Introduction to genomics in primary care

Abstract

Advances in genomic technology and the launch of the NHS Genomic Medicine Service (GMS) in 2018 have firmly embedded genomic testing within routine clinical care. As the gateway to the NHS, primary care practitioners will be managing increasing numbers of patients who are eligible for genomic testing, or who present with their own, or a family member’s genomic test result. This article provides an overview of recent developments in the field of genomics, explains key concepts and terminology, and details the current organisation of the genomics services under the GMS. It also discusses some common presentations within primary care to highlight the relevance of genomics to frontline GPs.

Background

‘We can deliver this genomic dream’

Dame Sally Davies, Annual CMO report entitled ‘Generation Genome’.

‘We share half our genes with a banana’ was one surprising conclusion from the completion of the Human Genome Project, an international collaboration which succeeded in sequencing and mapping the 3 billion base pairs of the human genome over the course of 13 years and at a cost of around 2.7 billion US dollars (National Human Genome Research Institute, 2013). The first published sequence became version 1 of the Human Reference Genome and facilitated the identification of the genomic ‘instruction manual’- the 20 000 or so genes, as well as the non-coding, regulatory areas in between. Only specific areas of deoxyribonucleic acid (DNA) within each gene – the exons, or collectively, the exome (all those sequences in the genome that code for amino acids), are translated into proteins. And different exonic combinations within each gene can be stitched together (‘spliced’) to allow a single gene to code for multiple proteins. Identifying the precise locations of genes and the exons within them was revolutionary and the hope was that this information could be used to further genetic research and to improve diagnosis and management of disease.

However, the utility of genomics in mainstream medicine was limited by the technology available at this time. Sanger sequencing, used for the Human Genome Project, is a slow process, as it analyses tiny fragments of DNA one at a time. Its use can be laborious in academic research and impractical in clinical settings.

Subsequent technological developments in the form of next generation sequencing (NGS) have been transformative though. A process which allows millions of DNA strands to be sequenced together, in parallel, has enabled whole genome sequencing in a matter of days and at a cost of less than 1000 US dollars. Furthermore, it is feasible to limit sequencing to the exome, or even to a single or small panel of specific disease-causing genes, thus further reducing time constraints and cost.

As front-line clinicians in an increasingly busy and rapidly changing NHS, GPs may be forgiven for feeling that the accelerating genomics movement of the past 10 years does not really apply to them. However, these technological advances have been the key to the feasibility and utility of genetic testing in routine clinical care and as such, it is now becoming mainstream practice.

The recently completed 100,000 Genomes Project (Genomics England, 2018), involved the whole genome sequencing of thousands of individuals from families with rare diseases, or patients with cancer. Patients were recruited into the Project by their specialists and Genomic Medical Centres (GMCs) were established to streamline the processes of informed consent, sample taking, genetic testing and analysis. The knowledge gained from this large study has been a driving force in the subsequent development of the NHS Genomic Medicine Service, including not only the GMCs, but also, the establishment of regional Genomics Laboratory Hubs for the processing of samples, along with a supporting informatics service to assist with the identification and interpretation of genetic variants and report back to patients’ physicians. A National Genomic Test Directory has been created, which allows hospital clinicians to request standardised genomic testing (NHS, 2019). In time, access to these tests may be extended to primary care clinicians.

This new infrastructure will facilitate the continued development of genomic research and industry and provide a framework for incorporating genomics into mainstream clinical practice (mainstreaming).

So, what does this all mean for us? With an increasing move towards mainstreaming genomics, this article aims to introduce basic genomic concepts, commonly used genetic tests, and to consider some of the ways in which we may encounter genomic medicine at the coal face, both now and in the foreseeable future.

Terminology

Genomics vs genetics

The term ‘genetics’ refers to the study of genes and their roles in inheritance, whereas ‘genomics’ refers also to that of the entire genome including intergenic DNA which comprises over 98% of the genome.

Historically referred to as ‘junk DNA’, intergenic regions (those stretches of DNA in between the genes) are increasingly recognised as highly relevant to the regulation and control of gene expression and therefore, the pathogenesis of disease. Natural variation within these regions may confer protection or susceptibility to common diseases and may even mitigate Mendelian expression of disease for some individuals who carry pathogenic gene variants.

Variants vs mutations

Clinical case scenario

Miss B is a 28-year-old lady who comes to see you bringing a copy of a genomic test report belonging to her father. It states he has a ‘pathogenic variant in the BRCA2 gene’.

DNA ‘mistakes’ that cause disease have been termed mutations; those which are not disease-conferring are variants or polymorphisms. However, with the increasing use of sequencing and subsequent exponential discovery of variation, all changes in the sequence of DNA are now classified as variants of differing types according to an internationally recognised set of guidelines, with disease-causing variants referred to as pathogenic (Ellard et al., 2019).

As each of us typically has millions of variants, many of which involve not just a single base change, but large deletions or insertions of stretches of DNA (IGSR, 2020), deciding whether a variant discovered on DNA sequencing is pathogenic can be difficult and time-consuming, and it requires expertise and skill. Using specially designed IT programmes, computer scientists may create a shortlist of a patient’s variants, thus creating a more manageable register of those variants which are most likely to be disease-causing. This complex process is termed bioinformatics. Clinical scientists may then consider each of these contenders; using information from databases of previously discovered variants, from literature reviews and from their knowledge of the type of variant and its position in the genome, variants can be categorised into five classes, with Class 1 determined benign, Class 5 pathogenic and Class 3 of uncertain significance (Ellard et al., 2019).

We may receive a report stating that a pathogenic variant or likely pathogenic variant has been detected, and this would be interpreted as likely to be the cause of the patient’s disease. Benign variants are not reported, but there may be comment of a variant of unknown significance and this does introduce uncertainty. These variants are indeterminate - at the time of interpretation, the evidence base is not strong enough to clearly state whether it is disease-causing. This uncertainty must be shared with patients along with an explanation that such variants are not clinically actionable at the time of testing. Box 1 summarises some of these points.
Box 1.
Key genomic terms and nomenclature.

• Variant: Difference in patient’s DNA compared with the reference genome

• Polymorphism: Common variant defined as a minor allele frequency of >1%

• SNP: Single nucleotide polymorphism - a variant caused by a single base change

• Mutation: A disease-causing variant

• Point mutation: A disease-causing variant caused by a single base change

• Pathogenic variant: Preferred term for a disease-causing variant

• Benign variant: Difference in patient’s DNA compared with the reference genome; not disease-causing

• Variant of unknown significance: Difference in patient’s DNA compared with reference genome, unknown if disease-causing

• Phenotype: The observable characteristics or traits of an organism that are produced by the interaction of the genotype and the environment: the physical expression of one or more genes.

Types of genetic testing

The advances in testing described (NGS) have been at the level of the individual base, with sequencing determining the precise base order, identifying deviation from the reference genome (the representative human nucleic acid sequence, first identified by the Human Genome Project) at each of the 3 billion base pair positions across the genome. Changes at the single base level are generally easily identified, as are larger DNA alterations, such as insertions or deletions of genomic material. Sequencing tests are in routine clinical use now, though usually restricted to the sequencing of a single gene or gene panel rather than the whole genome (see Box 2). This approach reduces turnaround times for tests and costs. Critically, it reduces the number of identified variants of unknown significance through restricting analysis to those genes known to be associated with the presenting complaint (Sun et al., 2015). Examples of gene panels currently utilised include those for investigation of cardiomyopathy, familial hypercholesterolaemia, arrhythmias and familial cancer predictive testing.
Box 2.
Key points of genetic tests.

Karyotyping

Direct microscopic visualisation of the chromosomes, suitable for detecting very large, or whole chromosome deletions or copies, e.g. Down Syndrome.

Microarray comparative genomic hybridisation

A molecular test to check for smaller chromosomal losses or gains, e.g. children with learning disability, autism, developmental delay or dysmorphism

Targeted polymerase chain reaction tests

Molecular tests to detect specific, known pathogenic variants, e.g. hereditary haemochromatosis or Fragile X syndrome. Also used for the detection of specific mutations in certain cancer cells to guide treatment

Gene panel tests

Sequencing of one or more genes known to be associated with the disease in question. As every position of the gene is checked against the reference genome, this will detect all known pathogenic variants as well as new ones, previously undescribed, which are then assessed for pathogenicity

Whole exome sequencing

Sequencing of the coding parts (the exons) of all the genes in the human genome. Currently limited clinical use due to large amounts of data generated, but may be used to assess children for whom other tests have not established a diagnosis

Whole genome sequencing

Sequencing of the entire genome, including the non-coding areas. Has been used in research, such as the 100,000 Genomes Project, and is used clinically for assessing viral and bacterial genomes and some cancer genomes. UK plans to sequence a further 5 000 000 whole genomes within the next 5 years

Whole genome sequencing (WGS) within routine clinical care remains limited to a small number of indications presently captured within the Genomic Test Directory, including some children with undiagnosed rare disease. WGS is used more routinely within infectious disease, as microbial genomes are smaller, and thus, the data generated is manageable. Presently, all new tuberculosis patients in the UK benefit from WGS of their specimens to identify drug-resistant mutations, allowing timely, effective and personalised therapy from the outset. Additionally, serial WGS of new pathogens, such as SARS-CoV-2, is now the key to tracking spread and mutation rate and to developing therapeutic strategies for patient care.

Whole exome sequencing (WES) is a middle ground between a gene panel and whole genome sequence, enabling the entire protein coding sequence to be identified. Although significantly more limited than WGS, it still generates a huge amount of data, but is beginning to be used in certain clinical situations, for example, the assessment of children with developmental delay and epilepsy, for whom other genetic tests have not yielded a molecular diagnosis. NGS does have its limitations; in particular, it is not very good at identifying molecular alterations in regions of sequence repeat, which are the cause of some disorders such as Huntington’s disease.

Although rare genetic diseases are usually heterogenous, in that a number of different pathogenic variants within one or more genes can cause the same disease, there are some exceptions. Up to 93% of individuals with hereditary haemochromatosis associated with the gene HFE have the same pathogenic variant, referred to as C282Y. So, rather than sequencing the entire gene, testing for that one specific area within the gene, using a Polymerase Chain Reaction (PCR) technique, ensures a rapid and cheap means of diagnosis for the majority of patients. This particular gene test is already available to GPs.

So far, we have considered testing for genetic diseases caused by small changes in DNA sequences - at the level of one or a small stretch of base changes. However, at the other end of the spectrum lie diseases caused by much larger DNA alterations. Chromosomal disorders due to additional or absent whole chromosomes, such as Down Syndrome (trisomy 21), Turner Syndrome (XO) and Klinefelter Syndrome (XXY) can be diagnosed with simpler tests, such as karyotyping, comprising the direct microscopic visualisation of the chromosomes in cultured cells. However, many children with learning disability, developmental delay, dysmorphic features or multiple congenital abnormalities have relatively smaller missing or extra pieces of their chromosomes, which are undetectable by karyotyping.

For these children, a molecular technique called microarray comparative genomic hybridisation (CGH) is now the standard of care in the UK (Bassem et al., 2006). CGH uses thousands of DNA probes distributed across the entire genome, comparing the ratio of binding of these probes at specific sites across the child’s DNA, to that of a reference genome. In this way, small chromosomal losses or gains are identifiable and can secure a genetic diagnosis. Except for the X chromosome in males, most people have two copies of every bit of chromosomal material, but deletions result in just one copy of a particular genomic region being present whereas duplications generate three or more copies. Thus, deletion and duplication can be referred to as copy number variation and may represent either normal or pathogenic variation.

Unfortunately, microarray may miss small DNA changes at the base level (insertions or deletions, so-called ‘in-dels’) or smaller structural duplications or deletions of chromosomal material, for example in Fragile X syndrome, where a specific PCR targeted test is necessary. When targeted tests, karyotyping and microarray CGH have failed in securing a genetic diagnosis for children with learning disability and developmental delay, WES may be an option (Bassem et al., 2006). Box 2 summarises the fundamentals of these genetic tests.

NHS Genomic Medicine Service

In March 2017, the NHS England Board set out its strategic approach to build a NGM Service, building on the NHS contribution to the 100,000 Genomes Project (NHS, 2017). This comprises:
A national genomic laboratory service through a network of Genomic Laboratory Hubs (GLHs)

A new National Genomic Test Directory to underpin the genomic laboratory network

A national WGS provision and supporting informatics infrastructure developed in partnership with Genomics England

Clinical Genomics Medicine Services

A national co-ordinating and oversight function within NHS England (Genomics Unit)

The National Genomic Test Directory is evidence-based and nationally agreed, identifying the most appropriate genomic test for each clinical indication, and inclusion criteria for each test, ensuring equality of access for patients to genomic testing (NHS, 2019). It also specifies which specialties can request each genomic test enabling direct access testing from non-genomic specialties via the GLHs: a cornerstone of ‘mainstreaming’ genomic medicine. For example, clinical neurologists can request an ‘Adult-onset Movement Disorder’ gene panel, cardiologists a ‘Long QT Syndrome’ gene panel and oncologists can request BRCA1 and BRCA2 gene testing in women with ovarian cancer.

The new NHS England GMS is complex and, at the time of writing, the infrastructure is not fully established. Regional Clinical Genetics Services continue to be integral, working closely within networks and with other providers to support mainstreaming and embedding of genomic medicine within a geographical footprint.

Clinical Genetics Services cover wide geographical areas, providing outreach clinics throughout. When a referral is received into Clinical Genetics, further information including family history may be sought and verified prior to triage. Patients may be sent a family history questionnaire to complete and specialist family history administrators will then seek consent to collect further information including cancer diagnoses from the National Cancer Registry and test results and histology reports from patients and their relatives.

Genetic counselling is an important part of genetic and genomic testing and is defined as ‘the process of helping people understand and adapt to the genetic, medical, psychological and familial implications of genetic contributions to disease’. It is a non-judgemental, non-directive process with shared decision-making at its core (Resta et al., 2006). Genetic counselling is performed to some extent by many clinicians within routine clinical care; genetic counsellors are healthcare professionals trained to deliver genetic counselling at specialist level. Patients referred to Clinical Genetics may see a genetic counsellor or a clinical geneticist.

It should be remembered that genomic test results can be highly sensitive, with implications not only for those individuals who have consented to testing, but also for their family members, who hitherto, may not have considered their own genetic risk. To assist with the processes of consent and confidentiality, a comprehensive resource has been produced (Joint Committee on Genomics in Medicine, 2019) and includes guidance on performing genomic testing in children. Fundamentally, testing for adult-onset disorders should be delayed if the test result does not change clinical management during childhood (examples are Huntington’s disease, BRCA1/2 gene testing). Also important is guidance regarding the sharing of information with insurance companies. Currently a code exists, whereby members of the Association of British Insurers must refrain from asking for the results of predictive genetic tests or if they do have access to such test results, must overlook them when assessing applications for insurance. The only exception to this code is for applications for life insurance cover of over £500 000, in individuals who have already had testing for Huntington’s disease (Association of British Insurers, 2020).

Current presentations in primary care

GPs are already seeing patients with genomic presentations in primary care. Our generalist and holistic approach, knowledge of family structures and well-honed communication skills, enable us to manage these patients well. For the purposes of illuminating how genomics may appear in primary care, we present the following cases.

Family history

Clinical case scenario

Patient A is a 29-year-old woman who is currently well. She is concerned that her mother, aged 50, was diagnosed with breast cancer 3 years ago. She wonders if she needs to have additional screening for breast cancer.

Concern regarding risk for inherited predisposition to cancer is a common presentation in primary care. Though only around 5% of patients diagnosed with cancer have an underlying inherited cancer predisposition syndrome, carrying a pathogenic variant in the BRCA1 or BRCA2 genes increases lifetime risk of breast cancer to around 70% and of ovarian cancer to 44% and 17%, respectively (Ollsen et al). These genes can also be associated with an increased risk of prostate cancer and pancreatic cancer. Taking a three-generation family history for these cancers is vitally important, as is noting ethnicity, as people of Ashkenazi Jewish ancestry have a significantly higher incidence of BRCA mutations – as many as 1 in 40, compared with 1 in 400 of the general population (Hall et al., 2009).

The National Institute for Health and Clinical Excellence (NICE) has produced some comprehensive guidelines for the assessment and management of patients with a family history of breast, ovarian and colorectal cancer (NICE, 2019a) and Guys and St Thomas’s Hospital have produced a cancer genetics app. This can be downloaded for use during consultations to categorise patients into low, moderate, and high-risk groups and aid decision-making as to the need to refer for screening and/or gene panel testing.

Using these tools, patient A could be reassured that as she has only one affected relative diagnosed above the age of 40, she is at near-population risk of breast cancer. However, she would need to be advised to report back, should any further relatives be diagnosed with cancer, so that her risk could be recalculated.

The coding of significant family history of cancer on current GP computer records is important though current coding systems are insufficient to allow comprehensive and dynamic documentation. The development of IT to accommodate accurate coding could allow computer-generated risk prompts on which clinicians could act.

Clinical case scenario

Patient B is a 35-year-old man who is concerned about his risk of heart disease. His mother died of a myocardial infarction (MI) at the age of 48. He has attended the surgery, as his brother has recently had an MI at the age of only 38 and was found to have a high cholesterol level at presentation. Neither relative was a smoker or diabetic. B has had a lipid profile done and his total cholesterol is 7.9 with LDL of 5 mmol/l.

This patient does have some red flags for genetic disease. He has more than one relative, with disease at a younger age than would normally be expected and without other risk factors for the disease.

According to the Simon Broome Diagnostic Criteria, Familial Hypercholesterolaemia (FH) is a possibility in this patient (NICE, 2019b). Should he be found to have tendon xanthomas, he could be diagnosed with definite FH even prior to genetic testing. Clearly, B would need aggressive lipid-lowering treatment and management of other risk factors. However, a genetic diagnosis would also be very helpful for him. If B, or his brother, has children, screening could be offered to them early, with a view to starting lipid-lowering treatment by the age of 10 (NICE, 2019b). Genetic testing for FH comprises a panel of the most commonly implicated genes and is currently accessed through a network of FH clinics.

Rare disease

Clinical case scenario. Patient C is a 23-year-old woman who presents with atypical chest pain and is particularly worried, because her father was found dead at home of a ‘heart attack’ at the age of 50. She also mentions that she has some low back pain for which she has been seeing an osteopath and he has mentioned to her that she has a scoliosis.

On examination, her GP finds that she is tender over the anterior chest wall, in keeping with musculoskeletal aetiology. However, when C stands for examination of her back, he notices that she is tall, very thin, does indeed have a lumbar scoliosis and stretch marks on her lower back. She wears thick glasses as she is highly myopic.

Her GP wonders if she might have Marfan Syndrome and checks the symptoms and signs, noting that she does have arachnodactyly with positive wrist and thumb signs, a high-arched palate, and pectus excavatum. In view of her family history of sudden cardiac death and phenotype, Marfan Syndrome is a possibility (Marfan Foundation, 2014).

Her GP needs to sensitively discuss referral to Clinical Genetics with this patient. She may never have heard of Marfan Syndrome and may have thought she was coming merely for reassurance regarding her musculoskeletal chest pain.

Marfan Syndrome is just one of thousands of rare diseases. Although, by definition, an individual rare disease affects less than 1 in 2000 people, collectively they are common, affecting around 1 person in 17 in the population. Thus, the average GP will see one or two patients with rare disease each day. As generalists, we cannot possibly be aware of the full spectrum of these diseases, but we can be alert to the red flags. A growing number of resources are available to help us. The database Mendelian (Mendelian, 2020), for example, allows clinicians to enter symptoms or signs into its search engine to produce possible genetic diagnoses, helping us to spot the zebra amongst the crowd.

Direct-to-consumer testing

Clinical case scenario

Patient D, a 29-year-old woman, is anxious. She paid for genetic testing through a commercial company as she has a strong family history of breast cancer. Though she was pleased that her breast cancer gene testing was negative, she tested positive for a variant in the APOE gene which places her at increased risk of late onset Alzheimer’s disease. She wants to be referred to the Clinical Genetics team for further testing and clarification.

Direct-to-consumer (DTC) testing is becoming more popular, with millions of people globally having taken a test. These tests may not offer comprehensive DNA sequencing, but targeted analysis of a few specific DNA sites. They offer details on ancestry and traits such as tendency to baldness, but also, some health-related testing. This includes checking for specific single nucleotide polymorphisms, which have been shown to be either disease-causing (such as a few BRCA pathogenic variants) or associated with increased risk of disease.

Unfortunately, these tests are prone to technical errors - a finding may not be accurate, leading to unnecessary anxiety or false reassurance. In addition, many of the variants associated with increased risk of common diseases are difficult to interpret - too little is known about the range of SNPs which together might increase or decrease an individual’s risk of common diseases, so that checking for only one of these will give a mere glimpse of the true clinical picture. And, assuming a true increased risk of, for example, Alzheimer’s disease, referral to the genetics clinic is unwarranted. Intervention at primary care level would comprise taking a family history to assess risk, and if at near-population risk then reassurance that Alzheimer’s disease is multifactorial, and that risk can be reduced by adhering to a healthy lifestyle.

Finally, it must be noted, that where there is a significant family history of cancer, reports of negative BRCA screening can be misleading, particularly if DTC testing surveys only a few, out of potentially thousands of pathogenic variants. Hence, a pathogenic variant may have been missed. If, after taking a family history, she fulfils the NICE criteria, D should be offered appropriate referral.

The RCGP has recognised the challenges for the NHS and primary care of these tests and have produced a Genomic Position Statement which provides further clarity as to how to deal with the results of these tests if presented to a primary care practitioner (RCGP / BSGM, 2019).

Reproductive issues in genomics

Clinical case scenario

Patient F is a 36-year-old woman who wishes to discuss pre pregnancy planning. She already has a 14-year-old son with Duchenne muscular dystrophy, but as she has remarried, she is wondering if she is still at risk of having another child with the condition.

Duchenne muscular dystrophy is an X-linked recessive disorder caused by a pathogenic variant in the dystrophin gene. Two thirds of cases are inherited along the maternal line, with one third arising from a new de novo mutation (National Institute of Neurological Disorders and Stroke, 2019).

In this setting, it is impossible to say whether both mother and son carry the pathogenic variant without them both undergoing genetic testing. Should F carry the mutation, she has a 50% chance of passing it on, so that half her daughters will be carriers and half her sons will be affected. The fact that she has a new partner is irrelevant.

F and her son should be offered genetic testing. This may confirm if she has the pathogenic variant and determine the risk for future children. Should she be a carrier and dependent upon local guidelines, she may be eligible for Pre-implantation Genetic Diagnosis, whereby embryos created by in vitro fertilisation are screened for the condition prior to uterine transfer.

What might the future hold?

There are bold ambitions for genomics to enable a personalised and individualistic approach to medical care. Within grasp is the widespread application of pharmacogenomics within medical care. Currently, pharmacogenomic testing (prescribing based on genetic variation) is advised for a handful of indications, such as checking for the HLA-B1502* gene variant in patients of South East Asian origin prior to starting carbamazepine, due to the significantly increased risk of Stevens Johnson syndrome in this group.

As there are around 200 medications, whose efficacy and side-effect profile may be altered depending on genotype, awareness of a patient’s pharmacogenomic status can be very helpful in guiding appropriate choice and dosage of medication (Food and Drug Administration, 2019). Given that adverse drug reactions cause 700 deaths in the UK each year and cost around £530 000 000 annually, the case for the cost-effectiveness of testing is gathering momentum (Policy Unit for Economic Methods of Evaluation in Health and Social Care Interventions, 2018). The 100,000 genomes programme will report back some variants with pharmacogenomic implications, and pharmacogenomic testing is envisaged as a key part of the developing GMS.

And it may not stop there. Imagine a world where every individual’s entire genomic fingerprint was available at the click of a button. It may not be as far away as we think. As Matt Hancock, Secretary of State for Health and Social Care, stated last year, ‘My ambition is that eventually, every child will be able to receive whole genome sequencing along with the heel prick test’. Watch this space!

KEY POINTS

Genomics is the study of the entirety of DNA, including coding and non-coding regions, together with genomic technologies it will allow sequencing, interpretation and analysis; it also considers gene expression and the interplay between genes

Genomic medicine is the use of genomic information and technologies to determine disease risk and predisposition, diagnosis and prognosis, and the selection and prioritisation of therapeutic options

Genomic testing covers a spectrum of tests from CGH Micro-array, WGS and WES, through to testing of single genes or multiple genes in ‘gene panels,’ or testing for a single gene variant

DNA variants are classified into pathogenic or disease-causing variants (previously known as mutations), benign variants, or variants of uncertain significance

Genomics is impacting and presenting in primary care within clinical areas of Familial Cancer, Rare Disease, Cancer treatments, Prescribing and DTC testing

Patients may present with a concern about their family history, ‘red flags’, eligible for genomic testing or with their own or a family member’s result, or a variety of related issues outlined within the MRCGP Curriculum Statement Topic Guide ‘Genomic medicine’

Footnotes

ORCID iDs

Dr Alexandra Whiter

Dr Judith Hayward

Dr Imran Rafi

References

ABI (2020) Code on genetic testing and insurance. Available at: www.abi.org.uk/data-and-resources/tools-and-resources/genetics/code-on-genetic-testing-and-insurance/ (accessed 01 May 2020).

Bejjani

Shaffer

, et al. (2006) Application of array-based comparative genomic hybridization to clinical diagnostics. Journal of Molecular Diagnostics 8(5): 528–533. DOI: 10.2353/jmoldx.2006.060029.

Davis S (2017) Annual report of the Chief Medical Officer 2016: Generation genome. Report for the Department of Health, UK. Available at: www.gov.uk/government/publications/chief-medical-officer-annual-report-2016-generation-genome (accessed 20 October 2020).

Ellard S, Baple E, Berry I, et al. (2019) ACGS Best practice guidelines for variant classification 2019. Available at: www.acgs.uk.com/media/11285/uk-practice-guidelines-for-variant-classification-2019-v1-0-3.pdf (accessed 01 March 2020).

Food and Drug Administration (2019) Table of pharmacogenomic biomarkers in drug labeling. Available at: www.fda.gov/media/124784/download (accessed 01 March 2020).

Genomics England. (2018) The 100,000 genomes project. Available at: www.genomicsengland.co.uk/about-genomics-england/the-100000-genomes-project (accessed March 2020).

Hall

Reid

Burbidge

, et al. (2009) BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer 115(10): 2222–2233. DOI: 10.1002/cncr.24200.

IGSR: The International Genome Sample Resource (2020) IGSR and the 1000 genomes project. Available at: www.internationalgenome.org/ (accessed 01 March 2020).

Joint Committee on Genomics in Medicine (2019) Consent and confidentiality in genomic medicine; guidance on the use of genetic and genomic information in the clinic. Available at: www.rcplondon.ac.uk/projects/outputs/consent-and-confidentiality-genomic-medicine (accessed 01 May 2020).

10.

Kuchenbaecker

Hopper

Barnes

, et al. (2017) Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317(23): 2402–2416. DOI: 10.1001/jama.2017.7112.

11.

Marfan Foundation (2014) Marfan and related conditions: What are the signs? Available at: www.marfan.org/about/signs (accessed 01 March 2020).

12.

Mendelian (2020) Mendelian for physicians. Available at: www.mendelian.co/ (accessed 01 March 2020).

13.

National Human Genome Research Institute (2013) The human genome project. Available at: www.genome.gov/human-genome-project (accessed March 2020).

14.

National Institute of Neurological Disorders and Stroke (2020) Muscular dystrophy, hope through research. Available at: www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Muscular-Dystrophy-Hope-Through-Research (accessed 01 March 2020).

15.

NHS (2017) NHS genomic medicine service. Available at: www.england.nhs.uk/genomics/nhs-genomic-med-service/ (accessed 15 May 2020).

16.

NHS (2019) National genomic test directory. Available at: www.england.nhs.uk/publication/national-genomic-test-directories/ (accessed 15 May 2020).

17.

NICE (2019a) Familial breast cancer: Classification, care and managing breast cancer and related risks in people with a family history of breast cancer. Available at: www.nice.org.uk/Guidance/CG164 (accessed 15 March 2020).

18.

NICE (2019b) Familial hypercholesterolaemia: Identification and management. Appendix F Simon Broome diagnostic criteria for index individuals and relatives. Available at: www.nice.org.uk/guidance/cg71/evidence/full-guideline-appendix-f-pdf-241917811 (accessed March 2020).

19.

Policy Unit for Economic Methods of Evaluation in Health and Social Care Interventions (2018) Prevalence and economic burden of medication errors in the NHS in England. Available at: www.eepru.org.uk/prevalence-and-economic-burden-of-medication-errors-in-the-nhs-in-england-2/ (accessed 01 March 2020).

20.

RCGP. Clinical topic guide: Genomic medicine. Available at: www.rcgp.org.uk/training-exams/training/gp-curriculum-overview.aspx (accessed 21 June 2020).

21.

RCGP and BSGM (2019) Position statement on direct-to-consumer genomic testing. Available at: www.rcgp.org.uk/-/media/Files/CIRC/Clinical-Policy/Position-statements/RCGP-position-statement-on-direct-to-consumer-genomic-testing-oct-2019.ashx?la=en (accessed 17 May 2020).

22.

Resta

Beisecker

Bennet

, et al. (2006) A new definition of genetic counseling: National Society of Genetic Counselors’ task force report. Journal of Genetic Counseling 15(2): 77–83. DOI: 10.1007/s10897-005-9014-3.

23.

Sun

Ruivenkamp

Vrijenhoek

, et al. (2015) Next-generation diagnostics: Gene panel, exome, or whole genome? Human Mutation 36(6): 648–655. DOI: 10.1002/humu.22783.

24.

UBQO. Cancer genetics (2016). Hereditary cancer risk assessment and referral guidance for clinicians. Available at: www.ubqo.com/cancergenetics (accessed 05 March 2020).