A study recently published by the National Health Service in the United Kingdom has highlighted the promising applications of Next Generation Sequencing in the diagnosis and treatment of rare diseases. While not directly involved in the project, Novogene support every effort made to improve the lives of patients and the emphasis placed on the potential of NGS technologies when it comes to this. We greatly admire the ambition of this project and are delighted to see awareness being raised of the services we offer and their contribution to treatment and improvement of quality of life for sufferers.

In the UK, a rare disease is defined as one that affects ≤1 in 2000 individuals, and over 80% of these diseases have an underlying genetic component. The majority of individuals suffering with a rare disease remain without a molecular diagnosis after routine diagnostic testing, which is where the advent of clinical genome sequencing has begun to lend itself to better diagnostic outcomes over the past decade. In 2013, the UK government launched the 100,000 Genomes Project to apply whole genome sequencing to the management and diagnosis of rare diseases, which are both expensive and disabling to live with.

The study enrolled 4660 participants, a cohort in which 161 rare disorders were represented. In terms of a clinical trial, a proband is the first individual of a family line in which a rare disease presents itself. Family members of probands are often included in such trials to facilitate more efficient variant prioritisation and to screen for carriers of such variants. The larger a family cohort recruited, the higher the diagnostic yield of the screening became, with an average of 32%.

The results published in November 2021 were overwhelmingly positive and highlighted the advantage of whole genome sequencing for patients and the healthcare system alike. 25% of the probands screened in this study were provided with a new genetic diagnosis that was immediately clinically actionable. A further 4 diagnoses lead to suggested changes to medication, 26 advised additional monitoring of the proband or relatives, 13 qualified the patients for clinical trials, 59 diagnoses were able to inform future reproductive choices and another 32 had various other benefits.

The cases that were immediately clinically actionable ranged from providing peace of mind to lifesaving treatment plans. A man in his 60s with two kidney transplants behind him and whose father, bother and uncle all passed away from kidney failure, was worried he had passed the disorder to his daughter and granddaughter. Once he received a genomic diagnosis of a mutation in his INF2 gene, his granddaughter could be tested. She was found to be negative for the mutation and could be released from clinical surveillance. A 4-week-old baby sadly passed away with no diagnosis, however later testing revealed a transcobalamin II deficiency. This protein is involved in vitamin B12 absorption and transport. This diagnosis was later used to test his younger brother within one week of birth. The brother’s positive diagnosis led to treatment with weekly, lifesaving hydroxocobalamin injections.

Numerous novel disease-gene associations were uncovered in this research, three of which have been independently confirmed and a further 19 which are expected to be confirmed soon. 13% of all diagnoses made from genome sequencing were due to mutations in non-coding regions of the genome and the mitochondrial genome, areas not covered by exome sequencing. An additional 2% were caused by coding variants of low coverage with exome sequencing. This supports the case for the use of whole genome sequencing for the diagnosis of rare diseases in the new NHS National Genomic Test Directory, which is also likely to save money for the NHS by allowing affective treatment as opposed to mere symptom management.

Living with a rare disease is a difficult situation in itself but adding the uncertainty of a lack of definitive diagnosis can turn a physical illness into a real mental challenge. Every additional diagnostic marker is a step in the right direction. With the help of whole genome sequencing and diagnostic panels, this study has certainly delivered on that front. Our motto here at Novogene is “Advancing Genomics, Improving Life”, and the work carried out in this study is a testament to the truth of this statement. Fund the research to develop the techniques and the real-life outcomes will speak for themselves.