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This is an important time in the history of genetics. Now that we have the sequence of the human genome in “working draft” form commentators predict a huge increase in activity in genetic medicine. Here we describe how the benefits of this rapidly expanding knowledge are being brought to the UK population as genetic services, and how they may develop in the future. Few doubt that medicine will be increasingly founded on the understanding of genetics and underpinned by testing. The biggest uncertainty concerns the large scale genetic screening of healthy people for susceptibility to common diseases: how widely this will happen, how soon, and how it might be organised.
Our information derives from the experience of the regional genetic centres in 12 UK health regions and international comparisons reported in recent scientific and official publications. Our vision for the development of integrated genetic services draws on these sources, recent initiatives to commission genetic services, and the literature on the impact of the new genetics in medicine.
UK genetic services are among the most highly developed in Europe, having evolved from academic departments into regional centres serving populations of 2-6 million.1 Regional genetic centres are multidisciplinary, with clinical and laboratory services united or working closely together. Each centre is broadly similar, with a “hub and spoke” structure including specialist clinics and clinics in district hospitals and community facilities. Outreach staff from some centres may visit families at home.2
Genetic services help families with the risk of a genetic disorder to live as normally as possible. After a consultation and investigations patients are given information about the condition in their family, their risk of developing or transmitting the condition, and the options for dealing with it (genetic counselling).
The clinical team comprises medical geneticists as well as counsellors whose background may be in nursing, science, or social work. Counsellors are becoming a recognised and registered profession, with formal postgraduate training in clinical practice and research.3
Counselling aims to be non-directive and to help people choose options appropriate to their needs. It is not aimed at reducing the birth incidence of genetic conditions, although this may be a secondary effect of patient choice. Support is offered during this process, and some families are followed up long term.
Molecular genetic laboratories offer tests based on analysis of DNA, and cytogenetic laboratories offer analysis of chromosomes. Biochemical genetic laboratories work closely with the regional genetic centres, offering diagnostic and screening programmes for inherited metabolic disorders such as phenylketonuria.
Commonest indications for cytogenetic tests
From the Laboratory Services for Genetics report of an expert working group to the NHS Executive and the Human Genetics Commission, Aug 2000 (www.doh.gov.uk/genetics)
Professionals working in genetics provide information and educational resources, contribute to teaching and updating clinical, scientific, and other healthcare staff, and provide answers to clinical queries from colleagues. The British Society for Human Genetics (www.bshg.org.uk) and the Public Health Genetics Unit offer web links to information services, mainly for professionals. However, advice to users on the quality of the 1.64 million pages of genetic information found on the web through a search engine using ‘genetics’ as the inquiry term is lacking.
About 50% of clinical referrals to regional genetic centres come from hospital specialties and 50% from primary care. Local arrangements may differ, but most centres have working relations with fetal medicine and obstetric units, cancer centres and units, paediatric and neonatal services, and adult specialties.
Genetic laboratories receive work from clinical geneticists, but a large proportion comes from other specialists. For example, cytogenetic laboratories accept referrals from obstetric units for prenatal testing for Down's syndrome, and molecular genetic laboratories receive requests from specialists for tests such as fragile X syndrome and Charcot-Marie tooth disease. Few laboratory referrals currently come from primary care because targeted testing usually requires input from systems specialists and clinical geneticists. Genetic clinicians and scientists have developed guidelines covering predictive testing in childhood for late onset disease, for a family history of cancer, children, and for interpretation and reporting of genetic tests.4–7 The use of guidelines and audit help ensure good practice and that the implications of testing have been considered and that resources are utilised appropriately.
Professionals working in genetics participate in national networks to ensure services are accessible and of uniform high quality. The box lists the services available.
The Dysmorphology Group, where clinicians present cases, facilitate diagnosis of rare patterns of birth defects, and delineate newly recognised conditions (genetics.ich.ucl.ac.uk/ddb/ddb.html)
The Public Health Genetics Network, strengthening commissioning (www.medinfo.cam.ac.uk/phgu)
The Cancer Genetics Group, developing research and services for familial cancer (www.bshg.org.uk)
Clinical governance and guideline initiatives (www.bshg.org.uk)
Regional genetic centres often have an overview of the needs of families with genetic disorders. Care involves diverse health disciplines and may extend over several generations. A recent Scottish initiative improved practice by establishing multidisciplinary guidelines to ensure that families receive planned and consistent care.8 Five conditions were chosen—tuberous sclerosis, myotonic dystrophy, Marfan's syndrome, Huntington's disease, and neurofibromatosis type 1—comprising 30% of all non-cancer genetic consultations. For each condition consensus conferences prepared guidelines and care pathways based on systematic reviews. It emerged that the evidence base for management of patients with these conditions was poor, perhaps because of their rarity. Structured review of records before and after the introduction of the pathways showed reducing variation between centres and established a mechanism for improving the evidence base.
Overall, 5% of cases of common cancers of the bowel, breast, and ovary are due to mutant genes of high penetrance. Asymptomatic carriers of the mutation have a lifetime risk of 60-80% of developing the disease. The challenge for genetic services is to identify those individuals and families at the highest risk and to reassure those at low risk. Referral guidelines have been developed to “triage” families.5 Those at low risk can be reassured, and those at moderate risk are advised to have additional surveillance. Patients at high risk are advised to see a cancer geneticist. On referral the genetic team construct a pedigree, confirm the diagnosis in affected individuals, estimate the risk of a mutation for predisposition to the condition, and, in some cases, request molecular testing. If the mutation in an affected individual has been identified, predictive testing can be offered to those family members at risk, following nationally agreed protocols involving at least two counselling sessions.
For those with a positive test result, targeted surveillance, treatment trials, or surgical options can be offered. Individuals with a negative test result, and their children, can be safely withdrawn from surveillance, reducing their personal burden and saving resources. The acceptability of predictive testing in families with syndromes that predispose to cancer has been shown: 91% (199 of 218) of people with a 50% risk of developing familial adenomatous polyposis chose testing as did 83% (41 of 49) of those with a 50% risk of developing Von Hippel Lindau disease.9,10 This contrasts with the much lower uptake of predictive testing, around 20%, for disorders such as Huntington's disease, where no useful treatment or prophylaxis is currently available.11
Overall, 3% of children have learning disability and of those seen by geneticists 20% have an identifiable cause.12 Referrals to regional genetic centres are usually from paediatric teams who have excluded identifiable non-genetic causes and may have requested genetic investigations. In the genetic clinic a pedigree, clinical history, and examination for dysmorphic features establish the features and course of the condition and may indicate a syndromic cause. Focused investigations are then instituted. After a precise diagnosis, accurate counselling and recurrence risks can be given to the nuclear and extended family. If there is no diagnosis then national networks such as the Dysmorphology Group (box) may be helpful. Even in the absence of a diagnosis, empirical data can help the family make decisions about reproduction and other issues.
The impact of genetic knowledge can already be measured for families at high risk of certain conditions. For example, in 1979 214 families with Duchenne's muscular dystrophy were known to our Regional Genetic Family Register Service, and 929 females had a greater than 10% risk of being a carrier of this serious condition. DNA tests have revolutionised carrier prediction for these women. By 1999 only 312 females remained at risk, and hundreds of women had been reassured they were not carriers (H Kingston, personal communication, 2001). Turner et al studied 225 families with fragile X syndrome and clarified the risks of transmitting the condition for 1363 women.13 DNA testing showed that 712 women were not carriers.
Currently, technical and resource limitations prevent testing of all but those at highest risk for a small number of single gene disorders. A recent review identified 895 genes responsible for monogenic diseases, but the number of genetic tests available as services in the United Kingdom increased from only 41 disease indications listed in 1991 to 178 by 1998 (www.cmgs.org).14 In the next five years it is likely that there will be a growth of about 5-10% per year in the volume of genetic tests for single gene disorders (see table on BMJ 's website).
Genetics will not remain the exclusive prerogative of regional genetic centres; every physician will need to use genetic knowledge, and for patients presenting with specific symptoms genetic testing will be increasingly important to aid prescribing and clinical management.15 Much debate surrounds the question of the genetic testing of healthy people. For common adult onset conditions such as diabetes and circulatory disorders the interaction between genes and the environment is starting to be understood, and there is great interest in the potential for DNA diagnostics.16 However, we already know from the well characterised genetic variants associated with monogenic diseases such as the haemoglobinopathies, thrombophilia, and haemochromatosis that the link between genotype and phenotype is poorly understood.17,18 As yet we have no idea if complex genotypes will be sufficiently predictive and interventions safe and effective to justify screening healthy people.19
Services need to listen to the experience of patients. Patient groups have become well organised through the UK Genetic Interest Group and share views about the integration of education and services. They work closely with regional genetic centres on service and research issues.20
The initiative on genetics and health by the Nuffield Trust and Public Health Genetics Unit recommended a systematic approach to genetic education for health professionals, a national strategy for regional genetics centres to reduce inequality in service provision, and a coherent mechanism for commissioning services.21 They recommended developing genetic counselling as a profession and a manpower review in regional genetic centres to reflect new responsibilities.
The figure presents current structures that can be further developed to guarantee equity of access to high quality services. In this model a patient presenting in primary care can access regional, national, and international expertise. Genetic counsellors are key to this integration. Based in the regional genetic centres with access to specialist resources, they already have responsibilities in outreach clinics, cancer and other units, and the community. As a development of the model they would be responsible for education and liaison between primary care teams and the regional genetic centre. Kinmonth et al stressed the need to develop expertise in primary care to classify patients into risk groups from family history.22 They stressed the importance of strong links with regional genetic centres to provide accurate information for the primary care team. In this model counsellors would serve as a first line of consultation, undertake some genetic counselling in the surgery, and facilitate referral of families at higher risk requiring specialist investigation and counselling.
Public Health Genetics Unit—www.medinfo.cam.ac.uk/phgu/
Online Mendelian inheritance in man— www.ncbi.nlm.nih.gov/Omim/
University of Kansas genetics information resource— www.kumc.edu/gec/geneinfo.html
Webliography for Clinical Geneticists— www.faseb.org/genetics/webliog.htm
European Directory of DNA Laboratories— www.eddnal.com
Contact a Family—www.cafamily.org.uk
Genetic Interest Group—www.gig.org.uk
National Coalition for Health Professional Education in Genetics (US)—www.nchpeg.org
Given the resources, regional genetic centres are well placed to coordinate services and education, using national networks for particular expertise and the development of guidelines. Genetic laboratories would continue to offer analysis for monogenic diseases and, for rare disorders, to contribute to national and international networks for testing. They would lend their expertise to local partnerships, with other service providers developing high throughput systems for pharmacogenetic testing and population screening. This model of service is widely accepted and supported by the Joint Committee on Medical Genetics, a forum on service provision, standards, and education, bringing together patient representatives, observers from the Department of Health, relevant royal colleges (Royal College of Physicians, Royal College of Pathologists, Royal College of General Practitioners, Royal College of Obstetrics and Gynaecology, Royal College of Paediatrics and Child Health, and Faculty of Public Health Medicine), and the British Society for Human Genetics.
We thank Professor Peter Farndon, Professor Robin Winter, Dr Helen Hughes, Professor Andrew Read, and our colleagues in Manchester for helpful comments on earlier drafts of this paper.
Competing interests: None declared.
Donnai and Elles provide a comprehensive description of the current organisation of regional genetic centres within the United Kingdom. Their account particularly reflects the foresight of the founders of this specialty service and the cooperative partnerships forged between universities and the NHS in the 1970s and 1980s. To deliver the health benefits of the post genome era, regional genetic centres need to respond to the rapidly accelerating pace of scientific and technical development. Whereas regionally based cytogenetic and molecular genetic laboratories have successfully implemented services for the most commonly occurring or easily tested inherited disorders, this model is unsustainable for the thousand or so genes already known to be involved in the rarer genetic diseases.
To cope with the increasing demand for a much more diverse range of genetic tests, molecular geneticists have developed an informal network for genetic testing throughout the United Kingdom. This allows samples to be cross referred between laboratories that offer different tests. The introduction of new gene tests is, however, rarely subject to critical cost-benefit analysis, and the transition from research into service is often ad hoc, being determined by local interests and enthusiasm. Support and validation for the network and new tests that might be offered is needed urgently. A recent report by an expert working group for the NHS Executive and the Human Genetics Commission has recommended that the Department of Health acts now to consolidate this network.1-1
The identification of genes involved in common diseases and responses to drug treatment raises further and even greater uncertainties for the future provision of services. Recent developments in cancer genetics provide useful insights. Several genes conferring a high risk of breast, ovarian, or colorectal cancer were identified during the 1990s. These genes seem to account for less than 5% of all cases but a higher proportion of cases with a strong family history and young age at diagnosis. Publicity surrounding these discoveries has generated unprecedented pressure on regional genetic centres, much of it from families in which the genes concerned are unlikely to be involved. Although centres are responding by establishing filtering mechanisms to identify the minority of families at high genetic risk, the concerns of those at moderate or low risk can only be effectively dealt with in partnership with primary care.
Further surges in demand for genetic information and testing in relation to common polygenic disorders are likely, although enthusiasts may be prone to overestimate this demand and the utility of genetic testing for complex polygenic diseases. By contrast, the recent genetics scenario project from the Nuffield Trust has emphasised the appreciable potential of pharmacogenomics to tailor drug choice and dosage in individual patients.1-2
In the face of these new developments there is a clear need for action. Firstly, a system throughout the United Kingdom must be consolidated for the evaluation and implementation of new genetic tests for rare genetic diseases. The planning of resources and manpower for counselling and clinical services, which are integral to genetic testing, must be included in this process. The recent formation of a Genetics Commissioning Advisory Group within the National Specialist Commissioning Advisory Group is an important development in this regard. Secondly, regional genetic centres must form partnerships with primary care and with public health to evaluate new developments in the genetics of common diseases. Thirdly, new partnerships will be required with other hospital based specialties. Pathology laboratories, for example, increasingly have the potential to identify somatic clues indicative of inherited mutant genes. For instance, detection of instability affecting repetitive DNA sequences in cancer tissue can suggest hereditary non-polyposis colorectal cancer. The increasing accessibility of DNA technology will force re-examination of the traditional divide between the analysis of somatic and germline mutations.
The experience of regional genetic centres in dealing with issues of confidentiality and the implications of genetic testing for family members will be invaluable in relation to these clinical and laboratory challenges. If resourced they are well placed to provide education and training on inherited disease for other specialties. And as Donnai and Elles suggest, the developing role of the genetic counsellor may be particularly relevant to primary care.
Competing interests: None declared.
A table showing the increase in number of tests for single gene disorders in the United Kingdom appears on the BMJ's website