How whole genome sequencing can improve disease management

Living with the symptoms of an undiagnosed condition can lead to significant anxiety for patients and make it difficult to plan for what feels like an uncertain future.

Neurogenetics clinics specialise in pinpointing a diagnosis for patients with suspected, inherited neurological conditions. A confirmed diagnosis means clinicians can plan the most effective treatment for individual patients based on their genes. Dr Helen Grote, neurology registrar and clinical champion for neurogenetics, tells us more.

Your genome is the instructions for making and maintaining you. It is written in a chemical code called DNA. All living things have a genome; plants, bacteria, viruses and animals. The human genome is 3.2 billion letters long, and contains around 20,000 genes. Learning more about genomes can help identify the cause of genetic diseases and potential treatment options.

In 2012 the Government announced the 100,000 Genomes Project which aimed to sequence 100,000 whole genomes from NHS patients with rare diseases, and their families, as well as patients with common cancers. This research project provided the foundation for NHS genomic medicine centres to be set up across England, allowing for whole genome testing to be delivered by clinical NHS services from May 2020.

Benefits of genome sequencing

In the neurogenetics clinic, we see patients who have confirmed or suspected inherited neurological conditions, or conditions affecting the nervous system. These range from inherited movement disorders (such as early-onset Parkinson’s disease, Huntington’s disease and ataxia), as well as genetic epilepsies, neuromuscular, and peripheral nerve conditions.

Many of the patients that we see in the clinic have lived with a progressive neurological condition for a number of years with no clear diagnosis. This makes life very difficult; without a clear diagnosis, clinicians cannot determine what treatments will help the most, and enrolling patients into therapeutic research trials is almost impossible. Living with an undiagnosed condition also causes significant anxiety to patients and their families. It is difficult to plan for the future when the progression of a condition, or the impact it will have on their ability to remain independent is unknown. Where there is no clear diagnosis, accessing benefits, and support at work and home can also be harder.

Dr Helen Grote"The confirmation of a genetic neurological condition is important for our patients – it means that we, as clinicians, can provide them with the best available treatment, support, and advice about the likely progression of their condition"

The confirmation of a genetic neurological condition is important for our patients – it means that we, as clinicians, can provide them with the best available treatment, support, and advice about the likely progression of their condition. For family members, it also means that they can be better informed about the condition, understand whether it could also affect them or their children, and be referred on for genetic counselling if they do not have symptoms, but want testing to find out their risk of developing the same condition too.

How to sequence a genome

For the patient, the process is relatively simple: we arrange for two ‘purple’ top tubes of blood to be taken from the patient and sent to the laboratory.

However, before the blood sample is taken, it is hugely important that the patient understands why they are having the genetic test, and what the potential implications of a positive result are for them and for other family members. We call this process ‘informed consent’ and document carefully in the records that the patient has given informed consent for their DNA to be tested.

Once in the laboratory, the DNA is extracted from the blood sample. The human genome is 3.2 billion bases (or ‘letters’) in length – so that’s a lot of code to be sequenced! The laboratory stores this information in a computerised format. When a clinician requests testing for a condition such as ataxia, for example, then a special search is done by the computer for any variants or ‘spelling mistakes’ in genes known to be associated with ataxia.

The results are then discussed at a multidisciplinary meeting with the patient’s clinician, a geneticist and a bioinformatics expert. Determining whether a variant or ‘spelling mistake’ in a gene is pathogenic (disease causing) is a complicated process.

How common are genetic neurological diseases?

At a population level, genetic neurological diseases, are not that rare. A study from the north of England, published in 2015, indicated that one in 1,100 people have a neurological disorder caused by a variant in a single gene. If we translate those figures to a large city like London, with a population of nine million people, that’s equivalent to nearly 8,200 people living with a genetic neurological condition.

Collectively, genetic disorders, or rare diseases, are quite common, affecting around one to two per cent of all babies born in the UK. In some, the diagnosis is made soon after birth, but others will be unaware that they have a genetic condition until features of the condition appear in later life. The latter was the case for Sarah, one of my patients.

Sarah’s story

We met Sarah and her family in the neurogenetics clinic two years ago. Sarah is a young woman who had some features of Parkinson’s disease, including difficulty with walking, and also tightness of her voice muscles, which made her speech difficult and strained. There was no clear cause for her symptoms from routine blood tests and other investigations.

Sarah and her parents were recruited as a ‘trio’ to the 100,000 Genomes Project. The results of this confirmed that Sarah has a variant in the ATP1A3 gene causing rapid-onset dystonia Parkinsonism, a rare movement disorder. Testing of her parents confirmed that neither of them carry the same gene variant – so we know that it appeared for the first time in Sarah herself.

While there is no effective treatment yet for the condition, the confirmed diagnosis makes it much easier for Sarah to access the support that she needs. Although Sarah’s condition will not improve, all the available evidence from the literature about other patients with the same condition indicates that it is unlikely to progress much, either.

Knowing the diagnosis and progression of the condition can be very helpful in planning for the future. Furthermore, research into genomics is advancing rapidly, and as new therapeutic options become available, those who have a confirmed diagnosis for genetic diseases, or who are known to be ‘carriers’ for these diseases are most likely to be able to access new treatments first.

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