A framework for genetic service provision for haemophilia and other inherited bleeding disorders
Christopher A. Ludlam, Professor of Haematology and Coagulation Medicine, Director Haemophilia and Thrombosis Centre, Department of Haematology, Royal Infirmary, Little France Crescent, Edinburgh EH16 4SA, UK.
Tel.: 0131-242-6811; fax: 0131-242-6812;
Summary. This framework document offers guidance to patients, doctors, nurses, laboratory scientists, funders and hospitals on the provision of clinical and laboratory genetic services for haemophilia. With recent advances in molecular laboratory techniques it is now possible to give the vast majority of individual patients and family members very reliable genetic information. To enable these genetic data to be used for both the optimal treatment of patients with inherited bleeding disorders and for appropriate reproductive decisions in carriers, there needs to be a clear and robust framework for systematically acquiring the necessary clinical, personal, family and laboratory information upon which decisions can be made. This document provides guidance on the range and standards of clinical and laboratory genetic services which should be offered to patients and their families. Included are arrangements for genetic counselling and testing (including consent and confidentially issues), management of early pregnancy, standards for laboratory genetic services, as well as advice on data storage, security and retrieval.
The benefits of advances in DNA technology should be available to individuals with haemophilia and other inherited bleeding disorders, and their families. As it is now possible to identify the causative mutations in the majority of patients this information can be used to directly assign carriership within the family and identify an affected fetus early in pregnancy. To assist with making benefits of these data available to patients and family members there needs to be a coordinated development of current clinical and laboratory genetic services. The current framework document outlines how these services can be provided and is in keeping with the recommendations in the UK Haemophilia Alliance National Service Specification . The full guidance document for the UK service has been published as a separate document  and it contains detail of specific legislation relating to arrangements within the UK National Health Service (NHS). Many of the key issues, however, are common to all haemophilia services and it is hoped that their consideration in this framework will be of help to those developing services in other countries. We hope, therefore, that the discussion of the topics and the recommendations can be seen as a paradigm and may be of help when designing clinical and laboratory genetic services.
This framework is set out in the following sections:
- 1Genetic counselling
- 2Consent and written information for genetic testing
- 3Data collection, retrieval, storage and disclosure
- 4Management of early pregnancy and antenatal diagnosis
- 5Guidance on genetic testing of children
- 6Clinical–laboratory interface
- I Information sheet and consent form
- II Specification for haemophilia genetic laboratories
Setting the scene
The National Service Specification for Haemophilia and Related Conditions states that all individuals with haemophilia (or a related bleeding disorder) and their families should have access to specialized genetic services. Genetic counselling should be available for all people potentially affected by, or at-risk of being a carrier of one of these conditions, before, during and after the process of genetic analysis .
The current provision of genetic counselling within Haemophilia Centres varies even within Comprehensive Care Centres. The involvement of different members of staff in genetic counselling depends upon their role within the multidisciplinary team, and the skills, knowledge, experience and qualifications held and used by individual members of the team. Centre teams tend to vary in their membership of professionals from social and psychological services and in the extent to which these practitioners are explicitly involved in genetic counselling.
All specialist medical and nursing staff within Haemophilia Centres provide information to patients and families on the following:
- 1Inheritance patterns.
- 2The nature and implications of inherited bleeding conditions.
- 3Treatment and complications.
- 4The options open to family members who may wish to have genetic testing.
Information on genetic testing and interpretation of results is primarily imparted to patients by haemophilia doctors. Specialist nurses know patients and families well and therefore have an important role in identifying and reaching individuals who should be offered genetic testing.
Whilst many health professionals use counselling skills in their work, genetic counselling is a specialized area of practice with a professional registration system operating in the UK. Essential competencies for practice have been defined by the Association of Genetic Nurses and Counsellors (AGNC) .
Preparing for the future
In the age of molecular genetics, families have greater options for diagnosis, including carrier and prenatal testing and preimplantation genetic diagnosis. The service provided by Haemophilia Centres has to respond to these developments and the expectations they generate. It is unlikely that all the requirements of the genetic counselling process can be delivered by one individual professional – different levels and depths of genetic counselling can be provided which address different issues . Families making reproductive decisions need access to all these areas of expertise. Haemophilia Centre staff have the knowledge of current treatment and implications of the condition. However, there may be issues that may need to be considered away from the day-to-day treatment setting.
Precedents have been set in services for other types of genetic condition, where specialist health care and specialist genetic counselling are offered in different settings or by different professionals. For example, patients affected by cystic fibrosis are cared for in specialist centres, but genetic counselling is usually offered to such families by separate specialist genetic staff. Similarly, pregnant women seeking genetic information about a potential or actual fetal abnormality are referred to genetic services by the obstetric team responsible for management of the pregnancy. In many centres, joint clinics are held between genetic services and other specialists to serve the needs of families concerned about conditions affecting a particular body system (e.g. joint genetics/ophthalmic clinic, genetic/skeletal dysplasia clinic, genetic/neuromuscular clinic). This enables families to discuss therapeutic options, prognosis for the condition and current reproductive options.
It is essential that those seeking genetic counselling feel free to make decisions that are not constrained by their commitment to existing family members. This professional issue has been identified recently in other areas of health care, such as midwifery  and is of particular importance when considering the ethical principles of autonomy and justice. The criteria for offering prenatal genetic testing to individuals include obtaining prior informed consent and confidentiality , and these criteria are more effectively fulfilled when a distinction is made between professionals offering management for a condition and those who offer genetic testing. The results of genetic tests should only be disclosed to others with the consent of the consultand. Haemophilia specialists are highly committed to the success of treatment and may, or may not, be conscious of the potential impact of this on their ability to remain ‘neutral’ in the genetic counselling situation. It is also important to consider whether particularly sensitive issues such as paternity can be addressed in a setting where staff and families know each other well. For these reasons families should have access to a genetic counsellor who is not directly involved in provision of care for the affected family, and a choice of venue for receiving genetic counselling, either within or outside their Haemophilia Centre. Reports by the Genetic Interest Group (GIG)  have indicated that families should be offered prenatal testing so that they can make decisions relevant to their own situations.
It is not feasible, or necessarily desirable, for all haemophilia specialists to attain the level of practice required for registration as a genetic counsellor, as their work with one group of conditions would not confer generic skills. However, there may be some haemophilia specialists, such as nurses or social workers, with a special interest in this area, who wish to develop competency to the registration level. This would entail accepting a greater proportion of genetic counselling work and therefore impact on the skill-mix and responsibilities within the haemophilia team. Becoming a registered genetic counsellor also requires knowledge of a wider range of genetic conditions and therefore a period of time working in the regional genetics centre. Strong links with the Regional Genetics Centre would be necessary along with clinical supervision by a registered genetic counsellor.
Developments for the future
The framework proposes the following developments:
- 1Continuation of the provision of genetic counselling by a multidisciplinary team.
- 2Creation of stronger links between Haemophilia Centres and regional genetics services.
- 3Education and competency development for haemophilia specialists involved in provision of genetic counselling.
Central to this is the development of a new role, a registered genetic counsellor specializing in haemophilia and inherited bleeding conditions. This genetic counsellor could work in two settings, the Haemophilia Centre and the regional genetics service, and with both staff teams. The responsibilities would encompass:
- 1Genetic counselling for members of families with haemophilia and related inherited bleeding conditions.
- 2Maintenance of a register of families affected by or at-risk of inherited bleeding disorders to enable the Haemophilia Centre to offer a full service to family members.
- 3Clinical supervision for Haemophilia Centre staff on genetic counselling issues.
- 4Development of education and training for Haemophilia Centre staff on genetic counselling issues.
- 5Contributing to the formulation and evaluation of a competency framework for Haemophilia Centre staff in the provision of genetic information.
This framework could be based on the AGNC competencies but incorporate different levels appropriate for staff working within a specialist area who are not seeking full registration as genetic counsellors. For haemophilia nurses, this would be a logical extension to the existing competency framework published by the Royal College of Nursing, Haemophilia Nurses Association .
It is suggested that two possible approaches are considered by individual Haemophilia Centres.
The first option would be the attachment of a genetic counsellor to the Haemophilia Centre. A specialist genetic counsellor could be employed on a sessional basis within the comprehensive care centre whilst based at the local genetic centre, enabling access to support, supervision and current genetics knowledge. Specialist training in relevant aspects of the management of inherited bleeding disorders would be mandatory, as would regular education and supervision from Haemophilia Centre staff. An appropriate portion of the salary would be funded by the comprehensive care centre. This model might be particularly useful for smaller centres. Patients would have the opportunity to consult the genetic counsellor in either the genetics or the Haemophilia Centre.
An alternative model would involve the registration of a member of the haemophilia multidisciplinary team, such as a specialist nurse, as a genetic counsellor. This would entail the identification of a suitable person with a special interest in genetics who would change their role within the centre and undertake full registration as a genetic counsellor. This person would have strong links with staff of the local genetics centre, for education, supervision and support, and would be expected to spend time regularly in the genetics centre, e.g. 1 day per week. Initially a period of training in the local genetics centre would be required. This option would incorporate the important principle of allowing the choice of consulting the genetic counsellor in either the genetics or the Haemophilia Centre.
In both approaches, the emphasis is on providing strong links between genetics centre and Haemophilia Centre, and enabling the genetic counsellor to access education and supervision in both areas. The system would also enable registers to be kept up to date and enable new developments to be available for families rapidly.
Consent and written information
Seeking informed consent for genetic testing requires careful and considered explanation. The recommendations of the European Society of Human Genetics  state that genetic testing should be based on respect for the principle of self-determination of the persons concerned and therefore subject to their express, free and informed consent. No condition should be attached to the acceptance or the undertaking of genetic tests. Written informed consent is also required for all types of DNA banking. These recommendations advocate careful consideration of the psychological complexities of testing and a multidisciplinary approach.
Informed consent for testing is conducted in the wider context of genetic counselling. For patients and family members it is recommended that written information is made available and that signed informed consent is obtained for genetic testing. Within the context of testing for a bleeding disorder a model patient information sheet has been designed by the UKHCDO Genetics Working Party (Appendix 1). This could be adapted to local circumstances and arrangements within each Haemophilia Centre. A photocopy of the completed and signed form should be given to the patient, a copy of the information sheet and the original of the consent form should be filed in the patient's case notes and a copy of the consent form filed in the family genetic file. Some key elements related to testing should be considered as part of the content of pretest discussion and follow-up.
- 1Establish that a bleeding disorder is present in the family and determine its type and severity.
- 2Establish a pedigree/family tree.
- 3Assess understanding, expectations, beliefs and wishes.
- 4Acknowledge the implications of individual and family experiences, values and culture.
- 5Address personal and relationship concerns related to testing.
- 6Provide the opportunity for questions to be asked.
- 7Provide the opportunity for the consultand to present their understanding of the information that has been discussed and its implications for themselves and others.
- 8Ensure information and its significance is understood and accepted.
- 9Offer a follow-up appointment.
- 10Where the need for ongoing support is identified in the course of the consultation, make appropriate referrals.
- 11Make clear arrangements for imparting the results of testing.
- 1The potential clinical effects of being a carrier or affected person.
- 2Current treatment and implications of the condition.
- 3The mode of inheritance and the individual's genetic risk.
- 4The rationale for identifying the genetic defect.
- 5The means by which carrier status is assessed.
- 6What is involved in genetic testing: sample collection; transfer/storage of data; research projects on stored material; insurance issues; risk of error.
- 7Information on the procedures for antenatal testing.
- 8Written information – the NHS consent policy and generic forms point to the importance of making written information available to patients to back up the content of face-to-face discussion. NHS organizations are held to be responsible for satisfying themselves as to the quality and accuracy of the information they provide to patients .
Data collection, retrieval, storage and disclosure
The GIG, an umbrella organization of genetic disorder support groups in the UK states in its document ‘Guidelines for Genetic Services’  that, ‘systems are needed to facilitate efficient, effective, long-term follow-up of service users and their families and contact of at-risk relatives’. In terms of specific recommendations, the same GIG document states that ‘the service should enable children and young people in a family to be offered the opportunity of referral for genetic information and counselling when appropriate’ and that ‘services should make direct contact with young adults in affected families when they reach the age of 16, and invite them to use the service’.
In order to enable this process, clinical genetic services have established a system of family genetic records and genetic family registers.
Family genetic records
In the UK, the genetic counselling of patients with haemophilia and other inherited bleeding disorders is generally undertaken by haemophilia specialists within Haemophilia Centres, rather than clinical geneticists. Genetic information, including pedigrees have tended to be filed either in the index patient's case notes or manually elsewhere in the Haemophilia Centre.
It is recommended that Haemophilia Centres develop family genetic records of patients with haemophilia and other inherited bleeding disorders.
It is recommended that these notes should
- 1be a separate ‘genetic’ file;
- 2be kept within the Haemophilia Centre;
- 3contain the family pedigree. The pedigree should be compiled in a standardized way for all haemophilia families using standard conventions;
- 4contain the results of all relevant genetic tests, whether biochemical, haematological, cytogenetic or molecular genetic tests;
- 5contain informed written consent for genetic studies, sharing of appropriate family information and inclusion on a register;
- 6contain copies of all pedigree-related correspondence;
- 7be kept confidential and only accessed by authorized staff of the Haemophilia Centre.
Genetic family registers
The maintenance of pedigrees requires continued commitment. It is difficult to be sure that the pedigrees are updated adequately, and a system needs to be in place to offer follow-up of possibly affected relatives, in particular for the recall and counselling of potential female carriers within haemophilia families.
In conjunction with the development of the family genetic records, it is recommended that a haemophilia genetic register system is also established in each centre.
In simple terms, a genetic register comprises a list of people affected by, or at-risk of genetic disease, linked as families, and linked to a diagnostic index . Such a confidential database of families can serve several functions:
- 1It can allow regular contact with families.
- 2Allow planned follow-up in order to offer counselling to at-risk family members at appropriate ages.
- 3Allow recall of families in the light of genetic research developments.
It is usual for such databases to be computerized. Whilst the follow-up and offer of genetic counselling to family members can be reviewed and planned at an annual clinic assessment of the index patient, a computerized register system is a more efficient means of storing and retrieving data, although means of safeguarding confidentiality must be in place.
It has been common practice within clinical genetic services to include on the genetic register those relevant family members who are included on the pedigree (with their documented relationships) but who have not attended the genetic counselling clinic. Such family members might include the younger sisters of affected male haemophilia patients who should be offered genetic counselling at an appropriate age. The issues of storing such data need to be considered in the light of the data protection regulations of each country, which in the UK is the Data Protection Act.
There is a strong argument to establish, in addition to genetic files, a computerized family register in each Haemophilia Centre whereby:
- 1Pedigrees are recorded in computerized format – an electronic picture and filing system for family members identified by name, pedigree number and generation; this makes it easier to access and to modify as additional members are added to the family. Some commercial programmes are available for this, e.g. Cyrillic (based in Oxford, UK) and Progeny (USA), although many genetic centres use in-house systems. These programmes contain more facilities than would generally be required within Haemophilia Centres.
- 2The data recorded on each individual on the register should include:
- I Standard information.
- a Pedigree or family file number.
- b Surname, first name, sex, date of birth, address.
- c Primary care doctor and referring clinician (if a haematologist or paediatrician outside the Haemophilia Centre).
- d Specific diagnosis (e.g. haemophilia A, haemophilia B, von Willebrand disease, etc.).
- II Test results – including the mutation, if known.
- III Agreed plans for follow-up of patients and of relatives at-risk.
Any computerized database is ideally interfaced to a system that can automatically generate follow-up letters at appropriate times for girls as they reach an age where genetic counselling can begin. The system would allow cross-referencing between different family members.
The pedigree should be updated at least annually, taking advantage of one of the regular clinic visits of the index patient where possible. At these updates it is important to try and confirm the family relationships that have previously been documented and to add new family members that have been born in the intervening period. Reminders should be put in place to ensure this happens.
Contacting relatives to offer genetic counselling
When a pedigree is taken for the first time or when it is updated, the genetic counsellor will seek to identify those other family members to whom the offer of genetic counselling would be appropriate, such as the close female relatives of a male with haemophilia. It is the usual practice in clinical genetic departments to indicate to the patient (or their parents in the case of a child) those relatives to whom this offer would be appropriate. It is usually regarded as the family's responsibility to contact these relatives and alert them to this offer. The Nuffield Council on Bioethics report in 1993  stated that the primary responsibility for communicating genetic information to a family member lies with the individual and not with the doctor. In the UK, the Medical Ethics committee of the British Medical Association  suggested that in those cases where the individual is unwilling to transmit the information but gives consent for the information to be shared, the genetic centre should approach the relatives through their primary care doctor (GP).
Clinical genetic departments often provide the family with an explanatory letter that could be sent to relatives. Certainly, it is considered good practice to write to all families following a genetic counselling appointment to provide written confirmation of the risk assessment given during counselling and a summary of the options open to the family, including the possibility of antenatal diagnosis where appropriate.
It is recommended that a post-consultation letter is sent to all families indicating the genetic risks, options available and the offer of genetic counselling to other at-risk relatives. The letter should include a recommendation to contact the haemophilia/genetic centre preferably prior to any pregnancy but in the event of a pregnancy, as soon as a pregnancy is confirmed.
Issues of consent and confidentiality in genetic counselling
Storage of data With regard to the storage of data, the UK Human Genetics Commission (HGC) in their report ‘Inside Information’  notes that the storage of information about other persons raises potential data protection issues. The report states that, ‘there is potentially a considerable amount of information about family members on most medical records. However, there is potentially far more significant information on records held by clinical genetic centres. This is especially true when family pedigrees are stored in combined files or where genetic registers are held’.
When families are seen in clinic they can be asked to consent for their data, including DNA results, to be stored on a local register. This is covered in the information sheet and consent form for molecular genetic analysis and, in the UK, by a leaflet explaining the National Haemophilia Register.
In the UK, consent to information storage is governed by the Data Protection Act and the common law of confidentiality. The data protection act covers information processing, which is a wide term that includes collection, storage, disclosure, retrieval, destruction and alteration. Schedule 1 of the Act states that personal data shall be processed fairly and lawfully and shall not be processed in the case of sensitive personal data unless at least one of the conditions in schedule 3 is met. Sensitive personal data cover a number of personal details including physical or mental health or condition. Section 8 of schedule 3 states that the processing can take place if it is necessary for medical purposes and is undertaken by
- 1a health professional;
- 2a person who in the circumstances owes a duty of confidentiality which is equivalent to that which would arise if that person were a Health Professional.
Medical purposes include the purposes of preventative medicine, medical diagnosis, medical research, the provision of care and treatment and the management of health care services.
There are potential issues for Genetics/Haematology Departments regarding the family tree. In the UK, the Department of Health white paper ‘Our Inheritance, Our Future’  states that, ‘under the Data Protection Act, a doctor or counsellor is required to tell relatives that information about them is recorded in the patient's medical records. Not only is this potentially very bureaucratic, it could also reduce the amount of clinically useful information that doctors feel they are allowed to record. The HGC also said it was possible in some cases that a relative may wish to stop the information about them being recorded. The patient's interests would then have to be balanced against those of the relative. The government have taken note of the comments made by the HGC and of other concerns about the application of the Data Protection Act to medical record-keeping and established the Health Records and Data Protection Review Group to examine the matter in detail’. It is important to recognize that those providing genetic counselling need information about other family members to advise the person who is being seen and to enable provision of accurate information for other family members who may seek advice in the future.
Access to records of a relative There are several issues for Haemophilia Centres in terms not only of the collection and storage of data for genetic counselling but also in the disclosure of clinical details and genetic test results.
Whilst referral of a patient implicitly includes consent to review their medical records, there may be occasions when in the genetic counselling of a family, it is important to have access to the records or test results from relatives.
- 1A woman is referred for carrier testing because she has a male relative with haemophilia – that male relative's records and test results may need to be accessed.
- 2A history is obtained that the mother of a boy with haemophilia had a male relative with a bleeding tendency. It may be important to try and obtain details of this relative to see whether there was evidence of a bleeding disorder, and if so, which one. Sometimes the relatives may be deceased.
Under these circumstances, information could be obtained from the patient's case notes. In terms of seeking information from case notes the legal position for living relatives is broadly that consent can be obtained for access to information from that person.
If the person is alive it is recommended that consent is from them or the person with parental responsibility to access the required information.
In the UK, access to the health records of the deceased is governed by the Access to Health Records Act 1990. This Act applies only to records compiled on or after 1 November 1991, although the record holder (usually an NHS Hospital) does have discretion to permit access to earlier records.
The record holder has the right to deny or restrict access if it is felt that disclosure would cause serious harm to the physical or mental health of any other person. Additionally, if the patient expressed a wish that all or part of their health record was to remain confidential then these wishes should be respected.
In the UK, the right of access to the notes of a person who is no longer alive is unclear. Some hospitals will only allow access if there is consent from the next of kin. In the past, advice from the Medical Defence Union and Medical Protection Society has been to permit access only if there is consent from next of kin or a ‘best friend’. The term ‘next of kin’ is used in legislation covering succession and inheritance but currently does not have legal significance in the context of access to information.
It is unclear what a Health Professional should do if there is no longer a personal representative due to the length of time elapsing between death and a request to see the medical records. The common law duty of confidence does apply to the deceased. However, unless there is good reason to believe the deceased would have refused access then the public interest regarding the relatives over-rides the principle of duty of confidence to the deceased. A ‘good reason’ in this context would be that the deceased stated that he/she did not want relatives seeing the notes after his/her death.
The needs of the living should be recognized and current legislation should be interpreted by Hospitals to reflect this. It is good practice for hospitals to release notes of a deceased person if consent is obtained from a close relative for whom the information is relevant unless the deceased person had specifically refused this. Request for information from medical records should state that the request is being made because the information sought is necessary for the care of a patient. In the UK, the argument can be advanced that the NHS is a mutual service and therefore a charge should not be made.
Disclosure of information about a relative without consent The above discussion was centred on obtaining information about relatives from medical notes. It is also possible to gain information from colleagues. Although there are many trusted links between departments and laboratories, the established links do not remove the need for consent for both information and sample sharing. However, in the case of a prenatal diagnosis where there is urgency to share information or samples it should be acceptable in the UK under current General Medical Council guidelines to proceed without consent, if necessary. An example of such exceptional circumstances would be the case of a pregnant woman presenting at an antenatal clinic and stating that her sister who lives elsewhere is a carrier for haemophilia. If the sister cannot be contacted then, in such circumstances, it should be professionally acceptable for the laboratory that established the diagnosis to share information/samples with those involved in the care of the pregnant woman. The reasons for doing so should be carefully documented.
Disclosure without consent should be carefully considered and documented including the reasons for disclosure and the absence of consent.
Another situation considered by the UK HGC in their report ‘Inside Information’  is the situation where a relative refuses to consent to the release of important information. The report took the view that, ‘bearing in mind the principle of genetic solidarity and altruism, we take the view that disclosure of sensitive personal genetic information for the benefit of family members in certain circumstances may occasionally be justified. This would arise where a patient refuses to consent to such disclosure and the benefit of disclosure substantially outweighs the patient's claim to confidentiality’. The UK Department of Health white paper ‘Our Inheritance, Our Future’  supports the principles argued by the HGC, ‘especially the balancing of respect for individual rights with the need for genetic solidarity and altruism so that genetic knowledge can be shared to help others and society’.
Consent for sharing of information with relatives could be achieved prospectively if such information sharing was discussed at the outset of a genetic consultation and consented to. If this is not the case then it is good practice to try to obtain consent retrospectively if this becomes possible, e.g. in this example above, if the carrier sister had been abroad.
In order to avoid these difficulties the working party recommends the use of an information sheet with written consent for genetic testing. The consent obtained includes the agreement for sharing the results of genetic tests for the benefit of other family members.
It is good practice to obtain consent for this disclosure whether the other family members are being seen in the same department or another one.
It is good practice to ensure that the proband both understands the benefit of keeping the primary Health Care Team informed as well as the potential implications of a genetic diagnosis. As mentioned earlier it is recommended that the proband gives consent to information sharing with other Health Professionals.
Guidelines for the management of early pregnancy and antenatal diagnosis
It is good practice to address issues related to the genetics of inherited bleeding disorders before the first pregnancy so that individuals and families are not faced with large amounts of information and potentially difficult decisions in a short period of time during early pregnancy. In addition, laboratories should not be asked to provide results under time pressure if this could be avoided. It is the case, however, that some known or potential carriers of bleeding disorders present during pregnancy and in these cases the relevant issues must be addressed urgently.
Good communication between all interested parties is essential to a successful process. This is best coordinated by the Haemophilia Centre. Communication should include the pregnant woman, obstetric/fetal medicine unit, laboratories and primary care doctor. There may be more than one laboratory involved in providing phenotypic testing, karyotype analysis and molecular diagnosis.
Confirmation of diagnosis
The family diagnosis should be confirmed unequivocally and if necessary affected family members should be reinvestigated. This may be particularly relevant if a diagnosis was made some years ago as reinvestigation with modern techniques and assays may yield important information relevant to genetic counselling and management. The coagulation factor level in the family should be confirmed. A definitive confirmation of the family diagnosis and coagulation factor level may not be possible if an affected family member is not available for investigation. The available phenotypic and genetic laboratory data should be critically reviewed. The quality of results should be reviewed with regard to the techniques and controls used.
A family tree should be drawn up or the accuracy of an existing family tree confirmed. The status of the pregnant woman can then be confirmed.
If the family is affected by a recessive disorder testing of the partner may be helpful.
The diagnosis, coagulation factor level and mutation within the family should be definitively confirmed, if possible, and the family tree updated to ensure that genetic counselling is accurate.
Genetic counselling should be conducted before pregnancy. For the woman who presents in pregnancy, genetic counselling should be available as early as possible. The environment should offer privacy and comfort. Staff involved should be competent in genetic counselling and knowledgeable about inherited bleeding disorders. In practice, this may entail access to more than one professional (see earlier). If antenatal diagnosis is being considered, appropriate staff from the antenatal diagnostic unit should be involved at an early stage.
Genetic counselling should cover the following topics
Clinical phenotype The bleeding disorder in the family should be described along with likely bleeding phenotype and potential complications. The expected quality of life of affected children and the impact on the family should be discussed. The efficacy, safety and side-effects of current treatment should be covered. It may be necessary to explore the individual's previous experiences of the disorder within the family, particularly in relation to infective complications and severe disability. Partners and individuals who have limited first hand experience of the disorder are likely to require extensive counselling about the condition and its current treatment and management.
Inheritance The mode of inheritance of the disorder should be described and the situation of the individual seeking counselling established.
Options The available reproductive options should be discussed. These would include taking no action and accepting the outcome of a pregnancy. For couples who have decided not to have an affected child, options include not having children, adoption, the use of donor gametes, antenatal diagnosis and termination of an affected fetus and preimplantation sexing or diagnosis. The procedures should be explained including how and where they would be performed, their availability, accuracy and success rates and potential risks to fetus and mother. The advantages and disadvantages of each option should be explored including the psychological affects on other family members and the family as whole. These discussions will be affected by the individual's and the family's previous experiences of the condition and its complications. Where appropriate, other antenatal diagnostic tests may be offered, e.g. karotyping, by those providing the diagnostic clinical procedure.
Counselling All options available for antenatal diagnosis should be discussed with the pregnant woman and, if appropriate her partner. The risks and benefits of each approach should be discussed and compared. Options may include continuing with the pregnancy, ultrasound for fetal sexing, chorion villus sampling (CVS), amniocentesis and cord blood sampling if genetic analysis was not informative.
Pretest counselling is undertaken by a combination of appropriate Haemophilia Centre and fetal medicine staff. The individual should be informed about the procedures; how they will be performed, the possibility of not obtaining an adequate sample, non-diagnostic results and potential side-effects for both mother and fetus. It should be agreed with the couple what tests will be performed and in what order. In particular it should be agreed whether tests unrelated to the bleeding disorder would be performed. It would be routine practice in most centres to offer karyotype testing, for example. An indication should be given about how long the tests will take to be performed. A crucial part of pretest counselling is a discussion of what options would be taken by the woman with each possible test outcome and the potential effects of these decisions should be explored.
The haemostatic cover for the procedure, if required, should be discussed along with issues related to maternal and fetal exposure to blood products if relevant.
Counselling for antenatal diagnosis should be performed by a combination of Haemophilia Centre and fetal medicine staff.
Communication of results It should be agreed in advance who, how and where the results of the antenatal diagnosis tests will be given. Once the results are known the options available to the woman should be discussed. It may be necessary to allow time for the results to be considered before a decision is reached.
For all invasive procedures that may be used for antenatal diagnosis it is important that the following issues are always addressed
- 1Obtaining written informed consent for the procedure.
- 2Assessment of the individual woman's need for haemostatic cover [e.g. desmopressin (DDAVP) or recombinant coagulation factor concentrates] for the procedure dependant upon their diagnosis and level of coagulation factor.
- 3Agreeing in advance and before leaving the hospital the arrangements regarding the method of communication of the result.
- 4Ensuring postprocedure check of the fetal heart.
- 5Ensuring administration of anti-D when appropriate.
Chorion villus sample
Chorion villus sampling involves taking a sample of chorionic villi for analysis. The main advantages are that it allows first trimester diagnosis and so avoids late termination and chorionic villi are a reliable source of fetal DNA.
Procedure Before the day of the procedure the mother is scanned to confirm viability of the pregnancy, gestation, number of fetuses and placental site. The procedure takes about 15 min and is performed under local anaesthetic by a clinician. On the day of the procedure the viability of the pregnancy is confirmed by ultrasound. Most centres use a transabdominal approach under continuous ultrasound control. This technique is used optimally between 11 and 12 weeks to allow a first trimester termination but may be used up to 14 weeks gestation. The sample is usually taken either by single needle aspiration or double needle aspiration and using either high-power suction or syringe suction. A transcervical route through a speculum may also be used but is associated with a higher risk of infection-related miscarriage and can only be performed up to about 12 weeks gestation. The material obtained is examined microscopically to confirm that it is adequate. The sample is placed in transport medium.
In multiple pregnancies the chorionicity should be established on ultrasound early in the first trimester. For dichorionic twins most authorities suggest that amniocentesis is preferable to CVS to minimize the risk of DNA contamination. For monochorionic twins a single CVS on a definitively monochorionic placenta may be acceptable, however, amniocentesis may be preferred as there is not a 100% correlation between chorionicity and zygosity. Advice should be taken from the local fetal medicine unit.
Adverse events The main adverse event related to CVS is miscarriage which is estimated at about 1–2% with an experienced operator. Fetal limb abnormality has been associated with CVS taken before 10 weeks gestation thus most are carried out from 10 weeks gestation . The woman should be warned that she may experience either discomfort or pain during the procedure. Systems must be in place to ensure adequate labelling and handling of the sample.
Laboratory testing In the case of X-linked disorders the fetal sex should be established initially. If the fetus is female no further tests are done apart from exclusion of maternal contamination. If the fetus is male tests are performed to establish whether the affected gene has been inherited. This may be done by direct mutation analysis, gene tracking techniques or a combination. Laboratories should be accredited for such work.
For antenatal diagnosis, procedures and communication between Haemophilia Centre, fetal medicine department, laboratories and GP should be formalized in a written protocol.
Cells for karyotyping and as a source of DNA can also be obtained from amniotic fluid after 15 weeks gestation. The miscarriage rate is about 0.5–1% with skilled operators. The main disadvantage of amniocentesis compared with CVS is that a termination, if necessary, will occur later in pregnancy and a surgical procedure would not be an option in most NHS hospitals. The main advantages are that the miscarriage rate is lower. Amniocentesis can be performed after 14 weeks gestation. Guidelines for amniocentesis are available .
Procedure Haemophilia Centres should make arrangements for amniocentesis to be performed in a specialist centre that complies with national or professional guidelines.
An ultrasound scan is performed to confirm gestational age, viability of the fetus, liquor volume and placental site. The procedure takes about 15 min and is performed by a skilled operator. The procedure should be under continuous ultrasound control and be performed by a person doing at least 30 procedures a year. The sample is taken by needle aspiration using continuous ultrasound.
In multiple pregnancies samples are taken from each sac and labelled with reference to placental site. Procedures in multiple pregnancies should only be done in a fetal medicine unit prepared to offer selective fetocide for discordant results.
Adverse events The miscarriage rate is between 0.5 and 1%. An increased rate of miscarriage and fetal talipes has been associated with early amniocentesis (before 15 weeks). The woman is likely to experience minimal discomfort during the procedure.
Cord blood sampling
Fetal cord blood sampling to investigate haemostatic disorders is very rarely performed and should only be considered if all other possible techniques cannot be used or do not give conclusive results . In the vast majority of cases molecular techniques will be available, will give more reliable results, have a lower risk of complications and a lower risk of artefact affecting the sample leading to misinterpretation of the results. Fetal cord sampling is a technique that should only be used to investigate severe deficiencies of coagulation factors where an undetectable level would suggest an affected fetus. In the majority of cases it should be possible to avoid fetal cord sampling by identifying the causative mutation in a carrier, even if an index case has not previously been studied, within a time frame that allows mutation analysis of the fetus using cells collected at amniocentesis or by CVS. Fetal cord sampling may be considered if a woman wishes to ensure that she does not have a child affected with severe haemophilia and a causative mutation cannot be identified. Pretest counselling should cover the possibility of artefact, incorrect or uninterpretable results.
Procedure Ultrasound fetal sexing is reliable in the hands of an expert by 18 weeks and so fetal cord blood sampling can be avoided in females. However, in the investigation of X-linked disorders, in some cases, the fetal sex may need to be confirmed by molecular techniques using cells taken at amniocentesis.
Fetal cord blood sampling should only be considered in tertiary referral fetal medicine units experienced in this technique and capable of performing coagulation assays on fetal blood. Written informed consent should be taken. A skilled operator can perform cord blood sampling from 18 weeks gestation. A blood sample is taken under continuous ultrasound control from either the umbilical vein at the placental insertion of the umbilical cord, fetal hepatic artery or fetal heart. There is a risk of the sample being contaminated by maternal blood leading to dilutional artefact or amniotic fluid diluting and activating the sample. One practice is to take three 1 mL samples and test the first and third for coagulation factor levels to ensure these are consistent. The middle sample is tested for haemoglobin (Hb) and mean cell volume (MCV) and compared with the maternal MCV to confirm that the blood is of fetal origin.
Adverse events The procedure has a 1–2% risk of miscarriage in experienced departments.
Laboratory testing A sample diluted by maternal blood may have an artefactually low level of all coagulation factors. A sample contaminated by amniotic fluid will be activated and there may have been consumption of all coagulation factors again resulting in an artefactually low level. The plasma should be tested for the coagulation factor under investigation and one other control coagulation factor level. Fibrinogen should be tested as a markedly reduced level would suggest activation of the sample and that other measured coagulation factor levels are unreliable. The results should be interpreted with regard to fetal blood normal ranges derived from the appropriate gestation. If two samples have been taken interpretation should only be undertaken if the results are consistent.
If the coagulation factor under investigation is undetectable and a control coagulation factor level, and fibrinogen level are within the expected range then a severe deficiency of that coagulation factor is confirmed. The test results would normally be available within 24 h. Samples from more than one fetus can be taken and labelled according to the placental site.
Preimplantation sexing and mutation analysis of embryos is technically feasible. Preimplantation sexing with reimplantation of female embryos is currently being undertaken for haemophilia and is likely to become a realistic option for more couples over the next few years [20,21].
Studies for preimplantation mutation analysis in haemophilia are currently being undertaken in a limited number of centres. In the UK, centres who perform the procedure are licensed by the Human Fertilisation and Embryology Authority (HFEA). Each new test requires a new license.
Procedure The ovaries are down-regulated and then stimulated to produce multiple follicles. Ova are aspirated transvaginally, under ultrasound control. Heavy sedation is required. Ova are fertilized in vitro. Embryos at the 8-cell stage have one or two cells removed which are tested for either the sex or the known mutation. If available, up to two non-affected or female embryos are reimplanted. The main side-effects are of ovarian hyperstimulation and multiple pregnancies. The success rate of in vitro fertilization is about 20–30%.
Detection of fetal cells from maternal blood
It is possible to detect fetal cells in the maternal circulation. Attention has focused on the fetal erythroblast as these cells have a short half-life in the maternal circulation and are abundant in early fetal blood. Currently, the sensitivity and specificity of this testing is not sufficiently high for clinical practice. Studies are also being performed on cell-free fetal DNA in the maternal plasma. At present these techniques are at the research level but may soon become routine practice.
If a woman decides to terminate her pregnancy management should be coordinated by an obstetric unit. The obstetric unit and the Haemophilia Centre should provide haemostatic cover, counselling and support as appropriate.
Suction termination of pregnancy under general anaesthetic can be performed up to 13–14 weeks gestation. After 13–14 weeks a medical termination is induced. It is important that the mother knows the gestation limit for suction termination for the obstetric unit in relation to the likely timing of results from antenatal diagnosis. For a termination after 21 weeks and 6 days feticide using an intracardiac injection of KCl is mandatory to prevent the possibility of a live birth.
If selective termination of a dichorionic twin pregnancy is necessary the affected fetus is terminated using an intracardiac injection of concentrated KCl. This is not suitable for a monochorionic twin pregnancy, as both fetuses will be affected, and cord occlusion or laser techniques must be used. Procedures should be carried out and coordinated by a fetal medicine unit.
Inherited-bleeding disorders: the value of genetic testing in children
It is recognized that genetic tests can only be performed on people who give informed consent after appropriate counselling and that some people decide that they would prefer not to know their genetic status for a variety of reasons.
Males with haemophilia
It is recommended that all children with haemophilia have their genotype established. This gives useful information regarding the risk of developing an inhibitor and may allow valuable information to be given to other family members. In future, individual genotype will be required if gene therapy becomes a realistic treatment option.
Females who are potential carriers
An area of particular difficulty revolves around testing female children who are potential carriers of haemophilia. This area is surrounded by potential ethical conflict and a distinction must be drawn between tests performed solely for future reproductive choice and those done to directly benefit the child in the immediate future. In the UK under the 1989 Children's Act the child's views on testing should be sought and depending on the intellectual capacity of the child, a child younger than 16 years may give a valid consent providing the implications of the test are understood.
If children are tested before they are competent to give informed consent they are denied their right to refuse the test and the knowledge gained from that test. In addition, confidentiality is lost as it is possible that not all potential carriers of haemophilia would want their parents or other family members to know their status. The ability to gain future insurance may also be affected. A report of the UK Clinical Genetics Society Working Party  on genetic testing in children reached a view that ‘carrier testing for genetic disease in childhood may not be the most appropriate approach, at least if practical alternatives can be devised and established. Inadvertent carrier testing…… should be avoided wherever possible. Research is needed to ascertain the psychosocial consequences, the adverse effects or the benefits, of carrier testing in childhood’. A widely held view is that genetic testing should be deferred until the child can give a valid consent for investigation unless the result leads to a direct benefit to the child.
The same reasoning holds true when performing antenatal diagnosis. The fetus should initially be sexed and if female it is accepted practice that no further tests should be performed unless the fetus is at-risk of inherited haemophilia (e.g. Turner's syndrome).
However, in female children who are potential carriers of haemophilia it is important to establish whether they have an increased risk of bleeding to ensure appropriate treatment at times of surgery or trauma. It is therefore of benefit to these children to have their baseline coagulation factor levels tested. Coagulation factor levels in potential carriers of haemophilia should be measured after 1 year of age and when peripheral venous samples can be easily obtained. The tests should be performed earlier if required for a specific clinical reason. Tests should be performed on more than one occasion to ensure reproducible results.
Whilst knowledge of a low coagulation factor level is of direct clinical importance to a child it may also imply that she is a carrier of haemophilia. The potential benefit to the child in this circumstance is thought to outweigh the disadvantages and definitive carrier testing will still be required at a later date. Females with normal coagulation factor levels will not be at increased risk of bleeding but they may still be a carrier of haemophilia A or B.
To ensure that families understand the implications of the tests performed they should be sent written information of the result, its interpretation and an indication as to whether further genetic tests should be considered in the future. To avoid confusion all people tested should have their own individual case notes and record number.
The following are recommended when considering genetic testing in children:
- 1Genetic tests can only be performed after written informed consent has been obtained.
- 2Boys with haemophilia should have their genotype established, as this has potential clinical benefit to the patient and his family.
- 3Phenotypic testing of females who are potential carriers should be performed when easy peripheral venepuncture is possible. Testing should be performed when the child is more than 1 year of age (unless required earlier for a specific clinical reason) with results confirmed on at least two occasions.
- 4Genotypic testing for females who are potential carriers of haemophilia should be offered when the individual is able to understand the issues concerned and give informed consent.
- 5In other inherited bleeding disorders all potentially affected children should be tested phenotypically.
- 6Individuals or families should be sent written information regarding the result and interpretation of any tests (genetic or phenotypic). This letter should indicate whether further genetic tests should be considered in the future.
- 7All individuals tested should have their own set of case notes.
The clinical–laboratory interface
Liaison and communication
For many Comprehensive Care Haemophilia Centres, the genetics laboratory forms part of the centre. For some units, however, such services may be geographically separate and formal arrangements need to be in place to ensure appropriate and effective liaison and communication. A close relationship between the coagulation laboratory, the genetics laboratory and the clinical genetic counselling service is fundamental to the provision of a successful genetic diagnostic service. The laboratory–clinical interface is best maintained by regular meetings between the clinical and scientific staff to discuss genetics-related issues including individual cases.
Within Haemophilia Centres regular meetings of clinical and laboratory staff from the genetics and coagulation laboratories are essential to review the genetics service, to identify any problems and to ensure the quality of the service.
Such meetings should include audit and review of the results of external quality assurance schemes. The results of recent laboratory studies should be reviewed. It is also important that where a Haemophilia Centre uses the genetic diagnostic services of another centre the two centres have appropriate meetings at regular intervals. This is required to facilitate the appropriate provision of genetic services to patients and families attending all centres.
An example of a specification for a Haemophilia Genetics Laboratory is set out in Appendix II.
Requests for genetic testing
There should be specific laboratory request forms for genetic studies in inherited bleeding disorders.
Clinical information Sufficient information must be made available by the requesting clinician to enable the laboratory to investigate a family appropriately. A referral letter or request form identifying the disorder and its severity (clotting factor levels), the individuals requiring investigation and the investigations required should be provided to the laboratory. The proband should be identified, and other relevant family details provided.
Pedigree An accurate and appropriately detailed family tree is an essential prerequisite for genetic family studies. A copy of the family tree must always be provided to the laboratory by the clinical team along with the request for investigations.
Consent Genetic testing can only be performed after written informed consent has been obtained. Receipt by the laboratory of a sample with a request for genetic diagnosis will be taken by the laboratory to indicate that appropriate informed consent has been obtained.
It is the responsibility of the clinician dealing with the particular case, and not the laboratory, to ensure that informed consent is obtained.
The laboratory should be made aware by the requesting clinician of any restriction on consent, e.g. storage of sample, and this should be indicated on the laboratory report. The completed consent form should be retained in the patient's notes and in the genetics file. Refer to section above on ‘issues of consent and confidentiality in genetic counselling’ for discussion of confidentiality issues and disclosure of results.
Sample requirements and patient/sample identification Details of samples required for laboratory services should be available to all staff members involved in genetic counselling. This information should also be available to outside hospitals/units/centres that may refer patients or samples for investigation. The clinician requesting the investigation should be clearly identified to the laboratory together with the address for reports. Known ‘high-risk of infection’ samples should be appropriately identified, although the laboratory should consider all samples to be of high risk and to be handled appropriately. The precise sample requirements and the type of anticoagulant may vary from centre-to-centre.
Samples and request forms must be clearly and accurately labelled with
- 1the patient's first name and surname;
- 2the patient's date of birth.
This is the minimum patient identification data set required for samples to be accepted for investigation.
Specimens must be clearly and reliably matched with the patient's details on the request form. The patient's hospital number or other unique identifier should also be provided. The use of a common hospital number for individuals within the same family is not acceptable. In the case of twins, some unique identifier (i.e. other than date of birth) must be supplied. A unique identifier will also be generated by the laboratory. The date of sample collection should be provided. Unlabelled samples will not be accepted by the laboratory. Samples from each patient or family member should be bagged separately with a separate request card for each individual sample. Each individual's postcode should be provided to the laboratory for workload monitoring/funding purposes.
Up-to-date mutation data on individual patients and families must be made available by the laboratory to the clinical staff involved in patient management and genetic counselling.
All putative mutations must be assessed for likely pathogenic effect, and validated so far as possible in other affected family members. Their absence in appropriate non-affected family members should be confirmed where possible.
In some cases the family mutation may be known, although the patient may not have been investigated by that centre, e.g. as part of studies performed elsewhere. Such data, if known, should be communicated to the laboratory on the request form together with a copy of the original report from the previous investigating laboratory. In cases where the family mutation has been identified elsewhere it is good practice for the current investigating laboratory to ‘confirm the mutation’ using a new blood sample.
Accurate and readily accessible records of all stored samples and patient/family studies must be kept for all families with inherited bleeding disorders. Such records should include the results of genetic and phenotypic studies. Mutation information should be maintained on a controlled and confidential database, and appropriately transferred to the patient's notes.
Records must be updated regularly to reflect changes in relevant information that may become available, and effective liaison between clinicians, the genetics laboratory and the coagulation laboratory is a prerequisite. Regular meetings between laboratory and clinical staff to discuss the results of laboratory studies are considered to be essential. Liaison with other centres may be necessary to investigate rare disorders where such expertise does not exist within a specific centre.
In haemophilia A and B it is envisaged that the mutation will be sought in all families. For these reasons, regular updates of sample requirements from family members for outstanding mutation analysis should be made available. This is particularly important for mild cases of haemophilia A or B, who may be seen infrequently.
Laboratory reports should be timely, accurate and concise. The clinical question being asked should always be restated in the text. Reports should include the following:
- 1a brief summary section;
- 2the family pedigree including name and date of birth of each individual together with the determined genotype;
- 3an interpretative section.
Reports should be referenced so that the original mutational data can be readily accessed if necessary. When reporting gene-linkage analysis, the polymorphic markers used, haemophilia-associated alleles and other alleles identified should be clearly indicated. A key to any nomenclature used should be included. Any further tests required or information needed to allow further investigation should be detailed. Reports should contain a disclaimer, acknowledging that the interpretation of the genetic data is dependent upon a variety of factors – the accuracy of the family information provided, non-paternity or mosaicism may affect the validity of the interpretation of the genetic data. All reports should be signed and dated by the individual carrying out the laboratory tests, and appropriately authorized, for example, by the scientific head of the laboratory.
The UK Clinical Molecular Genetics Society (CMGS) best practice guideline for report writing is available on-line at http://www.cmgs.org.
Refer to section above on early pregnancy and antenatal diagnosis for a full consideration. Close liaison between clinicians and scientific staff is essential for planning prenatal diagnosis. In addition to the laboratory performing the genetic diagnosis other individuals and departments need to be informed, e.g. obstetrician, clinical geneticist, cytogenetics department. For X-linked disorders, clear protocols describing how to access fetal sexing services must be available. If a fetus is sexed as female then the possibility of maternal contamination of the fetal sample must be excluded (e.g. by microsatellite DNA marker analysis).
A written protocol describing the local mechanisms of prenatal diagnosis should be provided to all of the clinical and laboratory services involved. A clear mechanism must be established to inform all relevant individuals of the results of antenatal diagnosis.
Where possible genetic testing to determine carrier status, and counselling regarding prenatal diagnosis, should be carried out before conception. This permits the laboratory to establish mutations or informative linkage markers in advance of any pregnancy and associated requests for prenatal diagnosis. This reduces the time and workload required for diagnosis, and allows more time to deal with any technical problems that may arise.
Research and development
A close and effective laboratory–clinical interface is essential to facilitate research and development activities in the genetics of inherited bleeding disorders.
Mutation databases on the Internet
Details of reported mutations in inherited bleeding disorders, together with other important related information, are available at the following websites:
FVIII/haemophilia A: http://europium.csc.mrc.ac.uk
FIX/haemophilia B: http://www.kcl.ac.uk/ip/petergreen/haemBdatabase.html
FVII deficiency: http://europium.csc.mrc.ac.uk
Laboratory best practice guidelines
Best practice guidelines for molecular diagnosis in haemophilia A and B are available on the CMGS website at http://www.cmgs.org.
A Word version of this information sheet and consent form for use (and if appropriate modification) is available from UKHCDO Secretaria http://www.ukhcdo.org .
Information on genetic testing and consent form for patients and families with bleeding disorders Bleeding disorders may run in families and someone from your Haemophilia Centre will have explained to you how this affects your family. The purpose of this information sheet is to explain the reasons why you are being offered genetic tests and the consent form you will be asked to sign before these are performed.
Genetic tests may answer the following questions:
- 1If you are known to have a bleeding disorder, what is the genetic change that has caused your condition in your case?
- 2Are you a carrier of the bleeding disorder?
Why do we resemble our parents? How does a single cell grow into a whole human? Genetics is the science that tries to answer these questions. Humans, like every other living creature, are made up of cells. We all start off as one cell at the time of fertilization. This cell contains two sets of genes, one from our mother and one from our father. For ease of storage and access, the genes are packaged up into 46 chromosomes. As the single cell divides the genes are copied so that every new cell possesses the full complement of genetic material. Genes are made of a chemical called DNA. Each cell holds about 2 m of DNA.
Humans have approximately 30 000 genes stretched out along their DNA. Each gene acts as the recipe for the production of a protein and together they make up the recipe book or blue print for you and me. Different genes or recipes are read at different times in different cells in response to the requirements of our bodies.
Sometimes genes, like recipes or blueprints, may have spelling mistakes in them or have bits missing. When this happens the proteins are either not produced or are abnormal. Genes, with these mistakes or mutations, function abnormally and so cause genetic disorders. As genes are passed on from one generation to the next, genetic disorders often run in families. These mistakes can arise when a cell does not accurately copy its DNA. A mistake or variation in a single DNA letter can lead to disease.
Someone from your Haemophilia Centre has already explained the nature of the disorder and the manner in which it can be passed down through your family. If you require further information, or you are unclear about what you have been told, please ask for clarification or more help.
Genetic testing can tell us which people in your family have the condition and who are ‘carriers’ who might pass the disorder on to their own children. Simple tests of the defective clotting factor (coagulation factor) can sometimes tell us if a person is affected by the disorder or a carrier. Sometimes the level is normal, although a person is carrying a defective gene. With modern genetic techniques it is usually possible to locate the faulty genetic change in each family, although this can sometimes take time. Although many families may have the disorder, it is common for each family to have its own unique genetic change.
1 What is the purpose of obtaining a blood sample? It is very useful to know what the exact mistake in the DNA is that is causing the disorder in you/your child. Sometimes this helps us to be warned about how the disorder may respond to treatment in the future. Measurement of the blood coagulation factor level does not always clearly indicate if there is a genetic mistake present or not; analysis of the DNA is a more accurate way of telling this. For this a special type of blood sample is required from which the DNA can be extracted. A second sample may be taken from you on a separate occasion to confirm the result of the initial test.
2 Where will the blood sample be tested? The tests needed to detect a change (‘spelling mistake’ or bit missing) in DNA are specialized. Some of them are performed locally, but depending upon the nature of the disorder, it may be necessary to send your blood sample away to one of a small number of specialized laboratories. In all these, there are strict regulations in place to ensure complete confidentiality of your details.
3 How long will the test take? The answers to genetic tests often take some time to obtain. Depending on the type of disorder and the purpose of testing the time course may take weeks, months and sometimes up to 1 year if you have one of the less common, or complicated disorder. Your doctor may be able to give you an estimate of the time it will take.
4 How long will my blood sample be stored? Sometimes it may not be possible with existing methods to find the genetic change in your family. In this case, the DNA will be stored until new tests are available. It is usual practice to store DNA samples indefinitely. Other new tests relevant to the disorder may arise in future, which will help us understand more about the mechanisms of the disorder.
5 What are the risks of genetic testing? In addition to information on the inheritance of a bleeding disorder, the results from these genetic tests are likely to be able to determine other information, such as confirmation of whether a child's parent is as assumed by the family. Therefore, occasionally unexpected results about family relationships arise from these tests, which, if known, could cause embarrassment within a family. If it is found, for example, that an individual's parent is different from that assumed by the family significant psychological problems can be caused and this may cause harm to the person being tested and other family members. The studies performed will be specific for the disorder known to be in your family. They will not exclude all forms of possible bleeding disorders.
6 What else might be done with my blood sample? We might want to use your sample to help develop or refine tests for bleeding disorders. In such cases your blood samples would not be linked back to you. The results would therefore be completely anonymous. From time-to-time it is very useful to run tests on a series of DNA samples anonymously to compare how some common changes in the DNA are which are not responsible for the condition. If your sample is used for such testing, no one will know whose it is, and there will be no comeback to you and your family.
7 Who gets to know about the results? The results will be told to you personally. Your family doctor will be sent the result.
8 Why might it be useful for other members of my family to know about the results? Information about the genetic disorder in you/your child is likely to be of benefit to other members of your family. It may, for example, be used to discover if a woman is a carrier and therefore if there is a risk of passing on the disorder to her children. With your permission we would like to be able to make the information about your genetic change available to doctors looking after other people in your family if they ask.
9 Are my genetic results going to be stored anywhere other than in my hospital and GP case records? There are local and national confidential databases, which keep information about genetic disorders of coagulation. We would like to record the information about your gene change. These databases are secure and protected.
If you would like to have your blood tested please read the consent form.
|(A) Patient details|
|Surname ……||Consultant ……|
|Forename ……||Hospital number ……|
|Date of Birth ……|| |
|(B) Collection and usage of samples|
|I, …… (print name) give consent for a blood sample to be taken from …… (myself or name of child) and the genetic material extracted, stored and tested for …… (specify disorder).|
|Please initial the boxes below to indicate your consent|
| The purpose for obtaining this sample and the potential implications has been explained to me and I have had an opportunity to have my questions answered|
| I have read and understood the above information about genetic testing|
| It is the intention to store the sample indefinitely|
| If no relevant test is currently available, I agree to the sample being stored until such time as an appropriate test is developed and the sample may then be tested|
| I understand that it may be necessary to use part of the sample anonymously, for example, for quality assurance or development of new tests|
(Patient/parent/legal guardian – delete as appropriate)
|(C) Use and availability of results|
| I hereby give consent for clinical and genetic information that may be relevant to other family members to be made available to relevant health care professionals|
| I agree to the results being entered into local confidential databases|
| I agree to the results being entered into national confidential databases|
|Signed ……||Date ……|
|(Patient/parent/legal guardian – delete as appropriate)|
|(D) Person obtaining consent|
|I have explained to the above patient/parent/legal guardian the purpose of obtaining a sample for genetic studies and their implications.|
|Signed ……||Date ……|
|Print Name ……||Position …|
|Job Title ……|| |
A photocopy of the completed form should be given to the patient, the original filed in the patient's case notes and a copy filed in the family genetic record file.
The Haemophilia Genetics Laboratory Network and availability of genetic diagnostic services in the UK: specification for Haemophilia Genetics Laboratory
The Network functions to ensure the provision nationally of a robust and high-quality genetic diagnostic service for the inherited bleeding disorders. A directory of laboratories affiliated to the Network, identifying services available and contact details is available from the UKHCDO Secretariat (e-mail: email@example.com), or alternatively on-line at http://www.ulehcdo.org).
UK laboratories providing a genetic diagnostic service for haemophilia and other inherited bleeding disorders should be affiliated to the UKHCDO Haemophilia Genetics Laboratory Network.
The UKHCDO Haemophilia Genetics Laboratory Network – affiliated laboratories are required to comply with the following quality standards:
- 1NHS provided and funded molecular genetics laboratory within the Comprehensive Care Haemophilia Centre.
- 2Facilities and expertise to allow the identification of mutations in haemophilia A and B (including handling risk of infection samples).
- 3Ability to assign carriership and make antenatal diagnosis.
- 4Turnaround time to reporting of 6 weeks for the majority of samples and 2 weeks for urgent ones, e.g. to allow antenatal diagnosis in newly presenting pregnant females.
- 5Clinical Pathology Accreditation
- 6Participation in appropriate genetics external quality control scheme National External Quality Assessment Service (NEQAS) currently.
- 7Active collaboration between all haemophilia genetic laboratories to provide a robust service available throughout the year.
Assessment of compliance with these standards is an integral part of the external peer-review audit system operated by the UKHCDO for UK Haemophilia Centres.
Adequate numbers of appropriately qualified state-registered staff are required to provide a high quality and up-to-date genetic diagnostic service in accordance with the quality standards identified above. Professional direction for the laboratory should be provided by a medically qualified consultant haematologist/geneticist or a state-registered consultant clinical scientist.