Letter from the Royal College of Obstetricians
Following the launch of the Inquiry into this
very important area and "call for evidence" we sought
advice from our Fellows with the appropriate expertise and interest.
A number of very important issues have been raised and we enclose
copies of three responses from the following which are of particular
Professor Bernadette Modell FRCOG.
Professor Dian Donnai FRCOG.
Professor Patricia Jacobs FRCOG.
The UK Thalassaemia Register, and the
UK Register of Prenatal Diagnosis for Haemoglobin Disorder (Thalassaemias
and sickle cell disorders)
Bernadette Modell, Matthew Darlison, Maren
Khan, Mary Petrou, John Old, Mark Layton, Lysandros Varnavides
1. The haemoglobin genes are the best understood
of all human genes, and detailed knowledge is available on the
biological and clinical implications of variation in their sequence.
Haemoglobin disorders (mainly thalassaemias and sickle cell disorders)
are the commonest group of human single gene disorders. Screening
for carriers of these disorders is standard practice in many countries.
Antenatal and neonatal screening for haemoglobin disorders is
included in the national plan for the health service.
2. The UK Register of Prenatal Diagnosis
for Haemoglobin Disorders and the UK Thalassaemia Register are
held for clinical and audit purposes. They are continually evolving,
and the information they contain overlaps extensively. It is planned
to merge them into a single diagnosis register in the future,
if continued funding can be identified.
3. The objective of screening for carriers
of haemoglobin disorders is to identify carrier couples (who may
have a one in four risk of an affected child in every pregnancy),
provide them with risk assessment and genetic counselling, and
offer prenatal diagnosis, before they have had an affected child.
Risk assessment and prenatal diagnosis depend on DNA analysis.
Only three UK centres provide DNA diagnosis for haemoglobin disorders:
University College London Hospitals (UCLH),
King's College Hospital (KCH)
and the Institute of Molecular Medicine at Oxford.
4. Excess DNA remaining following the diagnosis
is routinely stored at these three centres for future reference.
From time to time, samples from patients or groups of patients
are examined for other DNA variants that may be relevant to the
clinical care of patients, or counselling of at risk couples (eg
polymorphisms adjacent to the globin genes, or insulin, collagen
of haemochromatosis gene variants).
5. The UK Register of Prenatal Diagnosis
for Haemoglobin Disorders is a collaboration between the three
DNA diagnosis laboratories. The register includes clinical and
DNA data on couples at risk, any affected children they already
have, and all fetuses with a prenatal diagnosis. Thus the register
is a guide to stored DNA samples from patients at all three UK
6. The UK Thalassaemia Register is a patient
register held by Bernadette Modell, Maren Khan and Matthew Darlison
at the Department of Primary Care and Population Sciences, Royal
Free and University College Medical School. The register contains
clinical data for almost all patients with a diagnosis of a major
thalassaemia ever resident in the UK. It has become apparent that
a detailed DNA diagnosis is highly relevant to the course and
clinical management of the thalassaemias. Genetic data on haemoglobin
gene variants in patients and their parents, derived from protein
and DNA studies, is therefore collected from clinicians and the
three UK diagnostic laboratories for inclusion in the register.
It is planned to develop this aspect of the register in the near
future into an ongoing nation-wide genotype/phenotype studyprovided
continued funding can be identified.
7. The patient register is limited to thalassaemias
because it is maintained with research funding: the aim is to
demonstrate the potential of such registers for national service
audit, research, and quality patient care. With appropriate funding,
the register could be turned into a national register of patients
with haemoglobin disorders, including the far larger (but still
unknown) number of patients with sickle cell disorders.
8. Patient ethnicity is recorded in detail
in both the above registers. Though patients with stored DNA have
one or two thalassaemia or sickle cell mutations, they otherwise
represent random samples of the different at risk populations
in the UK. These DNA sample collections are therefore representative
collections from UK population "not of Northern European
origin". The registers provide a mechanism for tracking available
9. Why are these genetic databases being
assembled? The UK register of prenatal diagnosis for haemoglobin
disorders aims to provide national service audit by following
the number and origins of referrals, and to maintain the highest
possible laboratory standards by fully sharing information.
10. The UK thalassaemia register aims to
promote best possible care for a very unevenly distributed group
of patients with a rare (in the UK) genetic disorder with complex
management. The register is in contact with all clinicians with
thalassaemic patients (including 76 with only one such patient).
It both regularly requests information on patient status, and
provides a service by circulating reports, research results, clinical
guidelines and patient information materials directly to the clinicians
11. Taken together, the registers demonstrate
a powerful mechanism for national audit of services for both treatment
and prevention of a genetic disorder, as they include information
on every conception affected by a major thalassaemia in the UK,
whether the outcome is a live-birth or a termination of pregnancy.
12. How are these activities funded? The
UK register of prenatal diagnosis for haemoglobin disorders was
set up with a short-term audit grant from DoH, but now has no
special funding. All current work is funded by the Wellcome Trust
as part of their support for BM as a Principal Research Fellow.
13. What practical considerations will
14. Funding. Wellcome research funding has
now ended (a) because BM has reached retirement age, and (b) because
the Trust considers that the registers have shown their value
for service audit and R&D, and should be transferred to the
15. Lack of recognition within the NHS of
the need for national audit mechanisms for services for genetic
disorders, and so of dedicated long-term funding.
16. Lack of NHS clinicians trained in the
public health aspects of medical genetics.
17. Lack of training and support for NHS
clinicians to manage electronic databases. This type of work requires
some senior physicians trained in public health aspects of genetics,
with formal national responsibility, and supported by cutting-edge
informaticsthat is, recognition of the discipline of community
18. Rapid turnover and low pay for NHS clerical
staff makes it very difficult to obtain and retain staff capable
of consistently entering data into databaseseven when this
is held as a patient record.
19. Are there alternative ways of fulfilling
20. There is no alternative approach for
collecting national data on phenotype/genotype relations or conducting
national service audit. We see automated data aggregation within
electronic records as a more cost-effective approach for tracking
availability of genetic samples and genetic information.
21. The genetic information being collected
is restricted at present to variants in the regions of DNA where
globin genes are located, and in some cases on other genes eg
haemochromatosis, osteoporosis, HLA type and diabetes, where variation
may be relevant to the clinical management of the patients.
22. The data is stored (a) in the patient's
notes, (b) as paper records in locked filing cabinets and (c)
in a password-protected electronic database. Data is accessible
only to register staff. There are formal conventions on who the
data can be released to, and in what format.
23. The organisations involved: how they
see their responsibilities regarding privacy; consent; future
use; public accountability; and intellectual property rights?
The organisations are University College London Medical School,
University College London Hospitals, King's College Hospital and
the Institute of Molecular Medicine at Oxford (NHS-supported unit
within an academic unit).
24. Privacy is considered the same as for
25. Consent procedures vary at the three
institutions. The prenatal diagnosis consent form used at UCLH
and KCH contains a clause giving broad consent for samples to
be used for research related to treatment and prevention of haemoglobin
disorders. Consent at the Oxford centre is obtained by the clinician
sending the sample for analysis, and is unlikely to include broad
consent for research. Consent for data to be held on the UK Thalassaemia
Register is via the clinician caring for the patients.
26. Future usewe see existing permission
as giving consent for use of patient records and DNA samples for
the benefit of the family or for patients in general. For permission
for other research uses of the samples or data, we visualise that
we should go back to the patient or the family. Families in the
UK prenatal diagnosis register could be contacted directly by
the UCLH or KCH centres, which have direct patient contact, or
through their doctor by the Oxford laboratory. Families in the
UK Thalassaemia Register could be contacted through their doctor.
27. Public accountability. The existence,
methods and objectives of the registers have been widely publicised,
and are approved by the UK Thalassaemia Society (the patient support
association) and the UK Forum on Haemoglobin Disorders. We share
information arising from the registers with doctors and patients,
and have an ongoing consultation with stake-holders.
28. Intellectual property rights. We visualise
that these are owned by the curators of the data, UCL, UCLH and
the Wellcome Trust (though there is some vagueness here).
29. How will our activities in the area
of genetic databases develop in the future? What advances in sequencing,
screening and database technology do we anticipate?
30. In the future, genetic testing and screening
will become far more widespread, and significant aspects of health
care are likely to be based on it. Our experience shows that the
genetic information should be mutation-specific to be fully useful
at the clinical level.
31. We therefore anticipate widespread use
of an electronic health care record that will be able to handle
genetic and family information properlyand will have the
potential to link directly with genetic databases, for audit purposes.
32. Information is the therapeutic intervention
in predictive genetics. It will therefore become necessary to
provide everyone with a genetic diagnosis, with mutation-specific
information. We therefore visualise large-scale linkage between
databases of mutation-specific information including appropriate
patient information materials, and electronic health care records,
to underpin appropriate service delivery.
33. Registers of genetic diagnoses will
also be needed to audit delivery of, and patient responses to,
34. In conclusion, haemoglobin provides
the only presently available model of the clinical application
of precise genetic information on a population scale. The two
registers described here demonstrate the integral importance of
precise genetic databases for patient services.
Wessex Regional Genetic Laboratory
I can give evidence from two perspectives, namely
as director of a Regional Genetics Laboratory that provides both
cytogenetic and molecular diagnostic services for a population
of approximately 2.5 million and as an established researcher
involved with a number of human genetic research projects many
of which are population based.
1. Diagnostic laboratories are sent specimens
from patients most of whom are suspected of having a genetic abnormality
detectable by cytogenetic or DNA analysis. Our laboratory handles
about 8,500 diagnostic specimens a year and of these about 5,000
have DNA extracted and stored for an indefinite period. In most
of the remaining specimens, fixed cells are stored for a number
of years from which DNA could be extracted, albeit with difficulty.
Similar tissues must be stored in pathology laboratories from
which DNA could be extracted. For a substantial minority of the
diagnostic specimens we have detailed pedigree information.
In the course of our research we have obtained
collections of DNA and/or information from patients with a variety
of conditions including mental retardation, behavioural abnormalities,
diabetes, reproductive difficulties, cytogenetic abnormalities,
specific malignancies etc. We also utilise DNA provided by a large
regional cohort, namely the Avon Longitudinal Study of Parents
and Children (ALSPAC).
I presume our experiences as a diagnostic and
research laboratory are similar to many others in this country
and together they present a large (and often overlooked) collection
of DNA and genetic information on the British population.
2. These genetic databases are assembled
for diagnostic purposes, funded by the NHS, or for research purposes,
funded by research councils and charitable organisations. I cannot
see any reasons why the development of these types of genetic
databases should be constrained, nor do I see any alternative
ways of fulfilling the diagnostic or research objectives that
underlie their development.
3. As well as DNA, tissues and cell suspensions,
we collect information on the immediate or extended family, relevant
clinical information and the results of the various tests being
undertaken. The data are stored in computers and are protected
by restricted access, safeguarded by appropriate codes, and the
professionalism of our staff.
4. The privacy of our laboratory databases
is sacrosanct and information identifiable with a patient is given
only to other diagnostic laboratories or clinicians on an individual
basis where the information is necessary (i) to make a genetic
diagnosis (eg part of a family being investigated by two different
laboratories) (ii) to undertake an audit or (iii) to conduct ethically
approved research. Furthermore such information is only provided
with the written permission of the referring doctor. Written consent
is obtained from all research subjects and all research protocols
are passed by the relevant MREC or LREC.
We use diagnostic specimens in two ways: (i)
to diagnose conditions for which the specimen was submitted, (ii)
anonymously as control material for other investigations. We use
research specimens only (i) to undertake research on the condition
for which the specimens were obtained or (ii) anonymously as control
material for other investigations. We plan to continue to use
the stored specimens ensuring privacy protection for the individuals
from whom they have been obtained. Neither public accountability
nor intellectual property rights have been issues with these types
of databases but could be addressed if necessary.
5. I foresee the continuation of these types
of diagnostic and research databases as inevitable given the type
of work that we undertake. I do not anticipate that advances in
sequencing, screening or database technology will substantially
alter the nature of our databases, save to make our work more
streamlined and perhaps easier.
6. I am unaware of genetic database information
in other countries that will be helpful to us, in maintaining
or expanding our own databases.
Patricia A Jacobs DSc FRS
North West Regional Genetic Service
The inquiry is of some concern to those of us
involved in providing clinical services to individuals and families
with, or at high risk of single gene disorders. There is a risk
that DNA samples collected and stored from and for these families
might be caught up in regulations developed because of the public
concern about large scale collections of DNA where the aim is
to look for genetic polymorphisms which might predispose to common
diseases or to responsiveness to particular medications.
To amplify the above I would make the following
1. Collections that are part of the infrastructure
of clinical services
Many genetic service laboratories have large
DNA banks linkable to clinical information from patients and families
referred to genetic services. Samples may be from:
(a) Individuals known to be affected with
a genetic condition where a molecular diagnostic test has been
undertaken and an aliquot for the sample stored.
(b) Samples from individuals with a genetic
condition where scientific knowledge or NHS service development
does not allow molecular diagnosis currently. When the relevant
gene for their condition is identified other family members may
want testing to see if they have inherited the family mutation;
without material from an affected person it is impossible to interpret
negative mutation screening results.
(c) Samples from individuals with undiagnosed
abnormalities (particularly babies with congenital abnormalities
who may not live) stored in the hope that future research may
allow a definitive diagnosis and hence accurate counselling for
All these collections are usually funded as
part of the NHS service and linkable to NHS notes on the individual
with the usual NHS arrangement for access. Formation of such collections
is not subject to research ethics approval. In most centres consent
forms for DNA analysis and storage are not completed since they
are regarded as any other blood sample taken for clinical investigation
and care. However this may change, particularly with regard to
2. Research collections of material from people
with specific genetic conditions
Very many individual research projects depend
on collecting modest numbers of samples from people with a particular
condition and often from unaffected relatives. These projects
will normally require approval from a research ethics committee
which will cover questions of use, access, confidentiality etc
and will deal with the issue as to whether subjects or their GP
will be informed of their test results. Contributions to such
research will come from service departments who often have samples
from individuals and families with rare genetic conditions (see
above) or the researcher will seek out suitable subjects and ask
them to take part eg through patient support groups.
3. Large scale collections of samples used
for prospective studies
In general these studies will be population
based and will be looking for genetic polymorphisms which may
predispose or be protective with regard to the development of
later-onset common diseases such as diabetes, hypertension and
coronary heart disease. Similar studies may be done to identify
factors which may affect drug response. Such studies would be
without value if clinical outcomes were not linked to samples.
Studies such as ALSPAC (the Avon longitudinal study) have identified
a cohort of children with pregnancy, birth and later follow-up
data. These sorts of studies are usually not undertaken by clinical
genetic centres who, at the present time, focus more on those
disorders which are due to single genes of high penetrance.
Professor Dian Donnai MB FRCP FRCOG FRCPCH
Consultant Clinical Geneticist
25 September 2000
7 Head, Dr Mary Petrou, Perinatal Centre, RF and UC
Medical School Department of Obstetrics and Gynaecology. Back
Former head, Dr Mark Layton, Dept of Haematological Medicine,
King's College Hospital. Back
Head of prenatal diagnosis laboratory, John Old, Institute of
Molecular Medicine, John Radcliffe Hospital. Back
For example, survival data collected at the end of 1998 showed
that patient survival has improved far less on a national level
than had been anticipated from results obtained at specialist
centres. This "early warning" information, together
with advice on patient referral, was circulated to all doctors
on the register at the end of January 1999. It was not published
(in the Lancet) until June 2000. Fewer deaths have been
reported for 1999 and 2000 to date. Back
For example, a collaboration of the registers with the National
Confidential Enquiry into Genetic Counselling showed wide regional
variations in the quality of national audit of quality of carrier
screening and counselling, with a selective failure of service
delivery to British Asians. Back