Tailoring the analysis of whole genome sequencing to individual patients could double the diagnostic rates of rare diseases, finds a new study led by UCL researchers.

In 2018, the United Kingdom’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.

In the study, published in Nature Communicationsresearchers 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.

Personalized Analysis to Diagnose Rare Diseases

Researchers 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 personalized analysis.

They subsequently applied additional bioinformatic approaches, using advanced computer technologies to identify genetic alterations in a patient’s 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 personalized 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.

“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 analyzed,” says lead author, Robert Pitceathly, MD, co-lead for the London NHS Highly Specialized Service for Rare Mitochondrial Disorders and a research group leader at UCL Queen Square Institute of Neurolog. “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, specialized IVF, and drugs trials. It can also permit targeted screening of known disease complications and access to drug studies.

Pitceathly added: “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.”

“This work is a significant step forward in developing the best ways to maximise the benefits of genome analysis for patients,” says Professor Michael Hanna, director of UCL Queen Square Institute of Neurology. “It clearly demonstrates that by combining automated approaches to genome analysis with data interpretation by a skilled multidisciplinary team the diagnostic rates doubles. This is an important finding that will influence how genomic medicine diagnostic services should evolve world-wide.”

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

“The journey to reaching a diagnosis for children and adults with rare, complex, medical conditions can be a very long process, and genomic medicine provides a transformative and powerful tool in helping reach that goal,” says co-author James Davison, PhD, Metabolic Medicine Department at Great Ormond Street Hospital and chair of the British Inherited Metabolic Diseases Group. “This study highlights the importance of the collaboration between specialist clinicians and genetic scientists in interpreting the results of genome sequencing to maximise the opportunity of reaching a diagnosis which can then help guide medical management and treatment options.”

Featured image: Graphic representation of the DNA sequence. Photo: Gio_tto on iStock