Genetics and mainstream medicine-achieving the transformation
Hilary Burton
PHG Foundation
June 2009
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Key Policy Points
Six years on from the Genetics White Paper, Our Inheritance, Our Future, we have
increasing evidence, based mainly on detailed strategic needs assessments in
ophthalmology and cardiovascular disease, of the challenges facing the health
services. There is a need to consider the policy response.
We now suggest a paradigm for genetics in which, rather than specialist genetics
'moving into mainstream medicine', mainstream medicine itself develops and
expands to bring a set of new genomic technologies within its own specialist remit.
Notwithstanding this key recommendation, we wish to emphasise that the clinical
genetics service will be an essential element of our paradigm, without whose
expertise ‘mainstream medicine’ will not be able to further develop its own response
to the management of patients with inherited disorders.
The current pattern of 'joint clinics' in which, ideally, the two specialties work side by
side may be a practice of perfection. It is rarely realised equitably across the UK
even now and will become increasingly difficult with further expansion of genetics
within mainstream medicine. Further, our detailed policy work with a wide range of
stakeholders in these fields leads us to suggest that it is time for the specialties (and
those responsible for commissioning them) to embrace inherited disease for
themselves and properly integrate the necessary specialist clinical and laboratory
genetic expertise.
The fact that diagnosis of such disorders has implications for family members
provides a common thread. Knowledge of possible inheritance patterns imposes a
responsibility to consider risk and prevention options for other family members.
These elements lead to the requirement for new practice that services in 'mainstream
specialties' such as ophthalmology currently have neither the organisational systems,
nor the expertise to manage.
Evidence of increasing need for genetic aspects of mainstream medicine includes the
following:
 high numbers of patients and families due to greater knowledge of the prevalence
of the conditions
 further patients arising from population screening and systematic cascade testing
 new diagnostic methods and treatments that can make a difference to outcome
 recognition of complexity of inherited conditions which requires input from both
mainstream specialist and geneticist
 increasing capability for diagnostic testing with development for higher throughput
of testing
 wider utility of genetic testing to include reduction in morbidity and mortality,
information provision, assisting with reproductive decision making and improving
the pathway of care.
1
The prime elements for a strategic response are:
Engagement of specialised commissioners and provision of support to all
commissioners in mainstream services where there are substantial elements of
inherited disease.
Such support should include, on a national basis, the
development of commissioning guidance for mainstream specialities and agreeing
clinical pathways between primary, secondary and specialist elements of care. It will
require the development of commissioning competencies through the World Class
Commissioning Programme.
Consideration of current service development and comparators. Inequities exist
across the UK in access to high quality services for inherited disease. The response
will require increased overall capacity and some service reorganisation to ensure
critical mass.
Development of mechanisms (such as clinical networks) to support developing
services and ensure rapid translation of advances and most efficient use of available
expertise and experience.
Review of genetic test provision to respond effectively and efficiently to increasing
demand, rapidly developing capabilities and changing technologies. This should
include how genetic tests should be evaluated and regulated, how to maintain quality
in NHS services, how laboratories can best respond to increased demand for testing
and the development of mechanisms for requesting, finding and providing genetic
tests.
Increasing skills and developing capacity in genetics in the health professional
workforce with development of strategies aimed at medical, nursing, genetic
counselling and other investigative and supporting professions, to increase the
specialist workforce able to provide the specialised elements of services for inherited
diseases and to strengthen the supporting primary and secondary care elements.
Developing and evaluating methods for family record keeping and cascade
testing. A major strategic decision needs to be made about whether mainstream
services will develop their own 'stand alone' systems or whether cascade family
testing should use the network of regional genetics services. Unresolved questions
about the sharing of data across kindreds, particularly in relation to the introduction of
electronic patient records, must be addressed by policymakers through work with
relevant clinicians, patient groups, and legal and IT experts.
Audit and research programmes to evaluate effectiveness and costeffectiveness of services should be developed. This is vital in a climate where
health services will need to be prioritised and recognises the current paucity of
evidence about the overall effectiveness of specialised services and genetic testing
in improving outcome for patients and family members.
Ensuring that specialist genetics elements of services are developed and used
efficiently. As more professionals in mainstream services take on genetic elements
of the work, it will be important that they have access to supporting specialised
genetic services and that the latter are contracted to undertake the more complex
elements of care, including, for example, diagnosing syndromic disease, counselling
about prenatal diagnosis and interpreting complex genetic test results. There should
be debate nationally about what these supporting elements should include and the
organisational arrangements that will need to be made between mainstream and
genetic service.
2
1
Introduction
The devolution of genetic services from specialist to generalist was first signalled in
April 2001 by the Secretary of State for Health who noted that the NHS needed to
'change and adapt its services' to meet the challenge of genomics. Genetic services
would need to spread from specialist centres and into GP surgeries, health centres
and local hospitals.
In other words, genetic services would become more
'mainstream'. In 2003 developing genetics in mainstream services was one of the
main themes of the Genetics White Paper(1) with substantial initiatives in
modernising laboratories to provide essential infrastructure, engaging other
specialties to 'spur the take-up of genetics' through service development pilots in the
hospital sector and developing GPs with a Special Interest in Genetics. It was
expected that specialist genetics centres would play a leading role in 'spearheading
the diffusion of new genetic advances across the rest of the NHS'.
During the initial phases the paradigm was one of 'genetics' being developed within
mainstream medicine. In this paper we draw on detailed needs assessment and
reviews of genetics within two mainstream specialities (ophthalmology (2) and
cardiovascular disease (3)) carried out between 2006 and 2009 and both involving
expert, broad stakeholder groups. We look at emerging needs, effective service
developments and organisational aspects and provide a synthesis of current and
likely future services issues. Together these make the case for substantial service
change. Although our consideration is currently almost entirely limited to single gene
disorders, the future integration of genetic aspects into the management of common
complex disease further increases the imperative to service transformation.
Our analysis challenges assumptions inherent in the idea of 'genetic services'
becoming 'more mainstream' and leads us to propose some policy options to ensure
that advances from genetics are enabled to bear fruit throughout the healthcare
system. We suggest a future paradigm for genetics in which, rather than specialist
genetics 'moving into mainstream medicine', mainstream medicine itself develops
and expands to bring a set of new genomic technologies within its own specialist
remit. Within this suggestion, we emphasise the need for close co-operation with the
clinical genetics service, without whose expertise ‘mainstream medicine’ will not be
able to further develop its own response to the management of patients with inherited
disorders.
2
Background
In the 1998 Royal College of Physicians document Commissioning Clinical Genetic
Services (4) specialist genetics services were designed to provide for: the diagnosis
of inherited disorders including congenital malformation syndromes; genetic
counselling and associated support; up to date information on the availability of
genetic testing; and support and management, especially in the light of genetic test
results. There was close liaison between clinical geneticists and laboratory genetic
services to allow clarification of clinical factors and interpretation of genetic risks and
to ensure the appropriateness of investigations.
At this stage, therefore, much of the emphasis was on diagnosis of rare syndromes.
Geneticists were expert at recognising these syndromes, often on the basis of
dysmorphologies, and recognition of family history patterns. As now, they advised on
risk of recurrence, discussed reproductive options for parents and other family
3
members, and provided information for testing for patients and others who might also
be at risk either directly or by passing on the genetic abnormality.
Because they were often dealing with severe, highly penetrant disorders for which
prevention options were limited, there was much emphasis on genetic counselling
before and after genetic testing and acute awareness of the need to ensure that
'wider family and social and ethical factors are fully considered'. Huntington's
disease provides an extreme example of the need for counselling where the
condition is almost 100% penetrant, almost invariably severe and there is no means
of preventing the condition.
An important point, relevant to subsequent consideration of overall clinical
responsibility for patients with inherited disease, is that geneticists have usually not
been expected or equipped to provide clinical care and treatment for the phenotypic
manifestations of disease, although in the absence of overall care managers they
have sometimes adopted this role for some multi-system disorders.
In the last decade or so genetic science and technologies have developed rapidly,
bringing an exponential increase in understanding of the molecular basis of a wide
variety of inherited disorders across many clinical specialties. Geneticists and
clinicians with interest in particular disease areas have responded in many places by
the setting up of 'joint clinics' primarily aimed at achieving greater precision in
diagnosis and management of familial aspects. Ideally, the two specialties have
worked side by side. However, this may be a practice of perfection that is rarely
realised equitably across the UK even now and, as we show below, will become less
achievable with further expansion of genetics within mainstream medicine. Further,
our detailed policy work with a wide range of stakeholders in these fields leads us to
suggest that it is time for the specialties (and those responsible for commissioning
them) to embrace inherited disease for themselves and properly integrate the
necessary specialist clinical and laboratory genetic expertise into their services.
This paper is in two main sections. Firstly, we describe key factors that have
influenced emerging health 'needs' for genetics in mainstream medicine. Secondly,
we make proposals for policy responses, based on recommendations developed
through our two expert working groups.
3
Emerging health needs for genetics in mainstream medicine
Health 'needs' for genetic services are a function of two main elements:
epidemiology - the breadth of conditions and the numbers of people affected; and
effectiveness - capacity to benefit, which comes from enhanced ability to diagnose,
prevent or treat the condition. During recent years advancing knowledge in all of
these areas has meant that health 'needs' have increased and widened, with
increasing 'need' for specialised inherited disease areas within mainstream medicine.
This increasing 'need' is discussed in the following main areas:
1. The need to focus on inherited or heritable conditions
2. Increasing recognition and characterisation of inherited conditions throughout
clinical medicine leading to high total population prevalence
3. Screening programmes, family tracing programmes and better clinical practice
regarding risk to family members leading to identification of more patients
4
4. Complexity of genotype phenotype relationship meaning that clinical assessment
and genetic test interpretation require a true partnership of clinical and genetic
expertise
5. Increased capability for genetic testing
6. Wider utility of genetic testing (with some shift of focus from prediction, risk
assessment and counselling around recurrence to diagnosis, disease prevention
and treatment)
3.1
A focus on inherited or heritable conditions
The use of the word ‘genetic’ needs clarification. The focus for the debate about
developing genetics within mainstream medicine remains largely with the
consideration of how inherited or heritable diseases are identified, diagnosed and
managed. Testing of DNA may, or may not,, be part of this management
programme.
Many of the ophthalmological conditions (for example X-linked
retinoschisis, characterised by splitting of the retina, which can cause loss of vision)
can be diagnosed clinically on the basis of characteristic appearance of the fundus,
electrophysiological testing of the retina and family history. The fact that diagnosis of
such disorders has implications for family members provides a common thread.
Knowledge of possible inheritance patterns imposes a responsibility to consider risk,
and prevention options for other family members. These elements lead to the
requirement for new practice that services in 'mainstream specialties' such as
ophthalmology currently have neither the organisational systems, nor the expertise to
manage.
In contrast, technologies based on a knowledge of DNA and its products are widely
used within health services, such as for example, the use of gene expression
profiling to determine treatments in chronic myeloid leukaemia (using the targeted
drug therapy imatinib) or to decide on the use of the drug Herceptin® (trastuzumab)
in breast cancer. The development and application of such tests has taken place
within the context of clinical cancer and other services and their associated
laboratories and does not require expert clinical or laboratory genetic interpretation.
It is therefore not considered further in this discussion
3.2
Increasing recognition of genetic conditions throughout clinical
medicine
Knowledge of the increasing numbers and range of recognised inherited conditions
throughout clinical medicine lead us to the suggestion that, on sheer numbers alone,
'genetic' aspects of these conditions for many patients and their families will have to
be managed within the condition specialities rather than by the specialist genetics
services. The present discussion is limited mainly to consideration of single gene or
chromosomal disorders (the main inherited or heritable conditions). However,
increasing knowledge about the contribution of genetic factors to complex chronic
disorders such as heart disease, cancer or psychiatric disease emphasises even
further the need for mainstream services to incorporate genetic consideration into
their diagnostic, preventive and treatment models.
A good example is provided by familial hypercholesterolaemia (FH), an autosomal
dominant form of hyperlipidaemia, caused by a mutation that directly affects the rate
at which the low density lipoprotein cholesterol (LDL-C) is cleared from the blood.
Subsequent high levels of LDL-C cause accelerated atherosclerosis and increase the
risk of coronary heart disease. The condition is treatable with reduction of risk of
adverse cardiovascular events by lipid lowering drug therapies and lifestyle
interventions. The estimated prevalence of FH is 1 in 500, suggesting that the total
5
prevalence in the entire UK may be in excess of 120,000, with only about 15% of
patients so far identified and treated within lipid clinics in the UK (5). The condition is
thus far too prevalent for genetic testing or family aspects of the condition to be
managed by specialist genetics services. Indeed, NICE guidance is that health
professionals 'with expertise in FH' should take responsibility for cascade testing to
systematically identify family members with FH. Whilst they recommend a 'familybased, follow up system' they do not recommend the involvement of specialist
genetic services in this endeavour.
Also within the general scope of cardiovascular disease hypertrophic cardiomyopathy
has a similar prevalence (1 in 500).
Our needs assessment using best
epidemiological evidence across the whole range of inherited cardiovascular
conditions suggests that there may be a total UK prevalence of a further 180,000 to
260,000 individuals with these inherited conditions (excluding FH) - numbers that
greatly exceed those with whom specialist genetics could be routinely directly
involved.
In ophthalmology, there are also a great many inherited disorders which, combined,
have a noticeable impact on the burden of visual disability in the population. As well
as some more common conditions, such as retinitis pigmentosa, which has a birth
prevalence of 1 in 3-4,000 we identified 74 groups of monogenic conditions that
primarily affect the eye. In total, using best estimates from literature on birth
prevalence we estimated that we could expect around 1,500 new cases of
monogenic eye disorder with significant eye manifestations each year in UK. (There
are no estimates for overall UK prevalence). Epidemiological work in the UK (6,7)
provides evidence that inherited eye disorders account for approximately one third of
the 450 children diagnosed as blind or severely visually impaired each year, and
about 10% (250) of the 2,500 adults of working age who receive blind certification
each year.
Finally, widening the scope to all inherited conditions, the molecular basis is now
known for almost 2,500 disorders for which the phenotype is well described (8).
Physical manifestations are spread across disease in almost every speciality.
3.3
Increased diagnosis through screening, family tracing (cascade testing)
and good clinical practice
With new screening programmes, formal cascade testing systems and more
systematic and better developed clinical practice that properly identifies and follows
up individuals at risk, the need and demand for services for suspected and
diagnosed inherited conditions will rise rapidly.
New screening programmes such as those for sickle cell and thalassaemia, MCADD
(9,10) and cystic fibrosis will increase the numbers of new cases detected and
demand for follow up testing and testing of family members. For MCADD the new
screening programme pilot identified 87 cases in nearly 750,000 newborn babies
screened - a rate of 1.2 per 100,000. It is estimated that newborn screening
programmes will identify 2-3 times more affected individuals than those who would
present clinically.
At the same time, the use of family tracing such as that proposed for FH, whether as
organised cascade screening programmes or as enhanced clinical management of
cases, means that the overall numbers coming into contact with services will
increase. Sudden cardiac death provides a further example arising in cardiovascular
services where, under the new National Service Framework, pathologists are
6
recommended to take samples to determine a possible genetic basis for the death
such as the cardiac arrhythmia long QT syndrome with a view to identifying and
advising at-risk relatives.
In all areas where we have conducted detailed needs assessment (including also
work in inherited metabolic disease (11)), clinical best practice involves the following
up of potentially 'at-risk' relatives. All of these individuals will need to be tested
and/or clinically assessed within the mainstream specialty, meaning that the numbers
of patients requiring referral will rise rapidly. Although we might envisage that
eventually some sort of 'saturation' of the population might be reached, the fact noted
in the inherited cardiovascular review that cascade testing currently rarely reveals
individuals already known to the service suggest that we are a long way from
reaching this point (3).
3.4
Increased complexity of genetic test interpretation
The complexity of genetic testing and the relationship between genotype and
phenotype in many conditions has turned out to be immense. This means that
experts from the host discipline and specialist genetics must work in partnership to
bring together clinical and molecular assessments.
The diagnosis of inherited cardiac conditions, for example, presents a complex
clinical problem requiring a range of highly specialised medical professionals,
equipment and resources. Cardiological investigation may involve an array of
examinations including detailed analysis of the ECG, assessment of symptoms by
exercise testing, and echocardiography or cardiac magnetic resonance imaging to
detect defects in heart structure and assess their effects on function. Substantial
experience and expertise are required to distinguish ICCs from the more common
forms of heart disease. Genetic testing, where available, can help to confirm or refine
a provisional diagnosis. However genetic findings are not always clear-cut; for
example, genetic testing may reveal sequence changes that are difficult to interpret
and whose pathogenicity is uncertain. Both clinical and genetic findings must be
considered in the light of other features of the patient such as age and sex, clinical
history and family history. In some cases, clinical and/or genetic investigation of other
family members may be necessary to help confirm or rule out a suspected diagnosis
in the index case. This requires a multidisciplinary team approach.
Understanding of the complexity of the underlying molecular abnormality also shapes
the advice and treatment offered to the patient. Long QT syndrome (LQTS), for
example, is an inherited condition characterised by an abnormally prolonged QT
interval on the ECG and a predisposition to develop life threatening ventricular
arrhythmias. There are now known to be at least 12 genes involved and well over
400 mutations that cause abnormalities in the cardiac ion channel genes that
underlie the coordinated cardiac muscle cell contractions. Importantly, though our
knowledge of associated natural history of disease and evidence on best treatment
options remains incomplete, some tailoring of preventive and treatment advice to the
precise molecular diagnosis is currently recommended. For example, in the LQT1
subset of LQTS sudden cardiac death is triggered most frequently by exercise
(particularly swimming or emotion) while lethal cardiac events in LQT2 occur more
often when the patient is roused by a sudden noise during rest or sleep(12).
Similarly, patients with LQT1 respond well to beta blockers whilst those with LQT3 do
not. These examples serve to illustrate that, although the geneticist may be involved
in advising on the ordering and interpretation of genetic tests, overall patient care
must be managed by the cardiologist.
7
In a similar way, for FH, NICE guidelines recommend that the management of the
extreme hyperlipidaemia seen in these patients should be undertaken by the
lipidologists and not by the cardiologist or geneticist. The management of any
children identified by cascade testing also requires input from a paediatrician.
In summary, the large number of genes known to be involved in inherited disease
and the complexity of emerging understanding of genotype-phenotype associations
within any one specialty must be managed. The sheer volume of conditions will
make it impossible for geneticists to provide genetic elements of care for all patients.
Further, the complexity of the genetics that underlies each condition and the need to
associate this with an expert assessment of the phenotype mean that patients and
at-risk relatives will need to be diagnosed through an equal partnership between the
relevant specialists and geneticists. Subsequent care will then be largely speciality
led. With increasing sub-specialisation in inherited disorders, continuing research,
the development of phenotype genotype databases, clinical guidelines and protocols,
specialists in mainstream specialities will increasingly be able to manage elements of
genetics.
3.5
Increase in capability for diagnostic testing to deal with increased
volume and complexity
In the ‘pre-genomic era’, genetic testing technologies were largely limited to Sanger
sequencing or polymerase chain reaction (PCR). Whilst both of these key
technologies are highly accurate, they can be time consuming and are hard to scaleup to meet higher demands and increasing levels of complexity.
Since the beginning of the ‘post-genomic era’, there has been an explosion both in
the development of new genetic testing technologies and the sheer quantity of
sequence data. Detailed knowledge of the genetic sequence together with the
availability of relatively low cost high-throughput technologies means that clinical
genetic testing is now possible for many genetic disorders.
Perhaps the most notable of all the new genetic technologies is the use of
microarrays to investigate thousands of genetic features simultaneously. Applications
include DNA microarrays (‘gene chips’) that can be used to detect specific mutations/
polymorphisms or gene expression levels, as well as resequencing chips that
determine any changes in the DNA sequence relative to a reference genome.
Comparative genome hybridisation (CGH) has also been combined with microarray
technology for high resolution detection of chromosomal segments with copy number
changes.
Ophthalmology provides an example of how advances in technology have led to
increased capability and capacity for genetic testing. Microarray testing is now
available commercially through, for example, a company based in Estonia (Asper
Ophthalmics) with chips aimed at particular diseases including Leber Congenital
Amaurosis and Usher syndrome. This is thought to provide a useful first pass
screening method for disorders that are genetically heterogeneous (although it is not
suitable for diagnostic testing). In addition, it must be recognised that the use of
testing outside the NHS should also meet the same stringent criteria for laboratory
quality, clinical validity and utility. In cardiology developments have also allowed
significant expansion in the number of genetic tests offered in the clinic although they
are still limited. In this clinical area, mutational hot spots rarely occur, meaning that
full gene mutation screening is invariably required to identify mutations that are
unique to families.
This is laborious and expensive and, in moderately
8
heterogeneous families, such as HCM, DCH and LQTS, where up to 5 genes are
currently tested, represents the diagnostic limits of current technologies.
In both specialties examined it is expected that resequencing will greatly speed up
testing and increase its range. At a later stage, it is envisaged that the technologies
would be used to identify genetic variants affecting treatment response and
susceptibility to underlying complex diseases. However, careful assessment of these
technologies is required before access to such methods should be widely available.
Not least will be the interpretive difficulties; for example there are likely to be multiple
variants detected and identifying the causative variant(s) may be difficult.
As a final example, for FH a kit is now commercially available that tests for 20 of the
most common FH-causing mutations in UK patients (13). This has been reported to
detect up to 50% of all the mutations detectable by a full gene screen, and can be
completed within a week of sample receipt for a cost of approximately £50. A more
extensive and more expensive MassARRAY spectrometry method has been
developed for FH (14) and a commercial microarray that test for more than 200 FH
mutations has also been reported (15).
In the longer term cheaper, quicker and more powerful technologies could transform
genetic testing services and may become more widely accessible within mainstream
specialities. Thought will need to be given to the context of their use and the
competence of the professional ordering and interpreting them. They should be
made available within a well thought-out package of care that includes associated
evaluation of their clinical utility, criteria for testing, quality assurance and support for
any interpretive difficulties. Under such conditions, it may be appropriate that they
are ordered by the mainstream specialist (with the necessary competencies) rather
than, as at present, going through the clinical geneticist as intermediary.
3.6
Wider utility of genetic testing
The decision to offer a genetic test within clinical practice should be one based on a
careful evaluation of the test, and in particular of its clinical utility, or ability to assist
the patient or family to an improved health outcome. Here, again, as the paradigm of
our understanding of genetic disease shifts, the purposes for genetic testing have
widened and the strict requirement for genetic testing always to be accompanied by
genetic counselling may have relaxed.
Many single gene disorders are very variable in their severity, age of onset,
penetrance, and expressivity and in the degree to which they can be prevented and
treated. Such differences have implications for the utility of testing and the conditions
under which it should be offered. The purposes of genetic testing are now agreed as
follows (16):



To reduce morbidity or mortality
To provide information salient to the care of the patient or family members and/or
To assist the patient of family members with reproductive decision making
Such outcomes may be achieved for the proband or family members in whom
cascade testing becomes possible when the underlying molecular pathology is
identified. They may also be achieved by providing information to assist and
streamline the process of care. The literature contains very few examples of formal
evaluations of the clinical utility of genetic tests. In our needs assessment we
therefore used ophthalmology to explore some case histories through which clinical
utility in these dimensions can be demonstrated.
9
Genetic testing might, for example, now be the simplest and cheapest way to make a
diagnosis in the first instance and thus provide aetiological and prognostic
information or inform management or treatment decisions for patient and family. For
example, in X-linked retinoschisis the presentation can be atypical. A genetic test of
the one gene RS1 associated with the condition in nearly 90% of males with the
condition could be the quickest and easiest way of making the diagnosis. However, it
has to be noted that this is only the case if genetic testing is undertaken as a first-line
investigation and not after a number of other clinical and laboratory investigations
have already taken place. This implies that many ‘negative ’tests would be done for
people with a similar presentation, a factor that should be taken into account when
deciding the most effective and efficient investigation protocols.
Genetic testing can be used to make an earlier, more complete diagnosis in order to
give more precise information about prognosis and provide the best supportive care.
Thus, for example, the provision of a genetic test for Usher syndrome in the child with
congenital hearing loss can confirm that the child has the condition and will go on to
develop the characteristic retinitis pigmentosa and progressive visual loss. Such
information allows parents to be advised on early cochlear implantation for their child
to ensure maximum development of communication.
Genetic testing can lead to improvements in the process of care that can have a
direct effect on the patient and at risk relatives. In retinoblastoma, for example,
genetic testing is an important part of clinical management. It is used to test whether
the condition is caused by a germline or somatic mutation. For the patient a germline
mutation would have consequences for surveillance, implying the need for careful
surveillance of the symptomatic eye (if not enucleated) and also the contralateral
eye. Determination of a germline mutation also allows relatives to be tested and
surveillance (requiring examination under anaesthetic) offered only to those who test
positive and gives parents the option of prenatal testing for future pregnancies.
In such circumstances, where the clinical utility of genetic testing is clear-cut and
particularly where conditions are milder or treatable it is now accepted that there is
not necessarily the need for in-depth counselling provided by a genetic counsellor. In
some clinical areas, such as cancer genetics, counselling may be provided by cancer
nurses who have had special training in the genetics of the disease and the impact
on the wider family. Nonetheless, in many circumstances where testing is proposed,
patients, parents and other relatives will require help to understand the complexities
of testing (for example, factors such as mosaicism or incomplete penetrance) and will
require skilled support to understand the possible implications for themselves. This
need not necessarily be provided by a clinical geneticist or counsellor, but could
increasingly be undertaken by clinicians who have special interest in inherited
conditions within their own speciality.
4
Key Issues in the Policy Response
The speed of advancing science and clinical applications, and the rapid expansion
and complexity of ‘need’ outlined above in the two specialities examined, has
impressed on us the need for an urgent and fundamental policy response that will be
relevant to many other specialties. This response must recognise the realities of the
current limited services in the UK to diagnose and manage patients with inherited
conditions and trends in the development of clinical genetics as a specialist service.
Underpinning all of this response is the vital role of specialist clinical and
10
laboratory genetics to continue to provide the necessary tertiary and
quaternary services for patients and help to lead policy development.
Issues in developing a policy response include:
1. Engagement of specialised commissioners and provision of support to all
commissioners in mainstream services where there are substantial elements of
inherited disease
2. Consideration of current service development and comparators
3. Development of mechanisms (such as clinical networks) to support developing
services
4. Review of genetic test provision
5. Increasing skills and developing capacity in genetics in the health professional
workforce
6. Developing and evaluating methods for family record keeping and cascade
testing that can be use within or accessed from mainstream medicine
7. Building audit and research programmes to evaluate effectiveness and costeffectiveness of services
8. Ensuring that specialist genetics elements of services are developed and used
efficiently
4.1
Engagement of specialised commissioners and provision of support to
all commissioners in mainstream services where there are substantial
elements of inherited disease
It must first be recognised that rare inherited disease is likely to be found in many
branches of medicine.
These patients will present to, be diagnosed and
subsequently managed by that specialty. Genetic considerations can, and now
should, add value to that interaction by ensuring that the diagnosis (and hence the
management) is as accurate as possible, with fine-tuning to molecular sub-divisions,
and by considering and advising on the risk to family members. The genetic input
will have clinical (family history taking, examination, interpretation and counselling
elements) as well as laboratory elements.
We suggest that the paradigm of ‘joint clinics’ might not continue to be tenable and,
in the services examined, that commissioning for inherited disease within a specialty
should be led by that specialty with explicit arrangements for clinical and laboratory
genetics elements to be provided as part of a multi-disciplinary team. Formalised
commissioning of inherited disease services has largely not been undertaken so far.
In inherited cardiovascular conditions, for example, only two of the 19 services were
commissioned as part of the cardiac network provision. However, we recommend
that this element of service should now be formally included in commissioning
documents, contracts, service specifications and standards.
It is suggested that, in each of these clinical areas, guidance is provided on the likely
scope, size and nature of the clinical and genetic elements of the service. Such
guidance, prepared on a national basis, should include an indicative number of
services that would be needed to ensure critical mass and should explicitly state that
all mainstream service would not expect to have their own service but should
cooperate with neighbouring services to ensure access on a population basis.
Inherited conditions are likely to form an important subset of disease, but one which
crosses many boundaries within the specialty. Thus, for example, in ophthalmology,
inherited conditions might affect the retina, lens, cornea, optic nerve or, indeed any
structures of the eye and so need to be considered within many subspecialist areas.
11
In cardiovascular medicine we have also noted that genetic conditions might come to
the attention of those managing arrhythmias, cardiomyopathies, arteriopathies,
hyperlipidaemias and coronary heart disease. Within each specialty, therefore, the
services need to be planned and commissioned, and clinical pathways built, to
ensure that those with inherited conditions are identified within the district general
secondary care services and primary care and referred for specialist advice. Once
provided, shared care may be possible for long term management of patient and
family.
In some services, such as cardiovascular disease or cancer, there are major national
strategic planning frameworks to provide assistance and advice to commissioners.
Thus, for example, the National Service Framework for CHD and, in particular,
Chapter 8 dealing with arrhythmias and sudden cardiac death, deals to some extent
with inherited conditions. However, such examples are limited.
In many clinical areas, however, the capability to commission services that have
properly taken account of inherited disease elements will be the task of PCT
commissioners. The comparative rarity of the conditions will also mean that
commissioners will have other priorities. Developing the competences for PCTs to
commission services that properly incorporate new services and reconfigurations
arising from research and knowledge in genetics will be a major challenge for the
World Class Commissioning Programme. It is suggested also that progress in
commissioning will require national impetus and, in particular, the coordination of
guidance that includes outline specifications for services and professionally agreed
standards.
4.1.1
Recognition of genetics elements within other specialties as part of the
specialised services definition set.
As a complement to the mainstream specialty commissioning documents, the clinical
and laboratory genetic input that would be required to support other specialities (such
as cardiology, ophthalmology etc) should be specified within the national genetics
specialised services definitions set (definition no 20). The range that it might cover
within each speciality will include:






Detailed examination of family history with capacity to verify diagnoses through
family and other records
Identification of dysmorphic and other features associated with rare genetic
syndromes
Assistance with molecular diagnosis through detailed knowledge of possible
molecular pathology, likely utility of genetic testing and assistance in interpreting
uncertain results
Advice about recurrence or counselling about prenatal testing
Access to systems for family record keeping and undertaking family follow-up
Advice on ethical, legal and social issues such as consent, confidentiality and
issues related to ethically difficult areas such as testing of children, preimplantation genetic diagnosis, prenatal testing, termination of pregnancy, when
and how to contact relatives etc.
It will be very important that clarification is achieved for commissioning purposes
whether the genetic testing itself (as opposed to appropriate supporting referral and
interpretive advice) is included within the genetic service or the mainstream service
contract.
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4.2
Consideration of current service development and comparators
Although clinical services have been stimulated to develop in areas where there are
research interests and enthusiasms, across the UK as a whole our reviews of
services have shown many small services, with very few providing a comprehensive
service and great disparities in quantity and quality of services between geographic
areas.
In cardiovascular disease, we identified 19 providers of services for ICC, but of these
five were based in London. Fifty nine percent of outpatient clinics and 60% of
consultant staff time was in London. Eight of these services saw fewer than 200 new
patients per year (4 new patients per week). Across the rest of the UK there was a
10-30 fold variation between the highest and lowest level of provision on various
measures of activity including numbers of new patients seen and genetic tests
ordered. Using rates of new patient referrals for the London strategic health authority
populations as a benchmark, we estimated that there was an unmet need of some
7,000 new referrals over the whole of the UK and that activity needed to be increased
3-4 fold for regions outside London to reach equity with the London provision. For
FH, there are approximately 130 lipid clinics throughout the UK, and in a 2008
HEARTUK survey six services were identified as managing more than 200 FH
patients per year but 25 saw fewer than 25 patients. Again services were
concentrated in London and other metropolitan areas. Services for children with FH
were particularly lacking, with fewer than 600 of the predicted 14,000 under 10 year
olds currently having been identified and being managed in specialist clinics.
Similar findings from our work in ophthalmology showed that there were 19 service
providers, including two in London. A similar pattern was evident with a large
number of small services, and only three services seeing more than 300 patients per
year. Our needs assessment showed an estimated unmet need of 1,000 new patient
referrals per year across the UK. Disparities in provision between SHAs showed a
seven fold variation in clinic sessions provided and new patients seen between the
most and least active region.
The need for highly specialised clinical and laboratory services, coupled with the
need to have sufficient throughput to justify critical mass of clinical and investigative
resources necessary to make the service cost effective, leads to the inevitable
conclusion that fewer services, each with greater patient throughput, will be required.
This will require considerable political will and determination to implement.
It should start with the setting of stringent standards that commissioners could use to
determine appropriate services for their own populations. Formal designation of
services would be one route, but another would be a more informal process through
which services might cooperate to agree which services would major in which clinical
area, and in turn, where further development of services would not be pursued.
4.3
Development of mechanisms (such as clinical networks) to support
developing services
In relatively small specialised services, such as those examined and, moreover,
services that are developing rapidly, it is important to use available expertise and
experience efficiently; to have mechanisms through which good practice and ideas
can be quickly shared and services can work collaboratively to develop resources
such as guidelines and protocols, patient information or educational material.
Facilitating such collaboration through a network of providers has been
recommended as a result of all services examined in detail. Such networks would
13
also be powerful fora for development of audit and research and to provide advocacy
and leadership for the service on a national and international basis. For maximum
effectiveness such networks would require resources for leadership, programme
development, coordination, and dissemination.
4.4
Review of genetic test provision
Our cardiovascular disease review showed a 20 fold variation in genetic test
provision, in relation to population size (based on strategic health authority
populations). This has profound implications for the provision of genetic testing
services which needs attention strategically. Important issues include evaluation and
regulation of genetic test provision; quality; overall capacity; and arrangements for
accessing and funding tests.
4.4.1
Evaluation and regulation of genetic test provision
UK genetics laboratories receive over 150,000 samples for genetic testing each year
(17). The UKGTN, established in 2002, has a role to evaluate new genetic tests and
publishes criteria for specific tests that can be available on the NHS. However,
evidence is often limited by available data, particularly on clinical utility. In the UK as
a whole there is concern that many laboratory tests are undertaken in the absence of
any system to ensure clinical effectiveness and utility of individual tests. A recent
Diagnostic Summit hosted jointly by the PHG Foundation and the Royal College of
Pathologists recommended the establishment of a framework for evaluation and
regulation of genetic tests (18).
There is further concern related to the existing statutory regime for market
authorisation of diagnostic tests (the major component being the EU In Vitro
Diagnostic Devices Directive) which is generally restricted to an examination of
safety and analytical validity. Statutory regulation does not extend to requiring
evidence of a test's clinical utility. There is now agreement that this regulation could
be strengthened by a requirement that information about clinical validity and utility of
a test should be placed in the public domain.
4.4.2
Quality
There has been a huge investment in laboratory services during the last 20 years –
including the technology itself and the development of a network of genetic
laboratories and scientists with unique expertise and knowledge about the
interpretation of genetic analyses. However, there is a danger that other laboratories
start to undertake DNA and RNA based diagnostics without the required
qualifications, training and background and unable to take advantage of the high
throughput technologies that are available in the genetics laboratories. As a strategy
for developing genetics in mainstream medicine develops it is essential that testing
services continue to be provided by appropriately qualified scientists in appropriately
equipped facilities.
4.4.3
Capacity
Inequity in test provision, increasing numbers of requests for genetic testing, the
expected introduction of new technologies (including bioinformatics support) that will
further expand capacity and capability (so-called next generation technologies such
as new platforms for rapid gene re-sequencing, SNP typing and array CGH) have
called into question both the capacity and the current configuration, organisation and
funding of the laboratory genetic testing services. These should be reviewed in order
14
to ensure effective, efficient and equitable provision. It is anticipated that this might
result in recommendations to consolidate laboratory provision of genetic tests. For
example, in cardiac genetics it was suggested that, to provide economies of scale,
rapid reporting times and expertise in interpretation of results, it may be desirable to
focus activity and resources in two or three laboratories. These laboratories would
provide a comprehensive testing service, replacing the current rather fragmented
situation in which laboratories may set up testing services for a subset of genes of
their choice (subject to approval by UKGTN and GenCAG). This would, in the longer
term, facilitate the development of applications of DNA typing for common disease,
allowing both test provision and interpretation to be provided in designated
laboratories with appropriate evidence base and quality assurance.
4.4.4
Developing appropriate mechanisms for requesting, funding and providing
genetic tests
Our finding of wide variations in the use of genetic tests between different services
reflects limitation in resources as well as the fact that budgets for testing usually lie
within the relatively small genetic service budget rather than within the, usually larger,
mainstream budget. In nearly all services, the genetics service acted as the gatekeeper for tests, usually through a consultant clinical geneticist, and frequently also
involving the use of agreed testing criteria set out by the laboratories in conjunction
with UKGTN. This is particularly important for tests that are complex, and thus
expensive.
A system that requires individual agreement for genetic testing will be increasingly
stretched with more clinical referrals and more availability and utility of genetic tests.
It might also become less necessary as the price of tests reduces. Discussions
should take place about whether it would be more appropriate for decision-making
and access to budgets for genetic testing to be held by the mainstream speciality.
This would enable the speciality to prioritise the use of genetic tests alongside other
diagnostic methods and aspects of care within that specialty. Such a move would
require:



Contracting mechanisms that include the costs of genetic testing within the
average cost envelope for referrals to that speciality
Mechanisms to ensure the competence of those ordering and interpreting genetic
tests (this should require some specialist genetic input)
The continuing development, dissemination and application by UKGTN
laboratories of criteria for testing
The relative merits of specialist genetics or mainstream budget holding for genetic
testing elements of service provision require substantial discussion by
commissioners and others at a national level with leadership provided by clinical and
laboratory professionals through UKGTN and GenCAG. In particular it will not be
easy to resolve the tensions between allowing mainstream services to decide their
own priorities, the need to protect the limited expert services of geneticists (and not
just having them acting as gate-keepers to genetic tests) and the need to protect and
prioritise the limited budgets for genetic testing in UK laboratories as a whole.
4.5
Increasing skills and developing capacity in genetics in the health
professional workforce
Our reviews of both inherited cardiovascular disease and inherited eye disease
acknowledge that in some areas where there is research interest or particular
15
enthusiasm, joint genetics/mainstream specialty services are working well.
Examples include the CARDIGEN network, a relationship between cardiac genetics
and cardiology across the North of England Cardiovascular Network. However,
overall in the UK there is lack of capacity of appropriately specialised clinical and
laboratory services with implied unmet need that, according to all the trends we have
identified, is likely to increase in the future. In these and other specialties strategies
will be required through continuing professional development and specialist training
to build a cadre of professionals with relevant expertise in genetics aspects in the
particular context of that medical specialty. Thus, those in genetics need to develop
experience in that particular clinical area, and those in the specialty (cardiology,
ophthalmology etc) need to develop expertise in genetics. For example, in
cardiovascular genetics this would include cardiology, clinical genetics, genetic
counselling, cardiac nursing, pathology, lipidology (including paediatric lipid care) and
the associated investigative professionals such as electrophysiologists.
It will be necessary for leaders in each field to work with regulatory bodies, such as
the Royal Colleges, and, for medical specialities, the Postgraduate Medical
Education and Training Board (PMETB) to develop, where appropriate, highly
specialist modules, training programmes and placements and educational resources.
For those already in post, such as, in some cases specialist nurses who may have an
extended role for coordination of work with families, competence frameworks in
genetics should be written, building on those developed by Skills for Health in
conjunction with the National Genetic Education and Development Centre (NGEDC)
(19).
In addition, inherited disease services within mainstream medicine need to be firmly
embedded in secondary and primary care services that are able to recognise
individuals at risk, refer appropriately, support patients and families in interpreting
and acting on specialist advice, and provide a partnership for shared care and followup. This requires that all professionals in that specialty, primary care, paediatrics and
any of the secondary and tertiary specialties that interface with it have a necessary
basic level of understanding and competence. The NGEDC has programmes to
develop education in genetics for such professional groups (20).
4.6
Developing and evaluating methods for family record keeping and
cascade testing that can be use within or accessed from mainstream
medicine
Cascade testing for family members of patients with inherited disease in any of the
mainstream specialities is an important aspect of clinical care; it aims both to identify
other individuals at risk, with instigation of surveillance or treatment and, equally
importantly, to rule out increased risk for other family members, usually because they
do not share a pathological mutation.
Unlike genetics services, most mainstream services have not formalised their
methods for cascade testing and areas such as family record keeping, contacting
relatives, consent and sharing of genetic and clinical information within families, and
using genetic test results within families to streamline the processes of testing are
problematic.
Although some of the current joint speciality/genetics services
undertake their entire cascade testing through the regional genetics service, those
that are more embedded within the mainstream services (such as some of the more
established London based services in the specialities examined) may undertake this
work themselves, though not always in a systematic way. Whilst the routine use of
regional genetics services to undertaken cascade testing may seem an obvious
16
solution to achieving high quality, in the longer term, the predicted increase in volume
of such work arising from all relevant specialties as they expand into inherited
disease will challenge the capacity of genetic services, particularly genetic
counselling and administration for family records.
The implementation of the NICE recommendations on cascade testing for FH has
resulted in the piloting of an IT system for family cascade testing in Wales. This is an
important clinical area in which the predicted volume of family follow up required has
meant that there is general agreement that it should be speciality based rather than
genetics based. Interestingly, where this happens it is largely undertaken within
specialist lipid services with little or no input from specialist genetics across the UK,
even though the molecular genetics of the conditions and interpretation of test results
can still require advice from experts.
Systems for identifying, contacting, and advising at risk relatives should be able to
operate for a population where family members might be widely dispersed
geographically and in contact with different medical services. They should be
coupled with family record keeping. Plans should allow for informatics requirements
including the need to share information on genetic variants for diagnostics and
research and to store information in electronic patient records. The question of
whether these should be ‘standalone’ for a particular condition such as FH, more
‘multipurpose’ to cover a range of conditions (such as cardiovascular conditions), or
generic, (for example, using the regional genetics services), should be addressed
with a degree of urgency before a number of single disease ‘solutions’ to cascade
testing and family record keeping have been initiated. Whatever the chosen model,
there will be a need for expansion over and above the current systems.
At an even more fundamental level for future progress, there is a difficult and still
unsolved question over the sharing of data from large kindreds that may breach local
data security protocols and where it may be difficult to ensure the provenance of
data. These difficulties will become even more acute with the introduction of the
nationwide electronic patient records in England and Wales where the scope and
extent of the consents that apply to genetic information in different parts of the record
(held locally and nationally) could restrict legitimate sharing. These problems must
be resolved by national policy analysis and development and are vital if the health
benefits of cascade testing are to be realised for family members.
It can thus be seen that developing an appropriate clinical response to the need for
‘cascade testing’ within mainstream services will be complex. In developing strategy
it is vital that the expertise and experience of regional genetics services is harnessed,
alongside experts in informatics, information technology and legal aspects of data
storage and confidentiality. Such strategic thinking and coordination of effort might
prevent much duplication of effort, incompatibility of systems and systems that are
unduly restricted because of failure to address basic legal requirements for data
protection.
4.7
Building audit and research programmes to evaluate effectiveness and
cost-effectiveness of services
Specialist services in these developing areas need to remain aware of the need to
compete in an environment where resources for healthcare are stretched and
prioritisation will be for developments able to demonstrate cost effectiveness for
patient benefit. There will be demands for evidence for enhanced patient outcomes
with specialised services. Audit and research are thus vital aspects in the
17
development of high quality services for inherited conditions within mainstream
medicine.
Many services will be starting from a very low baseline of provision and so it is vital
that a monitoring and audit programme is set up to track provision and activity. Initial
steps will be to build on agreed standards and develop methods for benchmarking
inherited conditions services.
As cascade testing programmes are developed for different inherited conditions
within the services it will be essential to monitor outcomes, to ensure that the clinical
benefit to family members who are invited to take up the offer of testing outweighs
any physical of psychosocial risks resulting from anxiety related to (possibly
unwelcome) knowledge about risk, diagnosis and treatment. This will be particularly
important for individuals who are mutation positive but asymptomatic.
As more basic research goes on to understand the molecular basis of inherited
disease, increased capabilities to undertake genetic testing and provide preventive
and treatment options, there will be a need for careful translational research to
ensure that they are put to best use for patient benefit. Current assumptions, for
example, on the management of symptomatic patients cannot necessarily be applied
to asymptomatic individuals discovered by cascade family testing, or to individuals
with similar clinical manifestations but different underlying molecular abnormalities
(phenocopies). Fine tuning clinical management will depend on careful research
that identifies and investigates natural history and outcomes in cohorts of patients
that pass through the expert services for inherited disease (such as specialised
inherited cardiovascular conditions services) and other service provision. Finally,
since disorders such as FH appear to be at least as common in people from the
Indian subcontinent and from other ethnic groups, research needs to be carried out
to ensure that the approaches to cascade testing in different ethnic groups are
equally acceptable, or to adapt them to ensure high acceptability and take up in all
groups.
Important areas for research include:





Epidemiological work to provide information on disease incidence and prevalence
Genotype phenotype correlations
Natural history of disease including genotypic sub classifications
Effectiveness of interventions including genotypic sub classifications
Development and evaluation of methods for family cascade testing
Such studies will be essential to support future arguments for prioritisation of ICC
services.
4.8
Ensuring that specialist genetics elements of services are agreed and
used efficiently
With expansion of knowledge and capability for new applications in inherited disease
specialist genetics input into the diagnosis and care of patients and families within
mainstream specialties will continue to be important, but will become a scarce
commodity and must be used efficiently. For inherited conditions within mainstream
specialities there needs to be further developmental and strategic work at a national
level to agree:
18



the elements of care that should be provided by specialist genetics
the elements of care that could be provided by the mainstream services
themselves
the general organisational support that regional genetics services should provide
to the service
For example, it will be necessary to distinguish the high level ‘complex’ genetics
expertise that should be provided directly to clinical care by specialist genetics
services. This would include diagnosing dysmorphologies and syndromic disease,
counselling families about prenatal diagnosis and interpreting complex genetic test
results. This should continue to be provided by clinical geneticists and genetic
counsellors through appropriate contracted mechanisms of input into the service and
will be a specialist tertiary role. In contrast, services should develop capabilities to
provide much of the less complex care themselves. This might include, for example,
family history taking, genetic testing, follow up of family members. Support to such
genetic elements of care, for example education, mentoring, identification and
discussion of difficult ethical areas and overall organisational support, such as the
development of systems for consent, family follow up and family record–keeping
would then also be a vital element of the input of the specialist genetics service.
5
Conclusions
Between 2006 and 2009 the PHG Foundation led needs assessment and service
review of two clinical areas in which the diagnosis and management of people with
inherited disorders is an important clinical activity. A number of services throughout
the UK have responded to the increasing availability and clinical utility of genetic
tests. In many cases the main initiative has been from genetic services, which have
set up ‘joint’ genetics services with the clinical speciality. These services have
mostly been led and provided by clinicians with a particular research interest, with the
result that there is gross inequity of provision across the UK. Moreover, with scarce
resources for service development, the overall clinical capacity and quality is
extremely patchy.
From our detailed examination of need, based on epidemiology, anticipated clinical
utility, patient demand and desirable clinical quality we suggest that the need for such
specialist services will continue to increase rapidly in the future. With similar issues
in other specialities, it seems unlikely that today’s paradigm of ‘joint services’ with all
genetics elements being provided by clinical genetics departments will be practical.
Nor, with its emphasis on the ‘uniquely’ specialist nature of genetics elements, might
it be the desirable future pattern. Indeed, we find that this pattern is already being
eroded in the clinical area of familial hypercholesterolaemia. Further, as genetic
aspects of common complex disorders are increasingly evident and important it is
inevitable that these elements must be managed within mainstream medicine.
We suggest that the future pattern of care may be one in which mainstream services
encompass inherited aspects, and contract for necessary elements of specialist
clinical and laboratory genetics provision. This raises a number of issues in policy
development including issues related to commissioning, equitable service
development, developing networks, genetic test provision, increasing skills and
capacity in the professional workforce, methods for cascade testing and family
records, audit and research, the role of specialist genetics in mainstream services,
and mechanisms for requesting, funding and providing genetic tests.
19
The proposed policy developments amount to a transformation of services and
should properly position the UK NHS services to take advantage of new technologies
effectively and efficiently and for the benefit of the entire population. Our clinical and
laboratory geneticists and genetic counsellors with their special knowledge and
experience from basic science to clinical management of families, and their detailed
consideration and concern over the many ethical, legal and social aspects will be
essential in helping to lead this transformation. Vital also will be the leadership of
commissioners, public health specialists, other clinicians and voluntary organisations.
We recommend that the UKGTN should take a lead in bringing these many issues to
the forefront of debate for action within the UK NHS.
6
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16. Burke W and Zimmern R. Moving beyond ACCE: An expanded framework for
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Address for comments
hilary.burton@phgfoundation.org
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