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Divisions of Medical Genetics and Molecular Pathology Departments of Path. & Lab. Medicine, Pediatrics, and Human Genetics, UCLA School of Medicine, Los Angeles, USA
This paper presents an overview of the conclusions from an international conference convened to address current issues related to the provision of Cystic Fibrosis carrier screening within Europe. Consensus was not aimed at stating whether such a programme should be implemented. Instead the focus was to provide a framework for countries and agencies who are considering or planning its establishment. The general principles and target population of Cystic Fibrosis carrier screening, advantages and disadvantages, health economics, monitoring and future evaluative and research directions were covered. A range of screening strategies have been assessed and compared: pre-conceptional and prenatal screening; individual and couple screening; sequential and simultaneous sampling or testing. Furthermore, technical issues were examined with respect to the choice of the panel of mutations, its detection rate, sensitivity, management of intermediate ‘at-risk’ couples, screening approach to different populations and ethnic minorities, and assurance of laboratory quality control. The consensus statement also aims to establish the benchmarks for communicating with health care providers, the general public and potential and actual participants before and after the genetic test.
Advances in molecular genetic testing have made carrier-detection readily available for multiple genetic disorders. Concurrently, there is increasing consumer demand for information about the risk of offspring having an inherited disease. Attitudes towards carrier screening programmes, and specifically Cystic Fibrosis (CF) carrier screening programmes, have been changing accordingly. The US National Institutes of Health, the American College of Obstetricians and Gynaecologists, and the American College of Medical Genetics have recommended widespread genetic screening of couples planning a pregnancy or who are in the early stages of pregnancy [
Subcommittee on Cystic Fibrosis Screening, Accreditation of Genetic Service Committee, ACMG American College of Medical Genetics. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.
]. Consequently, there has been a substantial increase in the overall numbers of CF carrier tests carried out in the US and to a lesser extent, in Europe [
The spread of regional and pilot CF carrier screening programmes in Europe prompted the European Cystic Fibrosis Society (www.ecfs.eu), to organise a dedicated Consensus Conference. The European Society of Human Genetics (www.eshg.org), EuroCareCF (www.eurocarecf.eu) and the EU EuroGentest network (www.eurogentest.org), co-sponsored the meeting which took place in Garda, Italy, 20–21 March 2009. The purpose of the meeting was to establish a consensus document on CF carrier screening. A broad spectrum of European and US experts and various stakeholders including patient support group and industry representatives, were involved in pre-meeting consultations and the drafting of preliminary documents. Twenty among them attended the meeting itself, which addressed a wide range of issues, including the rationale and strategies for CF carrier screening, related technical aspects and communication issues.
This paper summarises the consensus achieved, outlining the advantages and disadvantages related to CF carrier screening and presenting standards for efficacious, safe and ethical practice of such programmes. Recommendations were established to align existing and future carrier screening programmes with previous position statements, for example, those of: the European Society of Human Genetics [
]. Relevant extracts from these guidelines are listed in the online appendix, while specialised terms used herein are explained in the “Definitions” section.
This document does not imply that CF carrier screening should be implemented, which should remain a decision of the individual countries or regions in accordance with local legislation. Rather it should be considered as a template to stimulate thought and debate amongst those planning such a programme, enabling it to be undertaken as comprehensively, effectively and efficiently as possible.
Whilst recommendations pertain primarily to CF carrier screening, many would also be applicable to carrier testing.
This consensus statement refers specifically to CF carrier screening. Issues related to screening of carriers for other monogenic disorders are not discussed.
2. The carrier screening strategy
CF is the most common, inherited, life-shortening disease affecting children and adults in European-derived populations. It results from mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein [
Most affected infants are born to parents with no family history of the disease and are either diagnosed at birth through neonatal screening programmes [
], or in infancy because of symptoms. Although some patients have milder forms of the disease, the vast majority present with typical clinical features of chronic lung disease, pancreatic exocrine dysfunction and elevated sweat chloride concentrations [
]. CF is a progressive disease which leads to marked decrease in quality of life (QoL), particularly during its' advanced stages. Treatment regimens are rigorous, demanding and time-consuming for patients and their families. The current median predicted age of survival is 37.4 years [
]. CF follows an autosomal recessive pattern of inheritance, whereby heterozygotes do not develop the disease. Carrier frequency varies from 1/20 to 1/80 [
]. Testing for CF gene mutations is available in European countries and can be used to inform people of their risk of having an affected child.
2.1 Aim and general principles of CF carrier screening
For the purpose of this document, CF carrier screening is defined as the detection of CF-causing mutations in persons who do not have an a-priori increased risk for having a child with CF. Conversely, CF-testing is defined as detecting these mutations in persons who do have an a-priori increased risk for having a child with CF, based on personal or family history. Therefore, the aim of CF carrier screening is to detect CF-causing mutations in individuals without CF or CF-related disorders, who do not have a family history of CF, or family history of CF carriership, or who do not have a partner who is a carrier, has CF or a family history of CF or CF carriership.
Knowledge of CF carrier status enables informed procreative choices. In particular, the reproductive options available to a couple of carriers include: having no more or fewer children, accepting the risk of having a child with CF, adopting, undertaking prenatal diagnosis (with the option of termination of an affected pregnancy or continuation of the pregnancy), achieving pregnancy with donor ova or sperm or IVF pregnancy with PGD. The full range of options will be available before conception, whereas limited choices can be made if a pregnancy is ongoing. Some of these actions may eventually lead to a decrease in CF incidence [
Implementation should be assessed both from individual, social and economic perspectives. In order to guarantee a fair and equitable approach with regards to individual human rights, the following principles should apply:
•
CF carrier screening should be voluntary and autonomy should be guaranteed.
•
Acceptance of the CF carrier screening offer should be based on an informed decision-making process, and duly documented.
•
With respect to the pre-screening phase, adequate information should be assured by the provider of the CF screening programme (henceforth referred to as ‘the screening organization’), to individuals or couples. After screening, genetic counselling should be available to those identified as carriers, and strongly recommended to carrier couples.
•
The spectrum of CF-causing mutations and their prevalence should be known in the screened population in order to achieve the highest possible population-specific mutation detection rate [
]. If this information is not available or does not apply to specific individuals (e.g. those from ethnic minority groups), the limitations of the carrier screening programme need to be effectively conveyed.
•
The genetic analysis for CF carrier screening should be performed in a timely manner and according to latest best-practice guidelines, optimally within an accredited laboratory setting [
]. (See “reproductive choices” paragraphs in the “Definitions” section)
•
Information about the risk of being a carrier can be provided to other family members after a carrier is detected (i.e., the “cascade” effect of the screening programme) [
Ionnou L, Massie J, Collins V, McClaren B, Delatycki M. Population-Based Genetic Screening for Cystic Fibrosis: Attitudes and Outcomes. Human Genomics 2009 (in press).
Screening programmes ensure equality between all citizens and avoid discrimination in service provision.
The disadvantages of being screened also have to be considered. These are:
•
The identification of an individual as a carrier raises anxiety, although this is often dispelled if the partner tests negative, and does not seem to be long lasting [
Discrimination as a result of identification as a carrier: by creating a difficulty for finding a partner if tested before partnering; by limiting health and life insurance options; or by limiting reproductive options [
A carrier whose partner tests negative may still have a higher risk of an affected pregnancy than before screening was offered due to residual risk of undetected carrier status in the partner, but has a few or no options to decrease such risk
•
Carrier screening disadvantages women who do not nominate a father if tested in early pregnancy
•
Some view carrier screening as a form of eugenics, which could change the attitude towards people living with CF and make patients feel diminished
•
Potential for misunderstanding of the test results by some individuals, e.g. carriers who think that they are “negative” and thus assume that there is no risk for their offspring [
Ionnou L, Massie J, Collins V, McClaren B, Delatycki M. Population-Based Genetic Screening for Cystic Fibrosis: Attitudes and Outcomes. Human Genomics 2009 (in press).
Decision-making could be complex and sometimes confusing;
•
Relatives who have not chosen to be tested may be faced with undesired information.
2.3 Timing the offer
Information about the availability of CF carrier screening can be disseminated through different channels (e.g., at medical visits to adult patients, or by gynaecologists to women planning pregnancy). Although such screening is most relevant to individuals or couples planning a pregnancy or who are already pregnant [
], the advantages and disadvantages which may be encountered should be carefully considered at each of the following time-points below.
Pre-conception screening is the ideal timing, because it allows full range of reproductive choices and adequate time for decision-making. Uptake may be substantially lower than in prenatal screening [
Prenatal screening is the most common entry point for CF carrier screening in current programmes, as couples are undergoing prenatal care and commonly have a high interest in the health of their offspring [
]. Depending on the carrier status of the couple, this allows either standard prenatal diagnosis in the first or second trimesters, or no testing of the foetus. Subsequent pregnancies have the full range of reproductive options.
Screening in educational establishments (e.g. high schools, universities), assure ready access for the delivery of pre-test information to groups which are in the pre-reproductive period of their lives [
Workplace or community screening settings are additional options for targeting the provision of information. Employer-sponsored screening should be avoided since the voluntary nature of accessing such programmes could be undermined. As with educational settings there are similar concerns in this case. The information provided should come from a reliable source, such as an independent genetic counselling service.
Donors of sperm and eggs. In view of the number of pregnancies resulting from egg or sperm donations, the same principles apply as to prenatal couple screening. In cases where a donor is identified as carrier, this does not rule him/her out as donor per se, providing that the recipient women are informed. Where there is national or IVF centre-specific arrangements, these situations could be dealt with accordingly by genetic counsellors working in assisted reproduction centres, in compliance with local legal provisions.
2.4 Individual versus couple screening
CF carrier screening may be offered and delivered to individuals, or couples.
Screening of individuals is the only option if there is no identified partner. A posteriori carrier risk can be calculated, but the probability of having an affected child will depend on the partner's carrier status. Screening individuals who are not in a relationship may affect their choice of partner, self-image or self-esteem [
], and is thus not recommended. Screening of pregnancies not known to be at increased risk by invasive foetal tissue sampling techniques such as chorionic villus sampling or via amniocentesis is discouraged.
Screening of couples may be carried out by considering the couple as ‘a unit’ or as separate individuals. The former involves informing them jointly of their risk status: which is ‘high’ when both partners are carriers or ‘low’ where neither is a carrier or when only one tested positive. This has been advocated as an effective and cost-efficient method of screening [
]. However, one major shortcoming is that this type of couple screening violates confidentiality principles where individuals have a right to receive their results independently from their partner's. Furthermore in a ‘positive–negative’ couple, the carrier would not be made aware of their status and as such cannot inform their family members, negating one of the major benefits of cascade screening. Re-testing would be required if one or both individuals choose a different partner.
An alternative is considering the partners as individuals with either a sequential or simultaneous sampling approach [
]. With sequential sampling the sample is taken from one individual and the partner is recalled for sampling and testing only if carrier status is initially identified. Either the same mutation screening panel or an expanded one can be used for the partner. However, this approach may temporarily increase anxiety for the couple. Simultaneous sampling may be followed by either simultaneous screening using the same panel of mutations or sequential screening with one partner tested first and the second partner tested only if a mutation is found in the first one. Either the same CF mutation panel or an expanded one is then used for the partner. The advantage of simultaneous sampling and testing is in reduced laboratory turnaround time, assuring timely provision of results. This may be important if screening occurs close to the legal gestational age for termination. Simultaneous sampling followed by sequential testing allows a 50% reduction in the number of couples where one partner is found to be a carrier and the other tests negative.
2.5 Health economics
Should a decision be made to include CF carrier screening in the services covered by health insurance, health economic evaluation can be used to compare the cost-effectiveness of different potential screening strategies. Besides determining screening strategies (e.g. sequential versus simultaneous testing of couples), this can also be used to identify target groups for whom screening meets the decision maker's requirements of cost-effectiveness.
Determining the additional costs per additional health outcomes incurred by CF carrier screening poses a range of methodological difficulties, e.g. because benefits cannot easily be established by standard clinical measures like life-years gained. Instead, the costs per case detected or the net costs can be determined (which can be considered inappropriate because final health outcomes, a key consequence of a health technology, are omitted from the evaluation). In any economic evaluation, it is necessary to include evidence on all costs and all parameters which affect cost-effectiveness. These are, for example, the costs of approaching and informing the target population and the probability of test uptake, the sensitivity and specificity to detect a truly ‘at-risk’ individual in daily practice (which may deviate from the analytic sensitivity and specificity of the DNA test) or the probability of carrier couples choosing prenatal diagnosis [
Decision makers who intend to include CF carrier screening in their reimbursement catalogue and use health economic evidence to inform that decision are recommended to conduct analyses specifically targeted to their health system context. In the economic evaluations presented by Radhakrishnan et al. [
], the costs per carrier couple detected ranged from $33,504 to $295,121 (results in local currency inflated and converted by purchasing power parity to US $, 2005). Among the six studies which assessed whether screening was cost-saving, two reported that it was the case and four reported the contrary [
]. It should be noted that these studies may have included testing among at-risk couples, where the costs per carrier couple detected are lower than for carrier screening according to this document's definition.
Given that economic evaluations typically do not include all elements of value relevant to decision makers, the results of economic evaluations alone cannot be used to justify a screening programme [
EUROGAPPP PROJECT 1999 - 2000 Public and Professional Policy Committee (PPPC)* Population genetic screening programmes: Proposed recommendations of the European Society of Human Genetics. Eur J Hum Genet. 2000; 8:998-1000
]. For example, decision makers may have strong concerns about tests which are likely to lead to pregnancy termination, so that pre-conception or prenatal screening is not offered, regardless of whether or not it is cost-saving for the health care system.
2.6 Monitoring and research directions
Any CF carrier screening programme should adequately monitor outcomes. Aspects of the programme which might be suitable for regular evaluation are: the provision of information, the resulting carrier frequency, laboratory and counselling-related quality issues, competencies, and the psychosocial consequences. Ideally, a secure database or registry could be created and include information on the number of individuals tested, gender ratio of individuals tested (expected predominance of females), gestational age at which the screening was initiated in pregnant females, number of prenatal or pre-implantation diagnoses for CF performed and their results, initiator of information about the screening programme (i.e., via the medical practitioner, genetic counsellor, midwife), number of carriers and carrier couples identified, whether all carriers had their partners tested, spectrum of reproductive choices made following the screening, false-negative and false-positive results.
Although much information is already available to initiate quality CF carrier screening programmes, further research is needed to improve these. The main fields of research should cover:
i.
psychological, social and counselling-related aspects regarding the barriers and facilitators for informed decisions: new information technologies for delivering pre-test information, (e.g. http://comex.presentation.it/); anxiety amongst carriers and understanding of residual risk by those testing negative; improvement for information retention by those individuals who have received counselling
ii.
cost-effectiveness comparison of screening programmes
iii.
new technologies that enable higher population-specific CFTR mutation detection rates and increases in sensitivity or robustness of methods used.
2.7 Recommendations
CF carrier screening must be voluntary, accessible and preceded by accurate pre-test information.
CF carrier screening should be offered preferentially to prospective parents, ideally before conception but acceptably during early pregnancy as dictated by practicability.
Direct foetal screening (without ascertaining that both parents are carriers) must be discouraged.
Minors and other persons unable to consent should be excluded from screening.
The screening programme should be regularly monitored over the long-term.
3. The carrier screening test
3.1 The rationale for a choice of mutations
The choice of the mutation panel/s for any CF carrier screening protocol is the key to the accuracy and overall success of the programme. The heterogeneity of CFTR mutations and of their clinical impact [
], the ethnic composition of the population to be screened and proper coverage of ethnic minorities, the sustainability of the increased workload at the genetic laboratory/ies performing the test, and the availability and accuracy of extended panel assays and platforms are all to be taken into careful consideration. Reimbursement issues related to genetic testing are also an important aspect in any national or regional CF screening strategy.
Allelic heterogeneity — To date more than 1600 mutations have been identified in the CFTR gene [
]. The most common mutation is F508del, often termed ΔF508, which accounts for approximately two thirds of all CFTR alleles in patients with CF, with a decreasing prevalence from Northwest to Southeast Europe [
The molecular genetic epidemiology of cystic fibrosis. Report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS http://www.who.int/genomics/publications/en/ and WHO Geneva, Human Genetics Programme WHO/HGN/CF/WG/04.02.
]. Because of the F508del geographical gradient, standard mutation panels utilised in current commercial assays achieve the highest sensitivity in North- and West-European populations, whereas in South-European populations more mutations need to be tested to achieve an acceptable detection rate.
CF-causing mutations — For less than 10–15% of all reported mutations, clinical association studies and functional assays have provided strong evidence that they cause CF [
]. These mutations account for the vast majority of clinically relevant mutations, and are named “CF-causing”. The detection of two CF-causing mutations allows the diagnosis of CF in individuals with consistent clinical manifestations or in newborns with a positive neonatal screening test [
]. Less than half of the remaining mutations may be empirically predicted to affect splicing, shift reading frame or introduce premature termination codons, and are likely therefore to produce a severe functional reduction of CFTR function, so as to cause disease. The clinical role of other mutations, mostly missense mutations, to cause disease is very difficult to assess. A missense mutation identified in a single individual or in few cases makes it impossible to understand whether it has any clinical effect, and to what extent. Some mutations might only partially affect CFTR function, or not affect it at all, being benign sequence variations.
CFTR-related disorders — Some CFTR mutations are known to be associated with mild CF-like clinical manifestations, which do not meet CF diagnostic criteria (70, 17). This association may result in a “CFTR-related disorder”, a condition which often involves isolated organs (e.g. congenital absence of the vas deferens [CBAVD]; recurrent or chronic pancreatitis) and is not clearly associated with severe life-shortening lung disease [
Furthermore, some CFTR mutations may be associated with different clinical outcomes, and result in mild CF disease, CFTR-related disorder, or no disease at all, a variability potentially explained by complex alleles, and non-CFTR and environmental factors [
One such mutation is R117H, which, when found in compound heterozygosity with a CF-causing mutation, may result either in pancreatic-sufficient CF, or in a CFTR-related disorder, or in no disease at all. This may be partly explained by the association of R117H with the intron 8 splice variant polythymidine sequences IVS8(T(n)), which occur in groups of 5, 7 or 9 repeats. R117H in cis with T5 (i.e. on the same allele) is considered a disease producing variant, whereas R117H in cis with T7 is usually associated with CFTR-related disorders or no disease [
The high frequency of R117H observed in CF newborn screening programmes has further added to the complexity of R117H clinical liability. The vast majority of these infants carrying R117H-T7 in compound heterozygosity with a CF-causing mutation are free of CF symptoms, although it cannot be excluded that they may develop manifestations of CF disease later in life [
]. A national collaborative study in France evaluated the disease penetrance of the R117H-T7/F508del genotype, based on the number of patients/individuals known to the French laboratories to carry this genotype and the measured prevalence of F508del and R117H alleles in the French general population [
]. This study revealed that only 3.1% of the individuals expected to carry the R117H-T7/F508del genotype have been tested for CFTR mutations because of clinical CF-related symptoms or family history of CF or CFTR-related disorders. The measured penetrance of severe CF in childhood was only 0.03% and that of delayed severe CF symptoms in adulthood only 0.06%.
3.2 Choosing the mutation panel
The high number of rare mutations and their heterogeneous clinical presentation render 100% sensitivity difficult to obtain. Mutation panels should be adapted to the target population of the screening programme.
CFTR mutations — Only mutations that clearly cause CF (i.e., CF-causing), should be included in a screening panel. Mutations associated with a variable phenotype, in particular those associated with CFTR-related disorders should not be included. Unless reflex testing assuring distinction between R117H-T5 and R117H-T7 is assured, R117H should not be included in a screening panel.
Sensitivity — When CFTR mutation analysis is used in clinical diagnostic practice, European guidelines advise to test for mutations that have a frequency above 0.5–1% in the CF population from which the individual originates [
]. Similarly, this consensus recommends that carrier screening panels should include mutations with a frequency above 0.5–1% in the CF population. This would translate to commercial assays including around 30–40 CF-causing mutations in most European-derived populations in order to achieve mutation detection rates ranging from minimally (70%) to optimally (90%), depending on the North-to-Southeast gradient of the F508del allele.
In Europe, median CF birth prevalence is around 1/3500 [
], and the a-priori risk of being a CF carrier for someone with no family history of CF is 1/30. If both members of a couple are tested, screening with a mutation detection sensitivity of 70%, which may be a conservative model in the CFTR-heterogeneous Southern European CF populations, would decrease the residual risk of having a CF child by a factor of about 10 in 95% of all couples. This residual risk is equivalent to the birth prevalence of many much rarer genetic disorders.
Screening by using a mutation detection sensitivity of 90%, a goal more easily attainable in Northern Europe, would diminish the risk of having a CF child by a factor of 100 in 94% of all couples, which is equivalent to the birth prevalence of very rare genetic disorders. Table 1 shows the projected results of a carrier screening programme with an assumed carrier frequency of 1/30, and mutation detection rates of 70% and 90%.
Table 1Projection of mutation analysis results of a CF carrier screening programme.
Option A: assumed carrier frequency 1/30 and mutation detection rate 70%.
100,000 screened individuals
Negative to test
Positive to test
No.
97,667
2333
%
97.667
2.333
Post-analysis carrier risk
0.0102388
1
Risk of CF in child if partner is not (yet) tested
CF carrier screening has high value when both individuals in a couple test either negative or positive. These couples will have respectively either a marginal risk of having a child with CF, or a 1 in 4 risk (25%), of having a child affected by CF. In the latter situation, a number of reproductive options will be available for the couple [
Nevertheless, in many cases there will be couples in which one partner tests positive while the other tests negative. In these couples, the partner who tests negative will most probably not be a CF carrier. However, test-negative partners have a small residual risk of being a carrier, and these couples have a risk of an affected child that is more accurately quantified due to screening, compared with the assumed risk before screening. In the aforementioned models, when test-sensitivity is 70%, the risk of a ‘one positive/one negative’ couple having a child with CF will be around 1/400. If the sensitivity is increased to 90%, the risk will be around 1/1200 (Table 1). Assuming a CF carrier frequency of 1/30 and the previously stated sensitivity rates, depending on whether testing is preformed simultaneously or sequentially, 2–6% of couples will end up in this situation [
]. At a detection rate of 96% in the test-negative partner the chance of an affected pregnancy approaches the a-priori risk of couples who have not had screening. The difficulty is achieving such a detection rate in heterogeneous populations or in non-European ethnic minorities where the spectrum of mutations has not been thoroughly determined. Furthermore, aiming for such a high detection rate could be incompatible with the workload of the screening laboratory/ies and undesirable because of the potential identification of mutations of unknown significance when mutation scanning strategies or sequencing would have been implemented.
An alternative option is to screen the negative partner with a more sensitive CFTR mutation panel, possibly tailored to the specific individual ethnic background. Indeed, such a partner would then fit more in a CF carrier testing programme context rather than a CF screening programme. Ninety-five per cent sensitivity would lower the couple's risk of having a CF child to 1/2300 if the partner tests negative. Pre-test information should stress this limitation. Such strategy should optimally be applicable pre-conceptionally which would provide more time for such a potentially time-demanding analysis. If the above described scenario would be faced post-conceptionally, the couple should be referred to a specialised genetics centre which can assure timely molecular genetic testing and proper counselling. The screening organisation should carefully survey prior to the implementation of CF carrier screening whether genetics services have the capacity to cope with an increasing demand for a more “in depth” testing in intermediate risk couples.
Although it is technically possible to use CFTR gene scanning or sequencing for the initial screening of an individual, or for the second person in a couple when the first is found to be a carrier, there is again a risk of identification of CFTR mutations of unknown significance, and of the consequent inability to pass on accurate information to that individual. Therefore, at this stage of knowledge scanning and/or sequencing of the complete CFTR gene is not advised in a CF carrier screening programme.
3.4 Other issues
Different ethnicities — Taking into account the diverse ethnic origins of participants in a CF screening programme is a difficult task, notwithstanding the challenges of assigning ethnicity to an individual. The availability of multiple ethnic-specific panels to match every situation is impossible, due to substantial technical and logistical problems. Besides, ethnicity data may be unavailable, inaccurately reported by the individuals themselves or not collectable according to local antidiscrimination legislation. Screening for geographically and/or ethnically-specific mutations may eventually be performed as a second step in case one partner is identified as a CF carrier (see above). Similarly, this requires time and a pre-conceptional approach.
Quality control — Molecular genetics laboratories participating in CF carrier screening programmes should be accredited (ISO 15189 or equivalent) and participate annually in international EQAs for CF [
]. The mutation panel/s must be duly validated and laboratory quality assurance should be in accordance with the OECD guidelines.
Correlation between carrier screening and neonatal screening — In populations where newborn screening for CF is offered universally, couples considering prenatal carrier testing should be made aware of newborn screening and the different purposes of each screening test. Babies born to parents who have had prenatal carrier screening should still have newborn screening as most newborn screening programmes offer screening for multiple diseases, and it may detect an infant with CF missed by parental CF carrier screening. It is unlikely that the uptake of carrier screening or the detection rate would ever increase to the point of doing away with CF newborn screening.
3.5 Recommendations
The prevalence of CF disease mutations in the screened population must be known. Carrier screening panels ideally should include all mutations with a frequency of 0.5–1% or more in the CF population.
Only CF-causing mutations should be screened.
Whenever possible, the negative partner of intermediate risk couples should be tested with a more sensitive CFTR mutation panel.
People from ethnic groups that have a lower sensitivity for detection than the majority for who the screening panel was selected should be informed about the limitations of the screening programme and when possible offered a customised approach.
CFTR gene sequencing or mutation scanning should not be used in the carrier screening setting at this stage of knowledge.
4. Communication
Well-established principles of communication are of particular relevance to the type of information that is necessary for CF carrier screening programmes. Potential participants may be unfamiliar with either CF or DNA technology and their implications. For some, CF carrier screening offers the chance to be informed about the current or future pregnancy, whilst for others it may invoke anxiety or necessitate psychologically difficult decision-making. Education has a vital role in helping achieve informed choice and in anticipating individual emotional responses.
Informing potential participants about CF carrier screening in an effective and timely manner can be difficult for a variety of reasons (e.g., barriers to identifying individuals and couples belonging to the target population, limited knowledge amongst health professionals and, most often, there being little or no time available to discuss matters face-to-face).
This section is based on four general principles:
1.
Initial information about CF carrier screening is best presented in writing, via a leaflet or more-detailed brochure. Written information needs to be presented in a way that is easy to comprehend, uses language that is structured, clear and understandable. Face-to-face follow-up need be provided when required.
2.
It is important that screening organisations: (i) develop a dedicated web-page or establish links to an ‘official’ web-site, where potential participants can access authentic and validated information, and (ii) provide a phone number for contact by potential and actual participants of the screening programme.
3.
During any verbal communication, health providers should clarify participants' beliefs, concerns, expectations and decision-making issues, and identify and enlist additional resources and support where necessary.
4.
Individuals need balanced information about living with the conditions being tested for [
‘Balance' is in the eye of the beholder: providing information to support informed choices in antenatal screening via Antenatal Screening Web Resource.
]. Consequently, health professionals should have up to date knowledge about CF, including the basic principles of CF genetics and carrier screening and the range of psychological, social and ethical matters that may ensue.
Screening organisations should evaluate the possible use of interactive computer assisted delivery of information for the release of initial or pre-test information, many of which are currently under development (e.g., http://comex.presentation.it/, [
‘Balance' is in the eye of the beholder: providing information to support informed choices in antenatal screening via Antenatal Screening Web Resource.
Development of an interactive computer-assisted instruction (ICAI) program for patient prenatal genetic screening and carrier testing for use in clinical settings.
4.1 Education of health care providers involved in informing potential participants
Although recommendations are that initial participant-information be presented in writing, continuing education of practitioners and evaluation of their competencies is vital for ensuring successful implementation of CF carrier screening programmes [
]. It is the responsibility of the screening organisation to ensure that this education is provided and understood. Easy to access, web-based learning tools may be the most efficient way to reach health professionals.
4.2 Informing and educating the general public
For organisations considering a CF screening programme for the general population, there is a responsibility to increase awareness of CF and promote a realistic view of the meaning of being a carrier of a recessive mutation and of ethical issues such as freedom of reproductive choice (e.g., through mass media or as part of school curriculum, biology/genetics education). Consequently, the possible risk of social pressure to use screening tests can be reduced.
Workplace and community-based information about the availability of screening could be provided.
4.3 Approaching the target population
It is very important that potential participants understand that screening for CF is a matter of personal choice. The choice to undergo screening should be based on knowledge, consideration of benefits, limitations, disadvantages, personal views and values. This is important when inviting people from the general population, as in pre-conceptional screening, but even more so when offering screening in ‘captured’ populations, such as pregnant women and high-school students. When approaching people in the general population, initially a brief leaflet might be considered. This could be followed up with a more comprehensive brochure or by giving web-site information. Initial information should be as balanced and comprehensible as that given subsequently.
4.4 Informing participants
4.4.1 Pre-test information
The purpose of providing information pre-screening is to assist participants in understanding the processes, the potential benefits and limitations, and the implications of each possible outcome. It is intrinsic to obtain properly informed consent.
Providing pre-test information by the screening organisation offers the opportunity to ensure that the information provided is validated and authenticated by reliable sources and all relevant stakeholders of the screening programme. In order to be fully representational, national CF organisations and patient support groups should be involved in writing and approving all information texts.
Many health care providers, national CF associations and other organisations provide information on carrier screening. Table 2 summarises the general principles and proper sequence that information-provision should follow within a CF screening programme.
Table 2Outline of recommended content for pre-screening information.
Issue
Content
What is CF?
Main clinical manifestations
Inter-individual variability
Treatment
Quality of life
Current life expectancy
Potential for new treatments following research developments
What causes CF?
Hereditary disease
Autosomal recessive inheritance pattern
What is a carrier?
One copy of the gene mutated; the other normal
A carrier is not affected by CF
Children of a carrier
1 in 2 chance of being carrier
Children of two carriers
1 in 4 chance of being affected
1 in 2 chance of being carrier
1 in 4 chance of being neither affected nor a carrier
Other family members of carriers
Raised risk of carrier status
What is your chance of being a carrier?
General population risks for the major ethnic groups in the area
Positive family history for CF: higher than general population, suggested referral to family doctor/genetic counsellor
How abnormal is it to be a carrier ?
Carrier frequency
Everyone is a carrier of some genetic disease mutation
What do we mean by carrier screening?
See “Definitions”
How is it performed?
Description of procedure
What are the limitations of CF carrier screening?
Partial sensitivity
Residual carrier risk
What are the possible outcomes of screening?
Individual: more frequently negative to the analysis; less frequently carrier (give expected frequencies)
Couple: most negative/negative; some negative/carrier; a few carrier/carrier (give expected frequencies)
Small risk of being found mildly affected by CF
What are your options if you are found to be a carrier?
Carrier individual: higher risk of having children with CF than before screening; testing partner is recommended; informing relatives is recommended.
Carrier couple: 1 in 4 risk of a child with CF; see reproductive option in “Definitions”; informing relatives is recommended.
What are the consequences of your participation for your family members?
If you are a carrier, their probability of being carriers is increased and if they plan to have children they should be informed that they could be tested. If you are not a carrier, your family members may still be carriers.
Weighing up possible advantages and disadvantages
Advantages: most individuals and couples will have their risk reduced; very few will have a 1 in 4 risk of a child with CF detected, and will be able to choose from some options (see above). If you are a carrier, you can inform family members
Disadvantages: one positive/one negative couples may have higher risk than before screening; costs (if applicable)
If you are a carrier you may feel pressured to inform family members
Voluntary basis of participation
It includes the possibility to change one's mind and not to receive the results.
How to arrive at an informed decision
Possible reasons to be tested
• If CF seems like a very serious disorder to you
• If the chance of being a CF carrier seems high to you
• If you and your partner would consider reproductive options (see definitions)
• Because test results are usually reassuring
Possible reasons not to be tested
• If CF does not seem like a very serious disorder to you
• If the chance of being a CF carrier seems low to you
• If you and your partner would never consider reproductive options
• Because the test is not perfect and will not identify all carriers
• Insufficient mutation detection rate in your ethnic group
Confidentiality and data protection
Where, and for how long, results and personal information will be stored.
Who will have access to the information.
How information may be used (e.g., disseminated for research and statistical purposes).
Where to obtain additional information and/or support.
Web-sites and phone numbers of: the screening organisation, CF scientific societies and patient support groups, genetic counselling services.
It is important that sufficient time is given to consider the range of physical, emotional and moral issues inherent to CF carrier screening. As such, programmes need to allow time between potential participants ‘becoming informed’ and giving consent. Carrier screening may be proposed only to individuals having capacity to provide voluntary informed consent.
It is advisable to document consent in writing. If a screening programme allows choice within the protocol, for example, as to who should be the first or only person to be tested or receive the result, then this should also be recorded.
4.4.3 Post-test information
The aim of post-test information is to let participants know their test result in a timely and sensitive manner. Post-test information needs to directly apply to the screening outcome, with issues relating to residual risk, and potential next steps, being outlined. Laboratories need to communicate the result to the health care provider involved, who would then inform the participants. Alternatively, the results can be mailed both to the health care provider and to the participants. Table 3 summarises the main messages which should be delivered.
Table 3Outline of recommended content for post-screening information.
One partner ‘negative’, no testing of the other partner
• No CF-causing mutations in the utilised mutation panel were found in the sample/s from one person.
• Inform about how much this results lowers the chance of being a carrier or a carrier couple.
• Explain concept of residual risk of an individual having an affected child after a negative screening test and inform about the amount of risk.
• Establish that a negative result does not imply that family members also will have a negative result if tested
• Sign-post where individuals can find out more information if they wish (e.g., web-sites, national CF organisations, patient support groups)
Both partners ‘negative’
• No CF-causing mutations in the utilised mutation panel found in the samples from either partner.
• Inform about how much this result lowers the chance of being a carrier couple.
• Explain the concept of residual risk of a couple having an affected pregnancy after a negative screening test, and inform about the amount of risk.
• Establish that a negative result does not imply that family members also will have a negative result if tested
• Sign-post where individuals can find out more information if they wish (e.g., web-sites, national CF organisations, patient support groups)
Both partners ‘positive’
• Detected ‘carrier’ status in both partners means that there is a 1 in 4 risk (25%) in each pregnancy that the foetus will have CF
• Couples need to be referred to genetic counselling in a timely manner (see Definitions ‘Genetic Counselling’)
• Cascade testing (i.e., testing other family members) needs to be made available to relatives of detected carriers
One partner ‘positive’, one ‘negative’
• One partner found to be a carrier, the other one negative to the test.
• Inform about how a negative test lowers the chance of being a carrier.
• Explain concept of residual risk of a positive/negative couple having an affected CF child.
• Establish that a negative result does not imply that family members also will have a negative result if tested
• Cascade testing (i.e., testing other family members), needs to be made available to relatives of detected carriers
• Genetic counselling should be made available if desired. Sign-post where individuals can find out more information if they wish (e.g., web-sites, national CF organisations, patient support groups).
Genetic counselling should be strongly recommended to ‘carrier’ couples. Genetic counsellors should be familiar with the range of severity of CF symptoms and the fundamentals of medical management consistent with the recommendations of the US National Society of Genetic Counsellors [
]. Genetic counselling will outline present or future reproductive options and help facilitate further informed decisions (e.g. informing others, taking up further testing such as Chorionic Villous Sampling (CVS) and/or amniocentesis).
Given the current status and limited number of licensed or certified clinical geneticists or genetic counsellors, it is unlikely that personalised genetic counselling would be realistically feasible or affordable for all intermediate risk couples. Consequently, a very clear written report should be produced and genetic counselling made available, if desired.
It is important to note that individuals and couples have the right not to know their results.
4.5 Psychosocial aspects of carrier status
There is potential for long-term psychological reactions in participants identified as CF carriers, these being anxiety, reduced self-image, lower self-esteem, inappropriate self-perceptions of impaired health and problems with partnering or relationships [
]. In several large studies on women attending antenatal clinics, carriers experienced a significant increase in stress at the time of the test result, although it almost disappeared when their male partners tested normal and it did not reappear later in pregnancy [
]. As discussed above, simultaneous sampling of both partners from a couple may reduce this type of stress.
There has also been a suggestion that positive screening results could augment pre-existing dysfunctional family relationships, leading to increased stress [
The purpose of counselling at this point is to ensure that CF carriers understand that they are healthy and do not have CF, even in its mildest forms.
4.6 Recommendations
Only health care professionals competent in CF carrier screening should offer it.
The decision to undergo CF carrier screening must be based on provision of pre-test information. Informed consent for the screening test should be recorded.
Genetic counselling services should be made available on demand, and are strongly recommended for carrier couples.
Participants must be informed of the screening result (whether screen positive or negative), and receive post-test information, that includes residual carrier risk. However, the wish of people not to know their result should also be respected.
Participants should receive their screening results in a timely manner.
5. Definitions
At-risk couple for CF: Both partners are carriers of a CF-causing CFTR mutation. At-risk couples have a 1 in 4 risk at each pregnancy that the foetus will have CF.
Carrier screening for CF: CFTR gene mutation analysis on a person without CF who does not have a family history of CF, a family history of CF carrier status or a partner who is a carrier, has CF or a family history of CF or CF carrier status. CF carrier screening may be applied to individuals, communities or populations.
Carrier testing for CF: CFTR gene mutation analysis on a person at increased risk of having a CF child.
Cascade testing: CFTR gene mutation analysis on a person with a family history of CF or family history of carriers for CF. In general, this involves specifically testing for CF-causing mutation(s) detected in that family. The partner of a person with CF or known CF carrier should also be offered a CF-causing mutation analysis.
CF carrier: An individual who is heterozygous for a CF-causing CFTR gene mutation, who has a risk of CF in her/his offspring, but who is not considered at risk of developing CF.
CF-causing mutation: A variation or change in the sequence of nucleotides in the CFTR gene that is permanent, is transmissible to children, and known to cause CF, when the other copy of the gene also carries a CF-causing mutation.
CFTR-related disorders: Clinical entities associated with CFTR mutations, but where a diagnosis of CF cannot be made by the current standard diagnostic criteria and which tend to have a better prognosis.
CFTR: The Cystic Fibrosis Transmembrane Conductance Regulator is an ABC transporter-class protein and ion channel that transports chloride ions across epithelial cell membranes. Mutations in the CFTR gene affect the amount of functional chloride ion channels in these cell membranes, leading to CF and CFTR-related disorders.
Cystic Fibrosis: An autosomal recessive inherited disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. This gene codes for a CFTR protein which is an ion transport protein in the epithelial surfaces of lungs, pancreas liver, intestines, sweat ducts and vas deferens.
Genetic counselling: A communication process that deals with the occurrence, or risk of occurrence, of a (possibly) genetic disorder in the family. The process involves an attempt by appropriately trained person(s) to help the individual or the family to: (i) understand the medical facts of the disorder, (ii) appreciate how heredity contributes to the disorder and the risk of recurrence in specified relatives, (iii) understand the options for dealing with the risk of recurrence, (iv) use this genetic information in a personally meaningful way that promotes health, minimises psychological distress and increases personal control, (v) choose the course of action which seems appropriate to them in the view of their risk and their family goals, and act in accordance with that decision, and (vi) make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder (www.eurogentest.org), [
Newborn screening for CF: Application of a screening test for the purpose of early diagnosis of CF in a newborn/infant. There are a number of strategies used, but most involve a combination of immunoreactive trypsinogen (IRT) measurement as a universal biochemical screening, followed by genetic testing of population-specific CF-causing mutations in those with an IRT above a pre-defined cut-off level. The purpose of newborn screening is clearly different from carrier screening in that it aims at early identification of affected infants, although detection of CF carriers is an unwanted consequence of most CF newborn screening programmes.
Pre-conception carrier screening for CF: CFTR mutation analysis in individuals who wish to have a child, are not a-priori at increased risk of CF, and are not yet in established pregnancy.
Pre-implantation Genetic Diagnosis (PGD): search for CF-causing CFTR gene mutations in one or a few cells of an embryo developing in vitro after assisted reproduction and before embryo implantation into the uterus.
Prenatal carrier screening for CF: CF carrier screening of pregnant women and of their partners.
Prenatal CF diagnosis: testing of a foetus via Chorionic Villous Sampling (CVS), and/or amniocentesis, for CF-causing mutations carried by its parents.
Reproductive options: This is a broad term that takes into account the many options available to a person or couple who are found to be carrier(s) of a CF-causing mutation. The timing of screening will determine the range of options available to an individual or couple. The range of reproductive options include: having no more or fewer children, doing nothing and accepting the risk of having a child with CF, adopting, undertaking prenatal diagnosis (with the option of termination of an affected pregnancy or continuation of the pregnancy), achieving pregnancy with donor ova or sperm or IVF pregnancy with PGD. Access to some of these options varies between countries according to local medical practices and national regulations.
Residual carrier risk: the risk of an individual being a carrier notwithstanding a negative test result.
Acknowledgements
The organisers of the Consensus Conference would like to thank Wolf Rogowski for external health economic advice as well as the organisations which supported the meeting: Mukoviszidose ev, Cystic Fibrosis Foundation, EuroCareCF (LSHM-CT-2005-018932) and the EuroGenTest NoE (LSHB-CT-2004-512148). Supported by MZOFNM2005 to MM.
This consensus conference was sponsored by some commercial companies: Bayer HealthCare, Solvay Pharmaceuticals, Luminex, Abbott Molecular, Innogenetics. These companies had no role in the design and conduct of the consensus conference, and in the preparation, review, or approval of the manuscript.
Subcommittee on Cystic Fibrosis Screening, Accreditation of Genetic Service Committee, ACMG American College of Medical Genetics. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.
Ionnou L, Massie J, Collins V, McClaren B, Delatycki M. Population-Based Genetic Screening for Cystic Fibrosis: Attitudes and Outcomes. Human Genomics 2009 (in press).
EUROGAPPP PROJECT 1999 - 2000 Public and Professional Policy Committee (PPPC)* Population genetic screening programmes: Proposed recommendations of the European Society of Human Genetics. Eur J Hum Genet. 2000; 8:998-1000
The molecular genetic epidemiology of cystic fibrosis. Report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS http://www.who.int/genomics/publications/en/ and WHO Geneva, Human Genetics Programme WHO/HGN/CF/WG/04.02.
‘Balance' is in the eye of the beholder: providing information to support informed choices in antenatal screening via Antenatal Screening Web Resource.
Development of an interactive computer-assisted instruction (ICAI) program for patient prenatal genetic screening and carrier testing for use in clinical settings.
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