It also detected potential disease-causing variants in a further 3.9% of patients. 

Official comments 

Lead author, Dr Robert Pitceathly, co-lead for the London NHS Highly Specialised Service for Rare Mitochondrial Disorders and a research group leader at UCL Queen Square Institute of Neurology, said: “The NHS has invested heavily in advanced genetic technologies. Consequently, the UK has established itself at the forefront of diagnostic whole genome sequencing. That said, some people with rare genetic diseases remain without a molecular diagnosis after their genome is analysed. 

“We believe investing in specialist genomic medicine teams is crucial, ensuring equitable access to dedicated multidisciplinary expertise and maximising diagnoses. On average, patients in our study waited over 30 years for a diagnosis – we now have the capability to solve such cases but need adequate workforce planning to support NHS diagnostic genetic laboratories in achieving this goal.” 

Receiving a genetic diagnosis is important as it allows patients to receive access to family planning, specialised IVF, and drugs trials. It can also permit targeted screening of known disease complications and access to drug studies. Dr Pitceathly continued: “In this study, every new genetic diagnosis had a direct impact on patient care. This included additional check-ups for heart problems, hearing loss, and diabetes, and access to clinical trials.” 

For further insight into whole genome sequencing, read this DDW exclusive content: Why genomic healthcare data matters in the development of new therapies 

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