Genomics explained

All a person’s DNA (deoxyribonucleic acid) equals their genome.  About 99.9% of our DNA is shared with other human beings, the other 0.1% makes us all individuals.  Genomics is the study of the entirety of a person’s DNA comprising both the coding DNA (within genes) and non-coding DNA (outside of genes) and the interactions between the two.  It also includes the complex interactions between multiple genes and the environment. 

Genomic medicine is the application of genomics to clinical care.

Sequencing the genome offers an unprecedented view of the human body, how it works and what can go wrong with it.  Genomic data is also a very different kind of medical investigation, as unlike radiology or biochemical tests, a person’s genome does not change over a lifetime.  The insights and actions possible from genomic data is, however, very likely to change as new research is added.  Whole genome sequencing may need to be done only once, but fresh insights and personalised treatments can be developed over a lifetime.

The UK is at the cutting edge of research in genomics which is already making big differences in cancer and other medical specialties with many spill-over benefits to the wider economy, including drug development.  Reducing the cost of genomic sequencing and increasing knowledge about how genes are expressed in a person mean that genomics will continue to transform medicine in the future.

The NHS Genomic Medicine Service (GMS) Research Collaborative has been created as part of the NHS Long Term Plan.  The UK has a world-leading genomic medicine infrastructure and will be at the forefront of this huge development of genomic medicine.

Genomics in the NHS

The 100,000 Genomes project completed recruitment in 2018.  The process of feeding back results is still on-going, however it has already added a huge amount of knowledge to the fields of genomics, cancer, and rare disease.  The NHS Genomic Medicine Service has now been launched as a diagnostic service, to integrate genomics into routine NHS patient care.  There will also be ‘mainstreaming’ of genetic testing outside of clinical genetics into non-genetic specialties.  This is forecast to transform all medical specialties, including general practice. 

Genomics has been referenced in the NHS Long Term Plan as a driver of change as part of the strategic recognition of the importance of genomics for the future.

Clinicians in primary care are in a unique position to support patients with genomic conditions, as generalists with a holistic view of the patient.  Primary care clinicians, when fully supported by their specialist colleagues, will be able to offer advice to their patients in a primary care setting and can help co-ordinate their care if given a genetic diagnosis.

Personalised medicine

Genomic medicine is a core component of predictive, preventive, personalised and participatory medicine (also called P4 medicine). 

Personalised medicine, sometimes referred to as precision medicine, is already used in the fields of rare diseases and cancer but could in future inform all aspects of patient care.  This could include chronic disease management, such as deciding which patients may respond better to treatments for hypertension or diabetes. 

Genomics is also likely to be increasingly used in diagnosing pathogens, informing antimicrobial treatment.  Biomarkers such as gut microbes and other organisms that make up our microbiome may in time also be significant. 

Polygenic risk scores (PRS) are being developed to integrate genomic information with patient data and demographics to predict risk of disease and guide treatment. Evidence is still being collected on the clinical validity of these scores but there are many potential benefits over traditional risk scores. 

Polygenic risk scores will require integration of genomic data with information from the patient record to be able to contribute to personalised health guidance (see Figure 1).  A potential benefit of PRS is more accurate risk scoring, allowing personalised early intervention before disease is established.  The use of genomic data in this way will need to be implemented carefully to mitigate potential risks such as overdiagnosis and overmedicalisation.  There is also a risk of diverting care towards the ‘worried well’, overlooking higher-risk individuals who may be reluctant to participate in risk scoring. 

Patients may present to primary care with results from genomic testing via commercial direct-to-consumer (DTC) testing (discussed below).  This may bring benefits such as encouraging patients to be more proactive about their health and becoming engaged with preventative medicine.  There is, however, a risk of patients being misinformed about testing, test accuracy or the results and relative weight of these.  Patients may not also be fully aware of the privacy implications of this testing and the personal and familial data generated.

Figure 1 | The virtual medical coach model with multi-modal data inputs and algorithms to provide individualised guidance (Topol Review, 2019)

Genomics in primary care

Genomic medicine is not new to primary care, but its role will grow substantially with increased knowledge and more testing.  As most patient contacts are in a primary care setting, primary care clinicians are likely to be exposed to genomic medicine in contexts such as patients asking about family history or interpreting genomic information from regional genomic centre or hospital specialists.

Clinicians are already experienced in taking and assessing family history and knowing when to refer for heritable risk.  Primary care clinicians should continue to use their skills in risk assessment, holistic care and managing expectations of testing.  This includes helping patients on the emotional journey through uncertainty to explaining the consequences of life changing results which may impact not only the patient, but also their family and descendants.

Benefits of genomics to primary care

The benefits of genomics to primary care include:

• faster diagnosis for all using state-of-the art technologies, including significantly increasing the speed of diagnosis for people who suffer from rare diseases
• enabling reliable genomic counselling and access to services such as antenatal testing (if wanted by the parents) in order to guide treatments and support families in making informed reproductive choices
• interdependencies between clinical care and research will become the norm, research will produce information that has clinical significance to trial participants
• advancement of precision medicine – if genomic information is embedded in the clinical record, it will facilitate decision support on prescribing to help with dosing or avoid adverse effects

NHS Genomic Medicine Service

The NHS Genomic Medicine Service (GMS), established in 2018, seeks to make the NHS the first national health care system to offer whole genome sequencing as part of routine care.  It will use genomic data to provide new diagnostic approaches, novel/breakthrough treatments and help patients make informed decisions about their care.  This includes detection and treatment of high-risk conditions such as familial cancer or familial hypercholesterolaemia.

The GMS aims to offer genomic testing routinely, including to people with cancer, seriously ill children likely to have a rare genetic disorder, people with a rare condition and where whole genome sequencing (WGS) supports diagnosis and influences treatment options.

This stands to open new avenues for improving care whilst achieving value for money for the NHS.  Examples include:

• the Newborn Genomes Programme which will sequence the genomes of 200,000 babies aiming to improve early diagnosis and treatment of rare diseases
• Our Future Health which aims to collect information from five million UK adults to discover more effective ways to prevent, detect and treat diseases. By doing so it aims to promote a personalised and predictive healthcare through the use of genomics

National Genomic Test Directory

The national genomic testing service is delivered through a network of seven Genomic Laboratory Hubs (GLHs), each responsible for coordinating services for a particular part of the country.

One of the most useful resources for Primary Care Clinicians is the NHS National Genomic Test Directory sets out which genomic tests are available, the patients who are eligible, and the requesting specialties that will be routinely permitted to request the test.

If GLHs receive test requests from clinicians whose role doesn’t fall neatly within a single requesting specialty, or whose clinical specialty is not listed for that clinical indication, the GLH can process that test if it is appropriate as per their agreed local pathways and the eligibility criteria for the clinical indication is being met. 

Types of genomic test

Testing may be through a blood sample, mouth swabs, tissue samples, or body fluids.  These can be delivered via home testing kits, laboratory tests or point of care tests. 

Testing can be categorised by the purpose, e.g. diagnostic, predictive testing, family testing, carrier testing, to inform treatment decisions such as in cancer.

Genomic variants can be benign when they do not lead to disease, pathogenic when they lead to disease, or variants of uncertain clinical significance for which not enough is known about their long-term effects to know if they are pathogenic or not.

There are many types of genomic test:

• Single location testing | This is useful for single gene conditions or single location conditions for which the gene alterations are well known, e.g. cystic fibrosis or haemophilia.
• Panel testing | This involves testing of multiple genes associated with the development of a condition or a collection of symptoms under investigation.

• Microarray | A chromosome microarray is used to identify genetic causes of illness and developmental problems by identifying small bits of missing or extra DNA. It can be used as a prenatal diagnostic test for copy number variants or a first-line test for children presenting with developmental delay or multiple congenital anomalies.
• Predictive testing | This is the use of a genomic test in an asymptomatic person to predict future risk of disease.
• Whole exome (protein) sequencing or whole genome sequencing | All the pieces of an individual’s DNA that provide instructions for making proteins (the exome) or all an individual’s DNA (the genome) are sequenced and analysed.

Whole genome sequencing is usually done using next generation sequencing (NGS) which analyses millions of small DNA fragments mapped to a reference genome.  Depending on how much information is needed, NGS can sequence the entire genome, just the exome (DNA coding genes) or a panel of selected genes.

Whole genome sequencing is used when an underlying genomic cause is suspected in specific clinical situations, and eligibility criteria are held within the Genomic Test Directory. 

The cost of whole genome sequencing has dramatically reduced over the last decade and testing capacity has increased which means it is accessible for an increasing number of patients. Analysing the data generated to identify patterns (artificial intelligence or AI/big data) has given completely new approaches using bioinformatics to defining and diagnosing disease.

• Retrospective analysis | When newly discovered information about the genome can be used to search databases of patient genomes to find other people affected. This means that patients may now directly benefit from being on genomic research trials.  As more is learnt about the molecular causes of disease, new treatments for rare genomic diseases could be introduced and patients enrolled on trials.
• Cascade screening | Genetic testing of the relatives of a patient with a confirmed gene variant linked to disease.

Rare diseases

Rare diseases are conditions that affect <1 per 2000 population.  Individually they are rare, however collectively they are common, affecting 1 in 17 people in the UK or 3.5 million people.  A typical GP practice of 8000 patients could expect to have as many as nearly 500 patients with a rare disease, although with an estimated 80% of rare diseases having a genomic basis, these patients remain largely undiagnosed.  Patients often report a ‘diagnostic odyssey’ likely going many years or decades without diagnosis, seeing multiple specialists before a diagnosis is found. 

Approximately 75% of rare diseases affect children and can often lead to disability or poor prognosis.

With increased access to information and testing clinicians in primary care are likely to have a greater role in the diagnosis and ongoing management of rare diseases.  They can revisit inadequate historical diagnoses, link clinical features, and help patients by suspecting and diagnosing rare disease.

The Deciphering Developmental Disorders (DDD) project led to many breakthroughs in this field using new genetic technologies to help doctors understand why patients get developmental disorders.  A large proportion of children with severe early onset obesity, for example, carry genetic variants that affect energy balance.

The ethics of diagnosing rare diseases is complicated, as whilst many rare diseases will not have an established treatment, diagnosing them could lead to new discoveries and the development of new treatments. 

Example | A child presenting with seizures was identified through genomic testing as having a rare genetic disease affecting glucose transport to the brain.  This knowledge allowed novel treatment approaches such as a ketogenic diet. 

Cancer

Cancer is a disease of the genome caused by genetic errors, some of which the patient may have been born with and some which may have developed over time, or as a result of environmental factors. 

Germline DNA taken from a patient’s healthy cells can be tested for the genes that predispose to cancer.  Somatic DNA from cancer cells can be tested for variants that are acquired during cancer pathogenesis.  Together, this information can inform which treatments are likely to be effective. 

Germline DNA shared with family members can be used to optimise screening protocols.

Circulating tumour DNA (ctDNA) ‘liquid biopsy’ is showing potential new approaches to cancer screening.  This is when tumour DNA present in circulating blood is identified through a simple patient blood test, e.g., the Galleri test being piloted in the NHS which hopes to detect more than 50 forms of solid cancer early.  Early data indicates it may be able to pick up many difficult to diagnose cancers at earlier stages.

There are a rapidly increasing number of treatments for cancer that target tumours based on the genetic make-up rather than where they came from in the body such as new treatment for tumours with NTRK gene fusions.

Pathogen genomics

The 2019 Coronavirus pandemic highlighted the benefit of rapid polymerase chain reaction (PCR) testing both to diagnose cases, but also to track the pandemic and map genomic variants of concern.

With whole genome sequencing (WGS) the entire genetic information of a pathogen can be found, shared, processed, and analysed. For example pathogen genomics is routinely used in tuberculosis to rapidly analyse patterns of resistance and guide treatment.  As cases with genetically related strains of a pathogen can be linked, this can also lead to new insights into epidemiology.

The characterisation and surveillance of pathogens causing infectious disease is rapidly advancing and can be linked to epidemiological data, yielding complex multidimensional information which can be analysed as ‘big data‘.

Non-invasive prenatal testing

Non-invasive prenatal testing (NIPT) using free foetal DNA (ffDNA) detects large changes at chromosomal level between maternal and foetal blood.  NIPT is a screening test already used in the NHS to screen for common chromosomal disorders including trisomy 21 (Down’s syndrome), trisomy 18 (Edwards’ syndrome), and trisomy 13 (Patau’s syndrome).  This simple blood test of a mother’s blood allows high sensitivity and specificity screening which has dramatically reduced the need for invasive testing.

NIPT is beginning to be used to test more widely for genetic disorders that are caused by single-gene variants.   As technology improves and the cost of genetic testing decreases it is likely NIPT will become available more widely and for a wider range of genetic conditions.

It is important to ensure parents are fully aware of the possible implications of prenatal testing before that testing occurs, and consent to test is fully informed.  It should be made clear that testing is voluntary, and that the NHS will strive to provide whatever care is appropriate regardless of whether testing is undertaken and regardless of any test outcome.

Pharmacogenomics

Pharmacogenomics is the application of genomic information to guide pharmaceutical treatment based on an individual’s response to a drug.  This can be used to predict the effectiveness of a drug or predict an adverse drug reaction in an individual.  This is already being used in oncology and HIV medicine to minimise drug reactions.  It is predicted to have an increasing contribution towards prescribing in primary care.   

What clinicians need to do

Clinicians should:

• think genomics in patients with red flags such as unusual family histories of illnesses, unusual presentations, and surprising test results such as unusually high cholesterol; and think genomics in children with congenital illness, developmental delay, failure to thrive or syndromic symptoms
• use common general practice management principles for preventative and personalised medicine in the form of surveillance, risk reduction (lifestyle advice) and symptom awareness, and remind patients NHS screening is available, and to seek review if their family history changes
• consider ‘red flags’ from family histories of cancer, in particular clustering of cancer, e.g. 3 relatives with a same (or related) form of cancer, or 2 relatives with a related form of cancer early in life (<60 years)

Practices should:

• ensure good clinical coding of all incoming letters and correspondence especially from genetic services using appropriate SNOMED codes
• record relevant family history of disease
• gain consent and follow guidance on record information on family members’ notes

Direct-to-consumer (DTC) testing

DTC genomic testing is already accessed by patients via non-NHS routes and companies are increasing their marketing of DTC genomic tests to healthy people.

Patients need to consider who will have access to their data and how this data will be used, shared, or processed.   Some DTC genomic companies, for example, discount their testing and make much of their value proposition from the value of participant data to pharmaceutical companies.

Genomic tests sold directly to consumers for medically related purposes are regulated as in-vitro diagnostic medical devices.  The validity, sensitivity, and utility of private DTC tests are not subject to the same regulation or standards as NHS laboratories so may significantly vary , resulting in risks of false positive or false negative results.

For a more in-depth analysis of DTC testing see: House of Commons, Science and Technology Committee, Direct-to-consumer genomic testing First Report of Session 2021–22.

Genomic counselling

Genomic counsellors work with patients and families to support them in making informed decisions about tests and incorporate this information into their lives, allowing them to make health decisions.  Genomic tests can have serious medical, ethical, and emotional implications for the patient and their genetic relatives.  It can also reveal unintended information about biological relationships.  These risks need to be carefully considered before testing takes place.

How to deal with secondary genetic results not related to the clinical presentation may present a dilemma.  They may predict disease and whilst it can be helpful for the patients in managing their risk, there can be difficult, unexpected new knowledge for the patient leading to worry, stigma, or over medicalisation, for example, a patient having to make difficult decisions about having risk-reducing surgery when breast cancer genes are identified.

The role of the primary care clinician is to be aware of these risks but also to refer to a genetic counselling service where appropriate.

Ethics of sharing of genetic information

All health professionals have a core ethical duty to maintain patient confidentiality.  This can be difficult with genomic medicine as it can lead to conflict between the duty of confidentiality and the need to disclose results to family members who may also be affected.  It also leads to the rights of an individual to benefit from their own genomic data, and the rights of society to benefit from a greater understanding of the whole human genome.

The British Society for Genetic Medicine provides a forum for professionals involved in genetics and genomics as a clinical service and research and has lots of guidance on the sharing of genetic information.

Legislation

Genomic tests are regulated by the Medicines and Health Regulatory Authority (MHRA) as .

Genomic testing and the processing of genomic data in the UK is also covered by general legislation such as the Equality Act 2010 and the Data Protection Act 2018.

Patients have a right to expect the NHS to hold genomic data securely and to place standards in place to protect them from unauthorised disclosures.  More detail can be found in the NHS Genomic Medicine Service privacy notice. 

Risks and issues

Risks and issues include with genomic medicine include:

• Interpreting WGS is challenging | The number of variants in every human genome (4-5 million) still poses a huge challenge in the clinical interpretation of genomic variants. Moving from whole genomic data to providing safe and accurate diagnoses to patient will require accurately recorded and coded patient information.

The utility of using big data to find patterns in whole genomes will depend on accurately classifying genotype variants (i.e. pathogenic, benign, or variants of uncertain significance) with phenotype describing patient medical conditions, physical characteristics, and symptoms.

• Genomics and implications for screening | Genomic tests may not be acceptable for some sections of the population based on religious or moral beliefs, particularly if the test itself carries a risk of harm, or the outcome of the test won’t alter management. This can be the case for antenatal trisomy screening, for example. There will inevitably be diagnoses of diseases for which treatment is solely management of symptoms as they appear , which may mean limited advantage in early diagnosis. 

Genomic screening, for example, new-born screening (NBS) should use known variants for which there are effective and accepted interventions available. Screening of an asymptomatic population should focus on targeted analysis to limit unsolicited findings.

The Wilson and Jungner criteria have until now been considered the gold standard in making screening decisions.  Advances in genomics have meant the rate at which new disease genes are being identified is outpacing the ability to assess the potential benefits and pitfalls of screening for individual disease and new criteria have been proposed.

• Genomic information and insurance | Patients may potentially have to disclose genetic testing, although this is currently protected by the Code on Genetic Testing and Insurance.   
• Ancestry-related data | In the USA, ancestry-related data has been shared with police to solve crimes, raising issues around privacy and the use of confidential information.

The challenges of data governance are particularly complex with genomic data due to the fact it is shared via the biological link with relatives.  An individual’s consent to sharing knowledge via genetic testing may conflict with the preferences of their relatives who share the same variants.

• Data challenges | Genomic datasets contain vast amounts of data and are, therefore, difficult to integrate into traditional healthcare IT systems. Facilities for handling the data generated by genomic testing are needed.  To be useful, they are likely to be needed to be held in a single, secure environment which allows for both identifiable clinical care and for de-identified research use, providing an appropriate legal basis is there.

Related GPG content

• Medical devices and digital tools
• Artificial intelligence (AI) and machine learning
• Clinical coding – SNOMED CT
• Consent to record sharing

Other helpful information

Videos

• Health Education England, Dr Sarah Jarvis, and Professor Nadeem Qureshi, Rare disease: the GP’s role 

Toolkits

• Royal College of General Practitioners (RCGP), A collection of resources that explain how genomics medicine can be incorporated in primary care, RCGP Genomics toolkit

Education

• Health Education England, GeNotes; genomic notes for clinicians
• RCGP Sage publishing, Editorial: Genomics, general practice, and genomic literacy
• Health Education England, Genomics Education Programme

Reports

• Health Education England, 2019, The Topol Review: Preparing the healthcare workforce to deliver the digital future

• British Journal of General Practice, Vol 69, Issue 684, July 2019, an editorial that began as a debate presented at the 2017 RCGP annual conference and summarises the potential benefits and harms of genomic medicine in the context of primary care, Should UK primary care be an early adopter of genomic medicine?
• Department of Health and Social Care, 2017, Chief Medical Officer annual report 2016: generation genome

Websites

• Health Education England, Genomics in Primary Care
• RCGP, YouTube, Genomics webinars playlist
• The Jackson Laboratory, standardised terms, and vocabulary to describe the phenotypic abnormalities encountered in human disease, the Human Phenotype Ontology (HPO)