The Rise of the Genome and Personalised Medicine

Home , Medical genetics, Whole genome sequencing

Clinical Medicine 2017 Vol 17, No 6: 545–51 CME GENETIC MEDICINE

T h e r i s e o f t h e g e n o m e a n d p e r s o n a l i s e d m e d i c i n e

A u t h o r s : H e l e n K B r i t t a i n , A R i c h a r d S c o t tB a n d E l l e n T h o m a s C

Virtually all medical specialties are impacted by genetic disease. that clinically useful information is typically provided through Enhanced understanding of the role of genetics in human dis- diagnostic laboratories in 2–12 weeks, depending on clinical ease, coupled with rapid advancement in sequencing technol- urgency. Fig 1 and Table 1 provide an overview and comparison ogy, is transforming the speed of diagnosis for patients and of the approaches using newer sequencing technology: whole providing increasing opportunities to tailor management. As genome sequencing (WGS), whole exome sequencing and ABSTRACT set out in the Annual report of the Chief Medical Offi cer 2016: targeted sequencing of genes via a static ‘panel’. Generation Genome 1 and the recent NHS England board paper Creating a genomic medicine service to lay the foundations to The genome and rare disease deliver personalised interventions and treatments, 2 the increas- There are an estimated 6,000 rare diseases, each defined ing ‘mainstreaming’ of genetic testing into routine practice and as affecting less than 1 in 2,000 people. 6 In the UK, these plans to embed whole genome sequencing in the NHS mean cumulatively affect 3.5 million people5 equating to a 1 in that the profi le and importance of genomics is on the rise for 17 lifetime risk. 80% are estimated to have genetic origins.7 T h e s e many clinicians. This article provides a brief overview of genom- include conditions with a virtually exclusive Mendelian genetic ics and its current clinical applications, including its contribution aetiology and rare Mendelian subsets within common disorders to personalised medicine. Physicians will be signposted to key is- (eg familial hypercholesterolaemia). In some disorders, highly sues that will allow the successful implementation of genomics targeted genetic testing remains best, for example cystic fibrosis, for rare disease diagnosis and cancer management. which is readily identifiable clinically with a single causative gene. In an increasing number of clinical settings, broader-based genetic investigation – such as gene panels, exome sequencing The rise of genomics Genomic medicine has the capacity to revolutionise the Key points healthcare of an individual with a rare disease or cancer by offering prompt and accurate diagnosis, risk stratification based Genomic approaches offer the capacity to understand the upon genotype and the capacity for personalised treatments. breadth of rare disease and cancer, including those that are exclusively genetic, common diseases with a Mendelian subset, Deciphering the genome polygenic complex conditions and somatic mosaic conditions The human genome comprises in excess of 3 billion DNA base pairs. 3 It was first mapped through the Human Genome The applications of personalised medicine are numerous and Project, an extensive international collaboration over exciting and are growing, but the evidence base and impact of 13 years.4 Advances in sequencing technology (known as ‘next each intervention requires thorough analysis generation sequencing’) have enabled a genome to be sequenced within hours, at a fraction of the initial cost,5 resulting in Every human genome contains around 3–5 million genetic widespread application for diagnosis and research. Previously, variants compared with the reference sequence. Caution is individual genes were sequenced exon by exon, using capillary therefore required in analysing genomic results and attributing electrophoresis (Sanger sequencing). Despite the speed and causation for any given variant; expert interpretation, preferably automation involved in the sequencing itself, considerable in a multi-disciplinary setting is required input is required in the interpretation of the results, meaning Detailed clinical information, in terms of phenotype and family structure, remains key in interpreting genetic variation Authors: A honorary clinical fellow in clinical genetics, Great Ormond Street Hospital, London, UK, Queen Mary University of London, UK It is important that patients and clinicians do not see a negative and Genomics England, London, UK ; B consultant in clinical genetics, genomic test result as a ‘clean bill of health’ Great Ormond Street Hospital, London, UK and Genomics England, London, UK ; Chonorary consultant in clinical genetics, Guy’s and St KEYWORDS: Ethics, genomics, personalised medicine, variant Thomas’ NHS Foundation Trust, London, UK, Queen Mary University classification and whole genome sequencing ■ of London, UK and Genomics England, London, UK

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Your genome is your unique sequence of DNA, 3 billion leers long, it's found in almost every cell in your body DNA The leers A, T, C and G represent the chemical elements, or bases, of DNA DNA is extracted from a blood sample

WGS WES Stac gene panel The exons from a Only the exons pre-determined (coding regions set of genes (a of genes) are Genomic DNA panel) are captured and is fragmented captured and then ampliﬁed then ampliﬁed by PCR by PCR

Sequencing The machine determines The 'reads' from the sequencing and mapping the sequence of short machine are matched to a pieces of DNA, 150 leers reference sequence. This is called long. These are called reads. mapping.

Reference human genome sequence

Each line of leers is one 'read' from Variant calling the sequencing machine – approx 150 leers long

A red leer indicates a diﬀerence from the reference sequence

Variant interpretaon Analysis

Fig 1. An overview of whole genome sequencing (WGS), whole exome sequencing (WES) and static gene panel techniques. Adapted from graphics provided by Genomics England.

and WGS – is recognised as advantageous, particularly where the uncontrolled cell division. Sequencing DNA extracted from phenotype is variable or non-speciﬁc and the range of plausibly a tumour constructs a picture of the mutational events and causative genes is wide. Table 2 gives examples of how patients drivers for oncogenesis. These somatic genomic mutations can can beneﬁt from WGS.2 In addition, WGS can detect non-coding direct therapy based on likely tumour response. variants that disrupt regulatory control of gene expression and Abbosh et al 8 outline the potential role in sequencing potentially uncover novel disease mechanisms. circulating tumour DNA (ctDNA), which is separate from cellular DNA, to identify tumour recurrence in advance of The genome and cancer conventional imaging modalities. This could offer a therapeutic window of opportunity and the potential to identify further Cancer is a genetic disease resulting from an accumulation mutations within the ctDNA sequence, indicating the of mutations in a particular tissue (the soma) causing development of chemotherapeutic resistance.

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Table 1. A comparison of whole genome sequencing, whole exome sequencing and static gene panel techniques Approach Definition Advantages Disadvantages Whole Sequencing of the > Comprehensive > Expensive genome entire genome > Even coverage enabling identification > Millions of variants, which can be difficult to sequencing of dosage abnormalities/structural interpret (WGS) rearrangements > Relatively shallow sequencing (fewer reads per > Detects non-coding variants gene), which can affect sensitivity; however, this is > Potential to detect disorders caused improving as technology advances by DNA repeats, including Fragile X, > Need a clear system to deal with additional myotonic dystrophy findings > Able to detect mitochondrial mutations Whole exome Sequencing of > Cheaper than WGS > Less even coverage of the genome, therefore sequencing the exons (coding > Analysis not restricted to genes known dosage abnormalities are more difficult to detect (WES) or region) of genes or to cause a given condition > Only 1–2% of the genome is covered clinical exome sequencing of the > Fewer variants than WGS so easier to > Need a clear system to deal with additional sequencing exons of known interpret findings disease genes > Deep sequencing increases sensitivity > Able to detect mitochondrial mutations Targeted gene Sequencing of a > Cost effective > Difficult to add new genes to the panel as they sequencing via specific list of pre- > Very deep sequencing are discovered as this requires a redesign of the a static gene determined genes capture process > Fewer variants detected so data easier panel that are known to to interpret > Less even coverage of the subset of genes, therefore cause a particular dosage abnormalities are harder to detect phenotype > Patients do not benefit from additional health findings

Sequencing an individual’s constitutional DNA (their interaction, will evolve. Currently, there are very few clinical germline) reveals inherited cancer predisposition syndromes, settings where testing for such variants alters management. conferring considerable lifetime risk of malignancy. Many of these are heritable as autosomal dominant traits and may Communicating genomics and ethical considerations therefore direct treatment choices, as well as surveillance, for Genomic test results have potential implications for the family members. sequenced individual, their family and future generations. Although there is currently no single accepted approach, The genome and common disease it is increasingly becoming standard practice to consider categorising the potential ﬁndings: In time, with access to large genomic datasets, the capacity to understand complex disease predisposition through multiple > p e r t i n e n t ( p r i m a r y ) ﬁ ndings – those related to the original small-effect genetic variants, coupled with environmental reason for the test, providing a diagnosis.

Table 2. Cases reported in the NHS England Board paper demonstrating a benefit from WGS Demographics Diagnosis Method of diagnosis Benefit 4-year-old girl Glut1 deficiency syndrome WGS via 100,000 genomes Specialised treatment with a low-carbohydrate diet project has led to symptomatic improvement Three sisters with Breast cancer Clinical diagnosis. No Ongoing active participation in research via the breast cancer mutations identified in BRCA1 100,000 genomes project to further the knowledge and BRCA2 genes on the NHS of the causes of breast cancer 10-year-old girl Life threatening WGS via 100,000 genomes Understanding about why she is prone to infections. chickenpox infection; project Altered her management as she is being considered CTPS1 mutations identified for a bone marrow transplant as a potential cure 29-year-old man Severe learning disability; WGS via 100,000 genomes Understanding the cause for his difficulties. mutation identified in a project Reassurance for family members that the new new disease gene mutation in him is unlikely to affect the wider family Annex A cases from page 8.2

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> a d d i t i o n a l ( s e c o n d a r y ) fi ndings – genetic alterations that our understanding of disease and its molecular mechanisms, confer the risk of another, unrelated disease. Conditions and therefore the capacity for personalised interventions. with an intervention to reduce the risk of an adverse Increasingly, other testing modalities will contribute, including outcome, including cancer predisposition syndromes with transcriptomics (RNA-based testing), metabolomics (analysing effective screening or surgical approaches, can be sought the metabolites present in an individual) and proteomics specifi cally. The American College of Medical Genetics (analysing the entire complement of expressed proteins). and Genomics (ACMG) have published guidance on this.9 Patients can choose whether to receive these fi ndings. Prediction and prevention of disease > carrier status – fi ndings of reproductive relevance, where risk of a specifi c condition is conferred upon future An important example in prediction and prevention of generations. disease is familial hypercholesterolaemia, where heterozygous 14 > i n c i d e n t a l fi ndings – other types of information, for gene mutations are expected in 1:500 of the population. example identifi cation of misattributed paternity. This confers a high risk of cardiovascular disease and is Management of these fi ndings, and consideration of inherited in an autosomal dominant manner. Risk-reducing whether it is appropriate to feedback, should be directed treatments have been recommended by the National Institute by professionals experienced in genetic counselling, for Health and Care Excellence (NICE) since 2007 (Table 3 ). considering the context of the sequencing and clinical Molecular diagnosis and familial cascade testing by genotype impact of any results. identify those who warrant aggressive lipid-lowering therapy, representing an exciting step towards primary prevention. More For those who have no clear diagnostic-grade findings from families with familial hypercholesterolaemia will be identified genomic testing, it is important this is not interpreted as a through analysis of secondary findings from genomic tests for ‘clean bill of health’. The negative predictive value of genomic unrelated conditions. testing is uncertain in many clinical settings, reflecting the current knowledge base, and would be expected to improve once our understanding of the phenotypic effects of an Targeted therapy based on effi cacy individual’s genome-wide variation gain precision. Reviewing There are long-standing examples of germline findings, such the phenotype and potential disease mechanisms, and offering as BRCA1 and BRCA2 mutations, used in the oncological research participation, may offer additional opportunities for a setting to predict the natural history of disease and enable genetic diagnosis. individualised choice regarding risk-reduction. Increasingly, these results also direct therapeutic strategies. Interpreting genomic data The cancer, or somatic, genome can predict therapeutic response through an understanding of the molecular Understanding variation within the human genome, to implications of certain mutations. For example, in malignant differentiate ‘normal’ from disease-causing variants, is melanoma, the BRAF V600E mutation is common and results challenging. Every human genome contains around 3–5 million in constitutive activation of downstream signalling pathways,15 genetic variants compared with the reference sequence. The leading to cellular proliferation. Vemurafenib, an inhibitor of vast majority of rare variants in the genome have no link mutated BRAF, has been shown to improve overall survival and to a patient’s disorder. Positive evidence needs to be sought progression-free survival compared with standard therapy,15 as to the pathogenicity for any given variant, accompanied leading to its recommendation by NICE. Table 3 summarises all by consideration of the phenotype, family structure and NICE approvals by genotype (germline and somatic). inheritance pattern. Therefore, a multidisciplinary approach including clinical scientists and clinicians is recommended. Development of new targeted therapies UK diagnostic genetics laboratories are adopting variant classification guidelines from the ACMG. 10 Accuracy is vital A number of conditions have progressed through the cycle of given the potential harm – not just for the individual, but gene discovery, pathogenesis research and development of a also family members and perhaps future generations – if an novel treatment, leading to clinical trials. One such example is inaccurate diagnosis is made. the delineation of FGFR3 signalling pathways and mechanism Increasingly, large databases of genomes across different of reduced bone formation in achondroplasia. This has led to ethnic populations, from sources including GnoMAD 11 a n d phase III clinical trials for BMN111 16 after promising pre- the 100,000 genomes project,12 will improve the accuracy of clinical and earlier phase studies, 17 which suggest this treatment interpretation. improves bone growth. Health Education England provide a range of courses on genomics, from formal qualifications through to continuing Pharmacogenetics to minimise the risk of personal and professional development modules ( www. adverse events genomicseducation.hee.nhs.uk/taught-courses). Genetic variation is already used to predict treatment response P e r s o n a l i s e d m e d i c i n e or adverse effects across a number of clinical areas. An example of this isabacavir treatment in HIV, where genotype can predict Personalised medicine represents a shift in approach from the risk of a severe adverse reaction. 18 Selection of an alternative ‘one-size-fits-all’ to tailored care and targeted therapies.13 T h e anti-retroviral drug in those at risk has been shown to be an application of new technologies, including genomics, enhances effective strategy.

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or BRCA1 apy and er 15 months will be met by the company. months will be met by er 15 art of treatment they have chronic kidney disease stage 2 or 3 at the disease stage chronic kidney have they st had three or more courses of platinum- have they based chemother there is evidence of rapidly progressing disease and the of rapidly there is evidence company provides it with the discount agreed in patient access scheme. people who remain on the drug cost of olaparib for treatment aft hypercholesterolaemia or mixed dyslipidaemia, only if: hypercholesterolaemia weeks. 2 mg every The dosage is 140 option for treating autosomal dominant polycystic treating autosomal dominant polycystic option for disease in adults to slow the progression of cyst kidney only if: and renal insufficiency, development > ovarian, treating adults with relapsed, platinum-sensitive who have tube or peritoneal cancer fallopian and whose disease has responded to mutations BRCA2 only if: platinum-based chemotherapy, > treating primary Optimised recommendation for or mixed dyslipidaemia, only if: hypercholesterolaemia are persistently concentrations lipoprotein Low-density maximal despite the thresholds specified above therapy. lipid-lowering tolerated That is, either the maximum dose has been reached or in the (as defined intolerance by is limited titration further and the hypercholesterolaemia), familial NICE guideline for company provides alirocumab with the discount agreed in the patient access scheme. > > Optimised treating primary Optimised recommendation for Optimised as an tolvaptan Optimised recommendation for Optimised Optimised olaparib as an option for Optimised recommendation for Recommended authorisation. in line with marketing Recommended Recommended authorisation. in line with marketing Recommended Treating primary hypercholesterolaemia and primary hypercholesterolaemia Treating mixed dyslipidaemia Treating autosomal dominant polycystic autosomal dominant polycystic Treating disease kidney and primary hypercholesterolaemia Treating mixed dyslipidaemia Treatment of relapsed, platinum-sensitive, of relapsed, platinum-sensitive, Treatment fallopian ovarian, mutation-positive BRCA response to after tube and peritoneal cancer second-line or subsequent platinum-based chemotherapy Treating primary heterozygous-familial and primary heterozygous-familial Treating hypercholesterolaemia non-familial non-familial hypercholesterolaemia non-familial Technology Condition Condition Technology Comment Categorisation with co-administered therapy initial statin Relevant Relevant genome Year of Year publication 2016 (2007)2016 Germlinemonotherapy Ezetimibe and 2016 (2007) primary heterozygous-familial Treating Germline Ezetimibe TA394 2016 Germline Evolocumab Table 3. Personalised interventions recommended by the National Institute for Health and Care Excellence (NICE) on the basis of genotype of genotype (NICE) on the basis Excellence Health and Care for the National Institute by recommended interventions Personalised 3. Table Technology appraisal number TA358 2015 Germline Tolvaptan TA393 2016 Germline Alirocumab TA381 2016 Germline Olaparib TA385 (&TA132) TA385 (&TA132)

CMJv17n6-CME_Brittain.indd 549 11/18/17 10:50 AM CME Genetic medicine Recommended in line with clinical practice for use within for practice in line with clinical Recommended only if the conditions in managed drugs fund cancer osimertinib are followed. access agreement for agreement of a patient access scheme. following company provides erlotinib with the discount agreed in of NICE in the context the patient access scheme revised guidance 258. Sections 1.1–1.5 of appraisal technology usage. summarise guidance for TA374 and following agreement of patient access scheme. and following and following agreement of patient access scheme and following and following agreement of patient access scheme. and following Low-density lipoprotein concentrations are persistently are persistently concentrations lipoprotein Low-density maximal tolerated despite the thresholds specified above That is, either the maximum therapy. lipid-lowering by is limited titration dose has been reached, or further familial in the NICE guideline for (as defined intolerance hypercholesterolaemia). with the discount The company provides evolocumab agreed in the patient access scheme. agreement of patient access scheme and following authorisation. marketing Recommended Recommended (CDF) Recommended authorisation and in line with marketing Recommended Optimised erlontinib, only if the Optimised recommendation for Recommended authorisation in line with marketing Recommendation Recommended authorisation in line with marketing Recommendation Recommended authorisation in line with marketing Recommendation Recommended authorisation in line with marketing Recommendation Recommended in line with Recommendation of TA70. update Partial elodysplastic syndromes associated with an associated elodysplastic syndromes Locally advanced or metastatic EGFR T790M or metastatic advanced Locally non-small cell lung cancer mutation-positive chronic and untreated leukaemia with 17p deletion or lymphocytic leukaemia TP53 mutation Treating non-small cell lung cancer that has non-small cell lung cancer Treating chemotherapy progressed after My deletion 5q cytogenic abnormality isolated Unresectable or metastatic BRAF V600 or metastatic Unresectable melanoma mutation-positive Locally advanced or metastatic BRAF or metastatic advanced Locally malignant V600 mutation-positive melanoma chromosome-positive chronic myeloid chronic myeloid chromosome-positive leukemia of chronic phase Philadelphia- Treatment chronic myeloid chromosome-positive leukemia andard-dose imatinib Technology Condition Condition Technology Comment Categorisation line) mg per day (first 400 Relevant Relevant genome 2015 (2012)2015 Somatic Erlotinib Year of Year publication (Continued) TA429 2017 Somatic Ibrutinib alone chronic lymphocytic treated Previously TA416 2016 Somatic Osimertinib TA374 (& TA374 TA258) 2014 TA322 Somatic Lenalidomide TA321 2014 Somatic Dabrafenib Table 3. Personalised interventions recommended by the National Institute for Health and Care Excellence (NICE) on the basis of genotype of genotype (NICE) on the basis Excellence Health and Care for the National Institute by recommended interventions Personalised 3. Table Technology appraisal number TA251 2012 2012 TA251 Somatic Somatic line) Nilotinib (first TA269 St of chronic phase Philadelphia- 2012 Treatment Somatic Vemurafenib [Accessed 3 April 2017]. Only the www.nice.org.uk/about/what-we-do/our-programmes/nice-guidance/nice-technology-appraisal-guidance/summary-of-decisions list of recommendations downloaded from the full from Compiled in brackets). (others referenced is outlined in full each technology most recent recommendation for

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For effective application of pharmacogenetic testing, the 4 Lander ES , Linton LM , Birren B et al. Initial sequencing and likelihood and severity of the predicted adverse outcome must analysis of the human genome . Nature 2001 ; 409 : 860 – 921 . be balanced against the risk of avoiding use of an effective drug. 5 National Human Genome Research Institute . DNA Sequencing In many cases further research is required to inform these costs: data. Bethesda, MD: NHGRI , 2016 . www.genome.gov/ decisions. The Clinical Pharmacogenomics Implementation sequencingcostsdata/ [Accessed 15 September 2017]. 6 Rare Disease Day. What is a rare disease? www.rarediseaseday.org/ Consortium19 (CPIC) are collating and curating such evidence, article/what-is-a-rare-disease [Accessed 15 September 2017 ] in a standardised format to assist with this. 7 Department of Health . UK strategy for rare diseases. London : Department of Health , 2013 . Health economics impact 8 Abbosh C , Birkbak NJ , Wilson GA et al . Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution. Nature Individual beneﬁts are clear regarding many of the applications 2017 ; 545 : 446 – 51 . described in this article. However, there are cost implications 9 G r e e n R C, B e r g J S, G r o d y W W et al. ACMG recommendations in identifying and testing the at-risk individual or population. for reporting of incidental findings in clinical exome and genome Therefore, another essential component in the required evidence sequencing . Genet Med 2013 ; 15 : 565 – 74 . base is health economic analysis. This varies by condition, 10 Richards S , Aziz A , Bale S et al. Standards and guidelines for the intervention and outcome; Peters et al provide an overview of interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the considerations in the case of monogenic diabetes.19 Genomics and the Association for Molecular Pathology . Genet Med 2015 ; 17 : 405 – 23 . Conclusions 11 Genome Aggregation Database. gnomAD browser. http://gnomad. broadinstitute.org/ [Accessed 15 September 2017 ]. Technological advances and the dramatically reduced costs of 12 Genomics England . The 100,000 genomes project . DNA sequencing have resulted in increasing ‘mainstreaming’ www.genomicsengland.co.uk/the-100000-genomes-project/ of genetic testing into routine practice and the prospect of WGS [ Accessed 15 September 2017 ]. becoming part of NHS diagnostics. Clinicians need to understand 13 NHS England. Personalised medicine. www.england.nhs.uk/ourwork/ the role of genomic medicine in their specialty, in offering prompt qual-clin-lead/personalisedmedicine/ [Accessed 15 September 2017 ]. and precise diagnosis for patients and in directing management 14 Neil HAW , Hammond T , Huxley R , Matthews DR , Humphries decisions. Detailed clinical information and multidisciplinary SE . Extent of underdiagnosis of familial hypercholesterolaemia in input remains vital for variant interpretation. routine practice: prospective registry study . BMJ ; 2000 ; 321 : 148 . 15 Chapman PB , Hauschild A , Robert C et al . Improved survival with The knowledge gained from genomics and personalised vemurafenib in melanoma with BRAF V600E mutation. N Engl J medical approaches is exciting. A number of applications are in Med 2011 ; 364 : 2507 – 16 . current practice and these are likely to increase exponentially 16 Biomarin Pharmaceuticals . Roadmap to a new therapy: understanding as WGS becomes embedded in routine patient care. Analysis of achondroplasia and the clinical trial process. London : Biomarin the evidence, from a clinical and health economic perspective, Pharmaceuticals , 2016 . Available online at www.biomarin.com/ is pivotal to the ongoing success of the genomics era. ■ pdf/BMN111_Infographic_Poster_Web_022516.pdf [ Accessed 15 September 2017]. 17 Fujii T , Komatsu Y , Yasoda A et al . Circulating C-type natriuretic C o n ﬂ i c t s o f i n t e r e s t peptide (CNP) rescues chondrodysplastic CNP knockout mice All authors are currently working for Genomics England as part of the from their impaired skeletal growth and early death . Endocrinology 100,000 Genomes Project. 2010 ; 151 : 4381 – 8 . 18 Mallal S , Phillips E , Carosi G et al . HLA-B*5701 screening for hypersensitivity to abacavir . N Engl J Med 2008 ; 358 : 568 – 79 . A c k n o w l e d g m e n t s 19 Clinical Pharmacogenomics Implementation Consortium. The authors would like to thank Genomics England for providing https://cpicpgx.org/ [ Accessed 15 September 2017 ]. a graphic regarding whole genome sequencing that was used to 20 Peters JL , Anderson R , Hyde C . Development of an economic produce Fig 1. evaluation of diagnostic strategies: the case of monogenic diabetes. BMJ Open 2013 ; 3 : e002905 .

References 1 Davies SC. Annual report of the Chief Medical Officer 2016: Generation Genome. London : Department of Health, 2017 . 2 NHS England Creating a genomic medicine service to lay the foundations to deliver personalised interventions and treatments. Leeds : NHS England , 2017 . 3 National Human Genome Research Instititue. The Human Genome Address for correspondence: Dr Helen Brittain, Clinical Project completion: frequently asked questions . Bethesday, MD: Genetics, Great Ormond Street Hospital For Children NHS NHGRI , 2003 . www.genome.gov/11006943/human-genome- Trust, Level 4, Barclay House, Great Ormond Street, London project-completion-frequently-asked-questions/ [Accessed WC1N 3JH, UK. 15 September 2017 ]. Email: [email protected]

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