Customizing Whole Genome Sequencing Doubles the Diagnosis of Rare Diseases

Adapting whole genome sequencing analysis to individual patients could double diagnostic rates for rare diseases, according to a new study by UCL researchers.

In 2018, the UK Department of Health announced an NHS genomic medicine service, which allows patients with rare diseases to have their entire genetic code read in hopes of providing much-needed diagnosis.

However, interpreting this data can be extremely difficult, and many people with complex and rare genetic conditions still do not have a molecular answer to the cause of their problems.

In the study published in Nature Communicationresearchers from the London Mitochondrial Center at UCL Queen Square Institute of Neurology and the UCL Great Ormond Street Institute of Child Health sought to give these patients a better chance of receiving a genetic diagnosis.

To do this, they tested how using a genomic medicine team of specialist doctors, bioinformaticians and scientists could boost the capabilities of NHS diagnostic laboratories beyond standard semi-automated analysis of data. The UCL team reassessed the undiagnosed cases to identify clues that could help guide a deeper and more personalized analysis. They then applied additional bioinformatics approaches, using advanced computer technologies to identify genetic alterations in a patient’s DNA that could cause disease but had been overlooked in routine testing.

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

This personalized approach increased the diagnosis rate from 16.7% to 31.4%. It also detected potentially pathogenic variants in an additional 3.9% of patients.

Lead author Dr Robert Pitceathly (co-head of the London NHS Highly Specialized Service for Rare Mitochondrial Disorders and head of a research group at UCL Queen Square Institute of Neurology) said: ‘The NHS has a lot invested in advanced genetic technologies. As a result, the UK has established itself at the forefront of whole genome diagnostic sequencing. That said, some people with rare genetic diseases remain without a molecular diagnosis after their genome has been analyzed.

“We believe it is crucial to invest in teams specialized in genomic medicine, in order to ensure equitable access to dedicated multidisciplinary expertise and to maximize diagnostics. On average, patients in our study have waited more than 30 years for a diagnosis – we now have the capacity to solve such cases, but we need adequate manpower planning to help laboratories genetic diagnosis of the NHS to achieve this goal.

Receiving a genetic diagnosis is important because it allows patients to access family planning, specialized IVF and drug trials. It may also allow targeted screening for known complications of the disease and access to drug studies.

Dr Pitceathly said: “In this study, each new genetic diagnosis had a direct impact on patient care. This included additional tests for heart problems, hearing loss and diabetes, as well as access to clinical trials.

Professor Michael Hanna, Director of the UCL Queen Square Institute of Neurology, said: “This work is a significant step forward in developing the best ways to maximize the benefits of genome analysis for patients. It clearly demonstrates that by combining automated approaches to genome analysis with data interpretation by a skilled multidisciplinary team, diagnosis rates double. This is an important finding that will influence how diagnostic services in genomic medicine are expected to evolve worldwide.

Co-author Dr James Davison (Department of Metabolic Medicine at Great Ormond Street Hospital and Chairman of the British Inherited Metabolic Diseases Group) said: ‘The journey to diagnosis for children and adults with rare diseases and complex can be a very time-consuming process, and genomic medicine provides a transformative and powerful tool to help achieve this goal.

“This study highlights the importance of collaboration between specialist clinicians and geneticists in interpreting genome sequencing results to maximize the opportunity to reach a diagnosis that can then help guide medical management and treatment options.”

The researchers involved in this study are funded by the Medical Research Council.

Patient story

Rachel North was one of the patients involved in the trial and described getting a diagnosis as “life changing”. This has since allowed him to be screened for complications of the disease such as osteopenia, and these have been treated.

She said: ‘I had been to so many hospitals over the past 20 years and searched for so long that I never thought I would get a diagnosis.

“Asking myself about it took so much energy, and I was worried about my 12-year-old son and if my condition would affect him. So getting a rare recessive diagnosis was a relief and took away the fear of the unknown.

“Having a diagnosis allows me to research my condition and be very proactive in managing it.

“Anything that helps me understand and make sense of what’s happening to my body helps me accept it and gives me confidence that I’m handling it as well as possible.”

Reference: Macken WL, Falabella M, McKittrick C, et al. The multidisciplinary contribution of specialists maximizes diagnoses of rare diseases from whole genome sequencing. Nat Common. 2022;13(1):6324. do I: 10.1038/s41467-022-32908-7

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