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Draft ESHG Document: Expanded Carrier Screening, February 2015

Responsible implementation of expanded carrier screening. Recommendations of the European

Society of Human Genetics

Lidewij Henneman1, Pascal Borry2, […………………], Davit Chokoshvili2,3, Martina C. Cornel1,

Carla G. van El1, Francesca Forzano4, Heidi Howard5, Sandra Janssens3, Hülya Kayserili6, Lovro

Vidmar7, Wybo J. Dondorp8, Borut Peterlin7, on behalf of the European Society of Human Genetics

1Section Community Genetics, Department of Clinical Genetics and EMGO Institute for Health and Care

Research, VU University Medical Center, Amsterdam, the Netherlands.

2Centre for Biomedical Ethics and Law, University of Leuven, Leuven, Belgium.

3Centre for Medical Genetics Ghent, University Hospital Ghent, Ghent, Belgium.

4Medical Genetics Unit, Ospedali Galliera, Genova, Italy.

5Centre for Research Ethics and Bioethics, Uppsala University, Uppsala, Sweden.

6Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey

7Clinical Institute of Medical Genetics, Ljubljana University Medical Centre, Ljubljana, Slovenia.

8Dept of Health, Ethics & Society, Research Schools CAPHRI and GROW, Maastricht University, Maastricht,

the Netherlands.

Running title: Responsible implementation of expanded carrier screening.

Corresponding author: dr. Borut Peterlin, Clinical Institute of Medical Genetics, Ljubljana

University Medical Centre, Ljubljana, Slovenia email: [email protected]


Abstract

Carrier screening is the detection of carrier status of recessive diseases in persons who do not have an

a priori increased risk of having a child with a certain disease based on their or their partners’ personal

or family history. Carrier screening aims to facilitate informed reproductive decision-making by

identifying couples at risk of having an affected child. In the last decades, carrier screening was

typically performed for relatively common, recessive disorders associated with significant morbidity

and reduced life-expectancy. New genetic testing technologies enable the extension of screening to

multiple conditions, genes or mutations with minimal extra cost or effort. Currently, most expanded

carrier screening panels are advertised and sold to physicians and the public on a commercial basis.

This document discusses the challenges on expanded carrier screening given the lessons learnt from

decades of population-based carrier screening and given the criteria for genetic screening and testing.

It aims to contribute to the public and professional discussion and better clinical and laboratory

practice guidelines.

In collaboration with the first author, the ESHG Public and Professional Policy Committee drafted this

document and Recommendations regarding the selection of disorders, timing, information and

counselling, and informed consent. This document is posted on the ESHG website and sent to the

ESHG membership and external experts to solicit comments and further suggestions until March 15,

2015. After integration of the comments the document will be sent to the ESHG Board for approval.

Keywords: carrier screening; population-based screening; expanded panels; recommendations; policy;

implementation


INTRODUCTION

There are more than 1300 recessive disorders (autosomal and X-linked), ranging from very mild to

severe, cumulatively affecting at least 25 in 10,000 children (UNSCEAR 2001). This means that 1 to 2

in 100 couples are carrier couples at risk of having a child affected with a recessive genetic condition

(Ropers 2012). Currently, in most countries, it is standard practice to offer carrier testing to adult

individuals who have a positive family history of a recessive disease; to partners and relatives of

identified carriers, and to partners of people with the disease. However, in this way, only a minority of

carrier couples will be identified, since the majority of affected children are born to couples with no

previous known family history, and only a minority of relatives in high-risk families request carrier

testing (Morris 2004).

Aim of carrier screening

Carrier screening is the detection of carrier status in persons, who do not have an a priori increased

risk of having a child with a certain disease based on their or their partners’ personal or family history.

Carrier screening offered before or during pregnancy determines a couple’s risk of having a child with

a recessive disorder, thereby facilitating meaningful reproductive choices for those at a high risk of

having a child with a serious genetic disorder. While in most Western countries there is consensus that

the aim of reproductive screening, including carrier screening, should be the provision of autonomous

choices, from a global perspective there are different views. In some (close) communities with a high

burden of devastating disease, prevention may well be regarded as the appropriate aim of carrier

screening, and in those cases reduced birth rates of affected children may be regarded as the measure

of success (Wert 2012). Furthermore, although not considered the primary aim, carrier screening could

also contribute to early therapeutic procedures in the neonatal period; when both partners are known to

be carriers, infants might be more closely watched, diagnosed and treated earlier, which consequently

might reduce morbidity and mortality related to recessive disorders.

When both partners are identified carriers of the same autosomal recessive disease, they have a 1-in-4


risk in each pregnancy of having an affected child with this disease. For X-linked disorders, half of the

male offspring of a carrier mother will typically be affected. Carrier screening can be considered for

different target groups, including pregnant women and their partners (prenatal screening), individuals

or couples before pregnancy, as part of family planning (preconception screening) or even before

marriage (premarital screening), high school students (school screening), and newborns (neonatal

screening). Each approach has its own pros and cons. While screening during pregnancy is considered

the most practical, the preconception period is generally considered as the ideal timing with regard to

the primary aim of screening (e.g. Castellani 2010), because it results in alternative reproductive

options being available and thus maximum autonomous choices, including preimplantation genetic

diagnosis (embryo selection), prenatal diagnosis, use of donor sperm or oocytes, accepting the risk,

refraining from pregnancy and adoption. Furthermore, in some cultures changing the choice of partner

is an existing practice, where the focus of screening is on spouse selection or carrier matching to

prevent disease.

Carrier screening can be offered to individuals or couples. For couples, screening tests can be

performed simultaneously or sequentially (after the first partner tests positive). Moreover, test-results

can be communicated to partners individually (i.e. full disclosure of individual test-results) or couple-

based (i.e. positive results are communicated only to those couples in which both partners are found to

be carriers).

From single diseases to expanded screening panels

Carrier screening can be organised as a population-based offer, irrespective of risk status, or aimed at

specific high-risk populations. Currently, carrier screening is typically performed for relatively

common, recessive disorders associated with significant morbidity and reduced life-expectancy.

Examples are carrier screening for cystic fibrosis (CF) (offered in countries including the United

States, Australia and Italy) and ß-thalassemia (offered in e.g. Cyprus, Sardinia, Israel and Turkey).

Other examples include limited panels of disorders targeted at specific communities, such as the

Ashkenazi Jewish (AJ) population, which have dramatically lowered the number of children born as


affected with diseases such as Tay-Sachs disease (Kaback, 2000). In contrast to a diagnostic setting,

for carrier screening the panel of mutations tested are usually restricted to the most frequent and

known pathogenic mutations.

With the introduction of new technologies, it is now possible not only to detect a much larger set of

mutations, but also to simultaneously screen for many more diseases at a faster turnaround time for

lower costs. Moreover, while some current screening programs are now ethnicity-based, expanded

carrier screening (sometimes referred to as “pan-ethnic” or “universal”) allows testing of all

individuals regardless of ethnicity, which increases equity and potentially reduces the risk of

stigmatization of ethnic groups. Technological advances have made it possible to extend the scope of

carrier screening with minimal extra cost or effort. An increasing number of commercial laboratories,

both in North America and in Europe, already offer panels for carrier screening for over 100 diseases.

Should these panels be implemented in the future in regular health care, this will pose major

challenges for physicians offering these tests. For one, offering carrier screening for multiple diseases

simultaneously will undoubtedly result in more frequent situations where difficult decisions need to be

taken. Responsible implementation of expanded genetic carrier screening thus raises many technical,

ethical, legal and social questions, including, among others: Which diseases and mutations should be

included in the panels and on what rational will these decisions be based? What are public and

professional attitudes and preferences towards expanded carrier screening panels? How can pre-test

education and post-test counseling be optimised, and thus facilitate informed decision-making?

Challenging the principles of carrier screening

A distinguishing feature of screening compared to diagnostic testing is that a test is offered without

any sign or symptoms of a specific health problem. To justify screening, a screening programme has to

meet certain criteria, and in many countries the Wilson and Jungner criteria (Wilson & Jungner, 1968)

form the basis screening criteria, as adapted to later developments, including genetic and reproductive

screening. For reproductive screening further refinements have been made as the aim here is generally

not early diagnosis for prevention and treatment, as for most screening programs, but to facilitate


reproductive decision making (e.g. Nuffield Council of Bioethics 1993; Health Council of the

Netherlands 1994). An important screening criterion is that the natural course of the disease screened

for should be adequately understood, and that an acceptable and reliable test should be available with

known sensitivity, specificity, and predictive values. In addition, in reproductive screening where the

aim is to facilitate reproductive decision making and where couples may be faced with the choice of

avoiding or terminating a pregnancy, an autonomous decision should be guaranteed. In 2003 the

European Society of Human Genetics issued a document on the principles, techniques, practices, and

policies that impact population genetic screening programs in Europe. It was stated that “Genetic

screening goals and the target population must be well defined; laboratory quality control stringent,

with limits of results clearly delineated; the confidentiality of the information protected by authorities;

procedures to protect individual and family privacy established in advance; voluntary participation;

genetic counseling offered and educational programs in place; and long-term outcomes monitored and

evaluated.” (Godard 2003). Expanded carrier screening panels clearly offer an opportunity to screen

for many more diseases at affordable costs but the scale of it clearly challenges these criteria and

principles.

In 2013, the American College of Medical Genetics (ACMG) published a position statement on

expanded carrier screening in which it listed criteria that must be met by a disorder to be included in

an expanded panel for general population-based carrier screening (Grody 2013). These criteria

emphasize several of the considerations that are of importance in the selection of disorders: for

example, the disorders chosen facilitate reproductive decision-making, and have known causative

gene(s) and mutations in the population tested with validated clinical association between the

mutation(s) and disease severity. Besides these criteria, suggestions were made for counseling and

informed consent in multi-disease (expanded) carrier screening. However, to further support guidance

in practice, more comprehensive recommendations are needed.

This paper aims to reflect on new challenges given the lessons learnt from decades of population-

based carrier screening, contribute to the public and professional discussion on expanded carrier

screening, to the development of clinical and laboratory guidelines, and to provide recommendations


for health care policy and professionals. The paper was prepared by members of the Public and

Professional Policy Committee of the European Society of Human Genetics (ESHG) and

recommendations were posted on the ESHG website from February 4, to March 15, 2015 for

membership consultation and comments from external experts. The final version will be sent to the

ESHG Board for approval.

Box: Summary points

- The primary goal of carrier screening is to facilitate informed reproductive decision-making

by identifying couples at risk of having an affected child.

- Expanded carrier screening refers to performing carrier testing on individuals or couples for

multiple recessive disorders, which is largely driven by new genetic testing technologies,

enabling the extension of screening with minimal extra cost or effort.

- Expanded carrier screening allows testing of all individuals regardless of ethnicity (“pan-

ethnic” or “universal”), which potentially increases equity and reduces the chance of

stigmatization.

- The best time to offer screening is the preconception period, since identifying carrier

couples before pregnancy allows the greatest number of reproductive options with more

time to make an informed decision.

1. Attitudes of health care professionals and the public

Decades of research have investigated the attitudes and perceived barriers and concerns among health

care professionals and the public toward carrier screening for specific genetic disorders. However, one

should be cautious to extrapolate these findings to offering expanded carrier screening, as some

concerns may be removed or reduced, while new issues may raise as discussed below.


Healthcare professionals’ attitudes and perceptions

The positive attitude of potential providers is vital to the success of a screening program. The attitudes

and perceptions of health care providers towards carrier screening have been studied primarily for

individual genetic disorders, especially for CF and hemoglobinopathies (HBPs; sickle cell disease and

thalassemia). Generally there is a positive attitude toward carrier screening (Janssens 2014), however

several concerns and barriers exist.

Sufficient pre- and post-test information and counseling plays an important role in limiting the

possible negative psychological effects of carrier screening, since increased genetic knowledge has

been shown to be correlated with lower testee’s anxiety (Gason 2005; Ioannou 2010a; Henneman

2002a). However, the lack of knowledge and the need for further education among both professionals

and the lay public have been a major concern among health care professionals in many surveys

investigating carrier screening programs for genetic diseases (Boulton & Williamson 1995; Darcy

2011; Mennie 1998; Morgan 2004; Poppelaars 2003a; Qureshi 2006). In addition, lack of time has

been mentioned as important barriers with regard to offering carrier screening (Poppelaars 2003a;

Poppelaars 2003b; Rowley 1993; Morgan 2004). Other practical issues experienced as barriers are

costs or lack of reimbursement, supporting services (Stark 2013; Poppelaars 2003a; Baars 2005), and

lack of awareness of (or use of) existing guidelines (Darcy 2011; Morgan 2004). In many countries

there are no clear guidelines or policies for carrier screening, and as a consequence testing is only

offered at a local level, or as pilot projects, resulting in very few health care professionals providing

screening to their patients. For example in the Netherlands, the lack of a national policy was seen as a

major barrier for not offering screening for HBPs (Jans 2013). In countries where clear guidelines do

exist, for example in the United Kingdom, where there are guidelines for HBPs, service delivery was

initially poor in some areas or insufficiently reached some ethnic groups (Modell 1997). Another

example of clear policies with faltering implementation are the CF carrier screening guidelines

launched by the American College of Obstetrics and Gynecology (ACOG) in 2001, where a decade

later, a significant number of obstetricians is still not informed about the guidelines (Darcy 2011).


In 2012, experiences and opinions on expanded carrier screening for >100 diseases of variable severity

were assessed among 222 gynaecologists and obstetricians in the United States. Although there may

have been a bias towards those who are the most informed about the topic, 15% of the professionals

offered this kind of carrier testing to all patients, and 52% offered this upon patient’s request (Benn

2013). Furthermore, the majority of respondents (66%) in this study believed that the optimal time for

expanded carrier screening was preconceptional. This was also recommended as the best time for CF

carrier screening, as this this allows couples the most complete range of reproductive options

(Castellani 2010). However, in practice, carrier screening in this context is mainly offered prenatally

(Morgan 2004).

Ready et al. (2012) surveyed the attitudes regarding expanded genetic carrier screening among 203

women’s healthcare providers (61% were physicians), which indicated that the majority of participants

believed that a post-test consultation with a genetic counselor would be helpful (84%), if not essential

(78%). In a focus group study by Cho et al. (2013) in 2011 with forty genetics professionals,

participants also stressed the importance of pre- and post counselling, and that counseling should be

provided by a clinician with expertise in communicating genetic information. As most people having

carrier testing are not familiar with the diseases screened for, receiving a positive (abnormal) test

result will raise questions among carrier individuals/couples, and will require more attention from

health care professionals in particularly from primary care physicians and reproductive healthcare

professionals. Screening for multiple diseases would thereby increase the necessity to refer patients

with positive screening results to a genetic centre since it will be impossible for health care providers

to be knowledgeable about every (rare) condition screened for.

In the aforementioned focus group study with genetics professionals, one of the major concerns

mentioned regarding expanded carrier screening currently marketed was the technical inability to fully

rule out the possibility of severe recessive diseases because rare mutations would not be detected (Cho

2013). Some participants therefore felt that an ethnicity-based panel may be more appropriate for

some patients, as many of the mutations would not be aimed at all ethnic populations.


Finally, among potential providers of expanded carrier screening, the (expected) lower costs of the

procedure has been cited as a great advantage over conventional (single gene mutation) screening. For

example, despite concerns regarding current technical limitations of expanded carrier screening,

genetics’ professionals noted the ability to include a wide range of mutations without significant

increases in the cost (Cho 2013). Then again it has been argued that the true costs of expanded carrier

testing including follow-up tests and counseling needs after positive results is still in need to be

evaluated (Stoll & Resta 2013). Future research should further assess how health care professionals

view and deal with this type of genetic testing, which may create the need for additional competences

and education.

Public attitudes towards carrier screening

Ever since the gene associated with CF was discovered in 1989, extensive research on public attitudes

has been performed with regard to carrier screening for this disorder. A recent systematic review

summarizing 23 years of research shows strong support among the public: the majority of people

(range 60-100%) believe CF carrier screening should be made available, while 80–96% believe that it

should be routinely offered (Ioannou 2013). Considering the best time to offer carrier screening, most

people, as with the health care professionals, prefer that it should be offered preconceptionally,

enabling the greatest number of reproductive options (Rowley 1997; Poppelaars 2003a). The highest

interest for carrier screening was observed among people of reproductive age, in particular if they had

no children at the time of the survey (Chen 2007). Previous studies have also shown that the majority

of CF parents support population carrier screening (Conway 1994; Janssens 2015), and only a

minority of parents and patients feel that screening should be restricted to families with a family

history of the disease (Conway 1994). Some fear that the expansion of screening to more diseases may

lead to more feelings of guilt and blaming of parents having a child affected by a potentially avoidable

disorder (Clarke 2014) .

In some genetically isolated communities carrier screening is a well-known and well-accepted

practice, as in the Ashkenazi Jewish (AJ) population. Positive attitudes in this population have been


reported ever since screening was made available, not only towards carrier screening in adults, either

in the context of a premarital confidential carrier matching programme (i.e. ultra orthodox Dor

Yeshorim program) (Ekstein and Katzenstein, 2001) or offered more openly (Frumkin 2011), but also

towards screening adolescents in high schools (Gason 2005; Barlow-Stewart 2003). Starting in the

1970s with the offer of screening for Tay Sachs Disease (TSD), carrier screening has extended to

include many more diseases, with panels ranging from 3 up to more than 16 disorders (Leib 2005;

Scott 2010; Fares 2008). Due to a founder effect and genetic drift, the AJ population is at increased

risk for several rare recessively inherited diseases, and disorders tested for in this community are

frequently referred to as “Ashkenazi Jewish Diseases” (Leib 2005). The attention that it has been

given may have lead to a higher sense of vulnerability in this population and thus more interest in

testing for multiple diseases compared to the general population (Leib 2005; Hall 2006). It has been

shown that this community generally accepts a screening offer, even for diseases with lower carrier

frequencies and/or detectability (Scott 2010), and also including relatively mild diseases (Leib 2005).

Although this inclusion has already created vivid discussions (Borry 2008; Zuckerman 2007). It has

been suggested that the expansion of carrier screening to other diseases may, in part, be driven by the

demand of the AJ population itself (Scott 2010).

In some European countries, disorders that were previously uncommon have now become much more

common due to global migration. For example, prevalence of HBPs has risen in Northern Europe due

to the increased number of immigrants from Africa and Mediterranean regions. In countries where

severe recessive disorders are common, the severity of the diseases has led to successful screening

strategies, in terms of high uptake and awareness. For example beta-thalassemia screening has a long

and successful history in several at-risk populations in the Mediterranean area (Cao 2002). Studies

have shown that migrant populations in countries such as the UK and the Netherlands are also positive

towards screening for these disorders, although acceptance of reproductive options such as prenatal

testing and termination of affected pregnancies may be low, especially when offer late in pregnancy

(Van Elderen 2010; Van der Pal 2013; Modell 1997; Ahmed 2006; Gitsels-Van der Wal 2014).


A limited number of studies have addressed attitudes towards screening for other conditions such as

spinal muscular atrophy (Prior 2010), and fragile X syndrome (e.g. Fanos 2006; Martyn 2013;

Metcalfe 2012), and despite the heterogeneous phenotype and complicated inheritance of the latter,

similar positive attitudes have been found. More research is needed to assess general public

perceptions about the benefits and barriers to expanded carrier screening panels.

Uptake of carrier screening

In countries where carrier screening programs aim to enhance reproductive decision making for

couples at risk for a disease, helping and empowering couples to make an informed choice is

considered a prerequisite for a successful program. Here, except for economic reasons, uptake per se is

considered of less importance, while facilitating autonomous choice is a key concept. The

effectiveness of a screening programme should thus ideally be assessed in terms of a measure of

informed choice (Ames 2014). Research, however, suggests that screening during pregnancy is

sometimes accepted just because of the ease of testing and because it is routinely offered and not

because of any perceived benefits (Henneman 2002b). More insight into the factors that influence

uptake, and the reasons why individuals or couples decide to have a test or not can give an indication

on the degree of informed choice. The empirical evidence regarding interventions to improve informed

decision making in screening is limited. Systematic development of interventions to enhance informed

choices in screening deserves priority, especially in disadvantaged groups (Van Agt, 2014).

Population-based carrier screening for CF has mainly been offered during pregnancy. In particularly to

women attending a routine antenatal clinic visit, where uptake rates of 46%-99% have been reported

(Ioannou 2013). In contrast, despite the overall positive attitudes of the general public (Ioannou 2013),

uptake rates in the general population, individual screening or couples planning a pregnancy, are much

lower, even when screening is offered free of charge (Clayton 1996; Henneman 2003). Based on these

findings, it might be concluded that there is high interest in screening among a group that is highly

receptive to the idea of screening (i.e. pregnant women). However, when reviewing reasons for having

carrier testing, it was shown that testing during pregnancy is sometimes accepted just because blood


samples had already been taken, it can be carried out in an easy way and because women believe all

tests in pregnancy are important, and not because of any perceived benefits of the testing (Rowley

1997; Henneman 2002; Chen 2007).

It has also been shown that uptake rates for CF carrier screening vary by the method of invitation.

Uptake was approximately 10% when invitations were sent by letter, and increased to 24-87% with

active opportunistic testing, i.e. a personal approach and immediate possibility for testing (Bekker

1993; Watson 1991; Payne 1997). It could be argued that the high uptake rate achieved in

opportunistic testing is the result of a supply push rather than a demand from the population (Bekker

1991). Moreover, it has been shown that when carrier screening is offered alongside other tests, taking

an informed decision is compromised (Hartley et al. 1997). A reflection period to decide whether or

not to have the test may be advisable to give people the opportunity to make a decision based on the

perceived benefits and not just because it is offered (Henneman et al., 2002). In contrast, the low

uptake rate achieved by mailed invitations might be due to other reasons, such as lack of knowledge

and perceived barriers such as inconvenience of the time or location for having the test (Henneman

2001; Clayton 1996; Chen 2007). Besides the way screening is offered, many other factors have been

identified to influence the uptake of screening, again most extensively studied for CF (Ioannou 2013;

Chen 2007). Besides factors related to individual characteristics (e.g. education) and perceptions (e.g.

of the benefits and barriers of screening) factors related to the quality of delivery of genetic services,

carrier testing information, and counseling also influence the screening uptake. For example, the low

uptake of HBPs carrier testing among immigrants in the UK was partly due to a lack of knowledge

among physicians about the diseases, misconceptions about the immigrants’ norms and values (Atkin

1998), and offering a test late in pregnancy (Modell 1997).

Uptake of screening if offering an extended panel

The question is if expanding the panel of diseases also influences the uptake of screening. It is most

likely that individuals and couples who are opposed to carrier screening because they do not accept the

available reproductive options, for example, prenatal diagnosis and termination of pregnancy, using


donor gametes, or choosing another partner, will also not easily participate in carrier screening if

testing for more disorders is offered. For others, however, offering screening for more than one disease

may increase the perceived benefits of testing thus resulting in more willingness to participate.

Indeed, there was an association between expanding a screening test in AJ high schools for one

disease (TSD) to seven diseases and an increase in uptake from 67% (Gason 2005) to 99% (Ioannou

2010). However, the authors concluded that this was mainly due to the use of cheek brush swabs (from

which to extract DNA) instead of taking blood samples (Ioannou 2010). Fear of a blood test is an

important barrier reported by people who decided to decline screening, especially in high school

screening programs (Chen 2007). More research is needed on how uptake is affected by the expansion

of panels and whether individuals and couples can make informed decisions with such an offer.

Impact of carrier screening on reproductive decision making

With regard to CF carrier screening, a recent review has demonstrated that 80–100% of the carrier

couples identified in, primarily prenatal, screening decided to have prenatal diagnosis (Ioannou 2013).

Termination of pregnancy was undertaken for almost all of the affected fetuses. Less is known about

prospective carrier couples identified other than during the pregnancy period (i.e. preconception), as

long term follow up is needed to assess their reproductive decisions. With regard to thalassemia

screening in the UK, it has been shown that utilisation of prenatal diagnosis differs by ethnic group,

and was much lower than expected (Modell 1997). It was concluded, however, that this was mainly

because of serious shortcomings in the prenatal screening practice and inadequate counseling delivery

(Modell 1997, 2000; Petrou 1995).

While improving informed reproductive choice is considered as the primary goal of screening, this

may also have as a consequence, not as a primary aim, that the birth prevalence will be reduced.

Expanded carrier screening will probably result in more couples deciding to have prenatal diagnosis or

preimplantation genetic diagnosis, and thus as a consequence, may lead to a reduction of the birth

prevalence of children with the diseases screened for.


In communities with high prevalence rates of carrier status, high disease burden and where carrier

screening is common and actively offered since decades uptake rates are very high. This, in turn, has

indeed resulted in a decrease of the frequency of the disease. For example, a 90% reduction of children

born with TSD was observed in the AJ community as a result of carrier screening followed by prenatal

diagnosis when indicated (Kaback 2000). Here, however, the reduction of the burden of disease or

prevention may be regarded as an explicit goal of screening and well-accepted by the community (De

Wert 2012). Scott et al. 2010 have argued that the success of preconception and prenatal carrier

screening as a disease prevention strategy has driven the expansion of screening panels targeted at the

AJ community. In Cyprus, both in the republic of Cyprus and also in Northern Cyprus, carrier

screening for thalassemia, which was at first set up as a mandatory programme to actively discourage

marriage between carriers to prevent the birth of beta-thalassemia patients, has resulted in a decrease

of the birth prevalence of over 95% of children born with the disease (Coussens 2010). In Turkey,

although it has became mandatory very lately in about one third of the cities in 2005 in the premarital

period, it had led to a similar decrease in affected newborn rates since the Hemoglobinopathy Control

Programme was initiated in 1993 (Keskin 2000; Acemoglu, Canatan 2006). Similar results were found

in Sardinia (Cao 2002). In other countries, such as Iran, Bahrain, and Saudi Arabia, (mandatory)

premarital screening programs have become widely accepted (Cousens 2010); some of these

programmes clearly mention prevention as their aim. However, these programs have not necessarily

led to a reduction of affected births in the related countries as a consequence of several factors,

including couples still getting married despite being diagnosed as carriers and prenatal diagnosis not

being available (Alswaidi & O'Brien 2009; Karimi 2007).

Box: Summary


- Attitudes towards carrier screening among the general public have been overwhelmingly

positive. The actual uptake of carrier screening, however, varies greatly among the countries

and ethnic groups. The uptake is highest in some Middle Eastern and Mediterranean regions,

where screening (for beta-thalassemia) is mandatory. In addition, some ethnic groups, such as

Ashkenazi Jewish communities, have traditionally been highly receptive to carrier screening

for recessive conditions.

- Research with healthcare providers has identified the following challenges to the

implementation of carrier screening programs: low genetic literacy among patients and

medical practitioners, costs and reimbursement issues, variability among different national

health services and regional health systems, as well as lack of or limited use of professional

guidelines. Many healthcare professionals agree that provision of information about screening

and obtaining informed consent will be highly challenging as well as time-consuming in the

context of expanded carrier screening.

- Carrier screening programs aiming to enhance reproductive decision making for couples,

should be evaluated in terms of a measure of informed choice.

2. The carrier screening tests

Although rapidly evolving genomic technologies technically facilitate carrier screening for a growing

number of diseases simultaneously, developing a screening panel which meets the criteria that justify

screening, including a known predicted value for each test, will be a challenge. One of the frameworks

to assess new emerging tests is the ACCE framework (Analytic validity, Clinical validity, Clinical

utility, Ethical, legal and social implications) developed by the Centers for Disease Control and

Prevention (CDC, USA), National Office of Public Health and the Foundation of Blood Research.

Analytic validity


Analytic validity of a genetic test defines its ability to accurately and reliably measure the genotype of

interest. Current commercial providers use mostly microarray based genetic tests covering most

frequent mutations in selected genes. Counsyl® reported validation results which were found to be

comparable to blood-based single-gene carrier tests (Srinivasan 2010).

Alternatively, whole genes, and not only selected mutations, can be enriched and sequenced by next-

generation sequencing (NGS) (Bell 2011). The accuracy of the test for SNP genotyping using

microarray based genetic tests was reported as high as 98.8% (Kingsmore 2012). Nevertheless, clinical

use of NGS is still in its early phase and recommendations are being developed for assuring the quality

of NGS in clinical laboratories (Brownstein 2014; Weiss 2013).

Clinical validity

Clinical validity of a genetic test defines its ability to detect or predict the associated disorder and

includes the following elements: clinical sensitivity, clinical specificity, prevalence of the tested

disorder, positive and negative predictive values, penetrance and genetic or environmental modifiers.

It is challenging to evaluate the clinical validity of carrier screening panels marketed by current

providers, as well as what is offered in the clinic.

Most genetic disorders are characterised by allelic heterogeneity, which means that more than one

mutation in a given gene is associated with the phenotype. For example, more than 1900 mutations

have been reported in the CFTR gene causing cystic fibrosis

(http://www.genet.sickkids.on.ca/StatisticsPage.html). While the most common mutation p.Phe508del

demonstrates a significant population specific distribution with decreasing prevalence from Northwest

to Southeast Europe, and fewer than 20 mutations occur at a worldwide frequency of more than 0.1%

in CF patients. On average, companies only test small number of all known mutations on a particular

gene, while the average number of mutations associated with genes included in the panel according to

the Human Genetic Mutation Database is 284 per gene (http://www.hgmd.cf.ac.uk/ac/index.php;

Peterlin, 2014). Furthermore, several mutations are very rare or associated with a milder or variable

phenotype, however data on the exact molecular pathology (frequency of mutations in a certain gene


or proportion of mutations in different genes if genetic heterogeneity is present) for a given genetic

disorder in different populations are still often not available. As the carrier screening panels are fixed

in the microarray based testing and focused to a limited number of mutations, they can not address

appropriately molecular pathology in specific populations, neither the spectrum of tested genes nor

the spectrum of mutations. Identification of novel genes and new gene panels are under development

for several genetic disorders.

All factors, population specific molecular pathology and number of mutations and genes tested per

genetic disorder affect the clinical sensitivity (proportion of the identified carriers if a tested person is

a carrier) of the test as well as the negative clinical predictive value (probability that the tested person

is not a carrier if the test is negative) and can not be generalised at a pan-ethnic level. An NGS

approach has a potential to increase clinical sensitivity (Bell 2011; Kingsmore 2012), however

professional standards related to the provision of test results are still under development (ESHG

recommendation). An NGS approach would also generate variants of unknown significance and

potential incidental or unsolicited findings.

The positive predictive value, which defines the life-time risk to develop the disease if the test is

positive, may differ across different disorders as a function of penetrance, expressivity and may be

mutation dependent. Furthermore a given mutation may be associated with different clinical severity

of disease manifestation even in the same family.

The exact prevalence rate for recessive disorders worldwide is not available and complicated by

geographic or population variability. A systematic survey of epidemiological data in Europe is offered

by Orphanet

(

http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_decreasing_preval

ence_or_cases.pdf), but information is not population specific. Bell et al. (2011) have shown that the

average carrier burden of severe childhood-onset recessive disorders after screening for 448 genes in

104 unrelated samples was 2.8 (range 0-7). There is evidence that Counsyl screening panel of 108


disorders and 417 disease causing mutations identified 24% of individuals as carriers for at least one

mutation and 5.2% as carriers for multiple disorders (Lazarin 2013).

Clinical utility

The clinical utility of a genetic test refers to the usefulness of the test and the value of the genetic

information to medical practice and describes how likely the test can significantly improve patient

outcomes. In the context of preconception carrier screening, clinical utility relates mainly to the

possibility to increase couple’s reproductive autonomy and choice. Options include preimplantation

genetic diagnosis, prenatal diagnosis, using donor sperm or oocytes, seeking adoption or refraining

from having children.

Additionally, preconception carrier screening, although still limited, might enable perinatal diagnosis

with early management of genetic disorders. Current providers market their genetic tests by stating the

clinical relevance of the test and a possibility of treatment either in pregnancy or after birth. The issue

of “clinical relevance” or “clinical utility” is not described by the providers and also not clear from the

selection of diseases in the screening panel. For example, hemochromatosis is often included in the

panel, (Borry 2011) but is not relevant for reproductive planning neither is it recommended for

screening in the general population (EASL 2010; Bacon 2011). Phenylketonuria (PKU), which is

included in the panels of most of the providers, is a treatable condition associated with good prognosis.

For some treatable disorders knowing both parents are carriers could improve the prognosis if the

diagnosis thereby can be made earlier, but this must be explained in the pre-test information.

The lists of disorders included in the expanded carrier testing panels clearly differ among test

providers. There are differences in numbers and types of diseases (autosomal recessive, X-linked

recessive), in the ages of onset (neonatal, childhood, adult life), and in treatability and severity

(Peterlin 2014). This huge diversity illustrates the current lack of coherent criteria to select conditions

to be included in panels. A comparison of gene-lists with overlapping number of disorders among four

providers (A-D) is shown in Figure 1.


Figure 1: A scheme showing the number of disorders that are already listed in the expanded carrier

screening panels offered by four different companies (A-D). The overlaps indicate the number of

disorders shared by the companies.

As previously mentioned, there are currently 1300 recessive (autosomal and X-linked) diseases

associated with a gene mutation (OMIM) and about 100 recessive disorders have a prevalence of >

1/100,000 (Orphanet

http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_decreasing_preval

ence_or_cases.pdf). Several of those, for example Duchenne/Becker muscular dystrophy and

Friedreich ataxia are not included in any of the marketed panels.

Pending further research and debate about various concerns before and below in this document, there

seems to be good reason for not moving beyond ‘serious congenital and childhood onset disorders’

when it comes to the scope of panel design. This is in line with the scope that was also proposed in

another ESHG document (Dondorp submitted). As expressed in that document: “This can be justified

in the light of the normative framework as providing women or couples with meaningful reproductive

choices rather than with the (theoretical) option of receiving all information that genomic technologies

can possibly reveal about the fetus. This is also in line with findings of attitudinal research among

British and Dutch pregnant women. Concerns about wider testing included a slippery slope towards


testing for minor abnormalities or cosmetic traits and a trivialization of abortion (Farrimond and Kelly,

2013; Van Schendel 2014).”

Although it is not considered the purpose of the screening, carrier screening may also reveal (clinically

relevant) information for a potential carrier. Several mutations for recessive disorders may increase the

risk of morbidity for heterozygous carriers as well. For example, heterozygous carriers for mutations

in the glucocerebrosidase gene (included in several screening panels and related to autosomal

recessive Gaucher disease) have a significantly increased the risk of developing Parkinson’s disease

(Anheim 2012). Carriers of ataxia teleangiectasia have a increased lifetime risk for cancer; and carriers

of a fragile X (FRAXA) premutation have a significant increased risk of premature ovarian failure and

can develop neurodegenerative disorder (fragile X-associated tremor/ataxia syndrome; FXTAS) in

adulthood (Sherman 2005).

It is likely that in the future more associations between carrier states and increased or decreased risks

for diseases will be revealed, but at present it would be impossible to predict the likelihood and the

extent of these findings. These issues are likely to even increase the complexity of the counseling

related with carrier screening of multiple disorders. This raises the question whether these disorders,

such as fragile X syndrome, should be included in the panel, or only offered as cascade testing in

families with a history of the disease.

In addition to the impact for the individual or couple, identification of some mutations may have

medical implications for the extended family members, leading to specific carrier testing and

reproductive options. Therefore, potential clinical consequences in heterozygous carriers should be

adequately covered in the provision of genetic information and in the informed consent before testing.

Ethical, legal and (psycho)social issues

Ethical, legal and (psycho)social issues of carrier screening include ethical issues related to the goal of

screening, informed consent in reproductive screening, individual and social impact of screening.


Issues of autonomy and informed consent

The introduction of genetic screening programmes in the general population raises many concerns, in

particular reproductive screening programmes, as they may involve complex decisions such as

prenatal diagnosis and selective termination of pregnancy. Various guidelines have underlined that

genetic screening in clinical practice should be voluntary and accompanied by a valid process of

informed consent. Every individual undergoing a genetic test has to be made aware of the purpose of

the screening, test sensitivity and specificity, possible implications of the test results as well as

potential risks and benefits of the procedure, including psychosocial risks such as discrimination and

stigmatization (WHO, 1998; Nuffield Council of Bioethics 1993; Health Council of the Netherlands

1994). If the aim of reproductive screening (including carrier screening) is not prevention, but the

provision of options for reproductive decision-making, the case for appropriate pre-test information

and voluntary decision-making becomes even more stronger: without providing such information, the

screening will simply not fulfil its aim.

The expected time needed to obtain an informed consent may become time-consuming task for the

professional offering expanded carrier screening. Although this may depend on the type of disorders

on the panel; a uniform panel may be more easy to counsel than a heterogeneous mix (serious/ non

serious, treatable/non-treatable, early/later onset, etc) of disorders. In order to keep informed consent

workable in view of an expanded carrier screening offer, the concept of generic consent could be used

(Elias 1994; Dondorp and Wert 2013). Elias & Annas proposed the concept of generic consent as a

way to safeguard informed consent in situations of threatening information overload. In this approach,

prospective screenees would be more generally informed about types of possible test outcomes and

implications (Dondorp and Wert 2013). They would be told that the procedure is carried out to

identify couples at an elevated risk of having a child with a severe disability. Some of these diseases as

well as associated clinical symptoms can be briefly mentioned as illustrative examples. Apart from

discussing benefits of the procedure, it is crucial to inform potential screenees about the limitations of

the test, such as the possibility of false positive and false negative results. Finally, in those cases where

individuals are identified as carriers, counseling as well as more detailed information has to be


provided on the medical condition(s) of interest (Elias 1994). Recently, the ACMG acknowledged the

advantages of generic consent in the context of expanded carrier screening. In a policy paper published

in June 2013 it is stated: “A highly multiplex approach will require a more generic consent process

than is typically used for single-disease screening because it may not be practical for a clinician to

discuss each disease included in a multidisease carrier screening panels” (Grody 2013).

It has to be noted, however, that generic consent comes with its limitations. By providing less detailed

information, this could lead to more ‘uninformed decisions’ as couples might make individual

decisions to what extent they might want to be informed (Hewison 2014). In contrast, some

individuals might require more specific and in-depth information to make a decision regarding

screening (Elias, 1994). For example, a study by Ormond and colleagues (2009) showed that highly

literate pregnant women generally preferred to receive highly detailed information related to all

conditions screened for. Although this might still be possible for a handful of conditions, it is difficult

to hold this if the panel includes more than 100 conditions. In order to meet the needs of individuals

seeking in-depth understanding of the carrier screening procedure, usage of appropriately tailored

information pamphlets, websites and other audio-visual aids can be used. It should be ensured that

through user-friendly tools all interested patients have an opportunity to better familiarize themselves

with all aspects of carrier screening programs.

Individual and social impact

Learning about carrier status information after participating in a carrier screening programme can

impact on: 1) psychological well-being, 2) perceptions of health, and 3) (feelings of) discrimination or

stigmatisation (social consequences).

Impact on psychological well-being. Upon receiving the test-results, carriers experience more distress

than non-carriers, however, usually within a normal range. For most carriers, anxiety levels return

back to normal, especially when their partner screens negative, although confusion may persist

(Axworthy 1996; Bekker 1994; Denayer 1996; Ioannou 2010a; Mennie 1993; Watson 1992).


Additionally, a negative correlation between genetic knowledge and the screenee’s anxiety has been

shown (Gason 2005; Ioannou 2010b; Henneman 2004), emphasising the importance of pre-test

education.

When screening is offered preconceptionally to couples planning a pregnancy or prenatally, taking a

sample of both partners at the same time prevents unnecessary anxiety and need for counseling that

might arise when one partner is tested positive and the other partner is asked to provide a sample

(Mennie 1992). This becomes even more important with the addition of more disorders to a screening

panel, as the chance that one partner is identified as a carrier increases. Moreover, couple-based

disclosure of test-results minimizes the possible anxiety in a +/- couple (i.e. one partner tests positive

while the other tests negative) (Wald 1991). An important disadvantage of this approach however is

that information is withheld from identified carriers who might need it at a later date with a new

partner or to inform relatives (Henneman 2002).

Most studies have addressed the impact of screening for one disease. In a study evaluating a carrier

screening programme in high schools for the Ashkenazi Jewish population in Australia, it was shown

that expanding the screening from one disease (TSD) to six other diseases increased predicted negative

feelings if found to be a carrier of one of the conditions (Ioannou 2010b). Considering that in an

expanded carrier screening programme many (rare) autosomal recessive disorders but also X-linked

disorders will be included, the potential psychological impact could increase, as this will also allow for

identification of carriers of multiple autosomal recessive conditions. The possibility of psychological

harms can be minimized by educating prospective test-takers about the screening programme, and

about the implications of being a carrier. Moreover, as testing becomes more common people will

become aware that all individuals are carriers for a limited number of mutations and this may

decrease anxiety. Efforts should be undertaken to promote programmes that enhance genetic

knowledge of the public.

Impact on perceptions of health. Some studies have described less optimistic health perceptions after

receiving positive test results (e.g. Marteau 1992; Axworthy 1996; Henneman 2002), although others


have found no impact of screening on health perceptions (e.g. Payne 1997). In a three year follow-up

study on prenatal carrier screening for CF there was a small negative effect on how carriers perceived

their current health (Axworthy 1999). Similarly, in a preconception CF carrier screening programme it

was found that carriers perceived themselves as less healthy (Henneman 2002). Several explanations

such as reduced optimism of carriers about their health and poor understanding of the test results have

been suggested for this finding (Marteau 1992).

Knowledge about the purpose of the test, quality aspects of the test and limitations, potential

consequences of positive test-results and available courses of action have been considered prerequisite

for making informed decisions. Expanding screening to more diseases has resulted in a decrease of

knowledge among participants (Ioannou 2010), which may increase the misconceptions about health

status of carriers and induce more anxiety. This may even get more complicated by the overall limited

public (and professional) knowledge on genetics and lack of awareness of genetic diseases.

Stigmatisation and discrimination. Stigmatisation is the effect of labelling a group or person with

negative social or psychological characteristics. Stigmatisation of carriers within the community is one

concern that has been described, for example, with regard to the orthodox Jewish premarital screening

programme Dor Yeshorim (Raz and Vizner 2008; De Wert 2012). Moreover, some genetic diseases

are more prevalent in certain ethnic groups. Therefore members of a particular group or subpopulation

may be or feel stigmatized or discriminated against as a result of carrier status information. Recent

studies revealed no predominant feelings of discrimination or social stigma among carriers. In the

1970s, however, screening programmes for sickle cell disease were developed to reduce the frequency

of sickle cell disease. At that time, no simple prenatal diagnostic technique was available for couples

at risk. Absence of public education and pre-test counseling led to misunderstanding of carrier status,

fear and widespread discrimination and stigmatisation of African-American carriers was experienced,

and insurance companies denied signing sickle cell carriers health and life insurance contracts (Markel

1992). Similar findings have been reported from other screening programmes in the early days of

screening (Kenen & Schmidt, 1978).


One way to avoid social stigma may be to provide community education and public campaigns and

more extensive pre- and post-test counseling. Moreover, with the introduction of expanded carrier

screening stigmatisation might be reduced as one can offer screening as a more “universal test” instead

of targeted screening aimed at a particular subpopulation. Alternatively, addressing the whole

population for screening but using a decisional aid to determine risk of disease, and thus eligibility for

testing as a selection from particular disorders, based on ancestral background might be used to avoid

stigma (Lakeman 2006), especially if almost any couple would be eligible for some form of testing.

Worries about possible detrimental effects of carrier screening also include confidentiality of test-

results and genetic discrimination by insurers, fear of undue pressure on individual choice (Godard

2003) in particular in socially tight communities (Wert 2012) or high schools (‘peer-pressure’), but

also concern that carrier detection devalues the lives of affected patients or impedes the search for a

cure. It is not clear whether the (fear of) these effects are magnified with expanded carrier screening.

False reassurance among non-carriers. For people who are found to not carry a disease allele after

screening, it is important that the different aspects of screening are well understood. A negative

(favourable) carrier test-result, received by the majority of those screened, may result in relief among

participants. Previous studies have demonstrated that this may, however, also result in a false sense of

security (false reassurance), as a considerable number of people who receive a screen-negative result

mistakenly believe that they are definitely not carriers (see e.g. Axworthy 1996; Henneman 2002). As

most carrier screening tests still convey a small residual risk - mostly due to incomplete sensitivity of

the test - after a favourable test result these couples may thus be confronted with the unexpected birth

of a child with the disease. Furthermore, many pregnancy risks other than recessive diseases have not

been included. Health care professionals thus need to address potential misperceptions that expanded

carrier screening can guarantee a healthy child.

Box: Summary

- Currently the commercial offer of expanded carrier testing is of limited clinical validity,


especially in the pan-ethnic context. Lists of disorders include also diseases that are not

relevant for reproductive decisions, which is considered the primary purpose of carrier

screening. Carrier screening may reveal clinically relevant disease risk for a potential

carrier.

- Generally there is no lasting negative effect of carrier status on anxiety, self-concept or

stigma, although a negative (favourable) screening result may induce false reassurance.

CONCLUSION AND RECOMMENDATIONS

By summarizing the knowledge gained from decades of population-based carrier screening, the aim of

this paper was to contribute to the public and professional discussion on expanded carrier screening, in

order to develop better clinical and laboratory practice guidelines, and to provide recommendations for

health care professionals and health authorities.

Carrier screening is defined as the detection of carrier status in individuals or couples, who do not

have an a priori increased risk for having a child with a certain disease, whereas with carrier testing,

the persons do have a higher a priori risk based on their or their partners’ personal or family history.

Carrier screening can be offered on an individual basis, but also as an organized screening program,

either during or before pregnancy. The introduction of new technologies, such as next generation

sequencing, provides opportunities for expanded carrier screening panels. In order to minimize

potential adverse psychosocial impact of preconception carrier tests and ensure their good quality, it

has been advised that such tests should be provided within the traditional health care system, and if not

possible, companies offering such tests should comply with quality control and information standards

equivalent to those applying to healthcare services (Fears 2013). Studies on financial aspects of

introduction of expanded carrier screening into the public health system are needed. Alternatively,

new funding models facilitating participatory model (private payment of tests) and access to high

quality public sector facilities might be explored.


As we have shown, carrier screening for single gene disorders is not new, however the scale of it

augments with expanded carrier screening. Expanded carrier screening panels offer the possibility to

screen for many more conditions, genes and mutations at affordable costs than the current screening

panels that are focused on a limited number of recessive conditions associated with significant

morbidity and reduced life-expectancy. This paper led to the identification of further research

possibilities and future policy which have been summarized in the following recommendations.

1. Primary purpose of carrier screening: The primary objective of carrier screening in

couples without a known family risk of recessive disorders should be awareness of the

individuals or couples for possible genetic disease risks in future offspring and of

reproductive options available in order to provide autonomous choices.

2. Expanded carrier screening: In line with the primary purpose, carrier screening panels

should be focused on (a comprehensive set of) severe childhood-onset disorders taking into

account clinical utility of the test. Test should be designed to achieve high clinical validity

(clinical sensitivity, negative and positive predictive values). The main focus should be on

reporting of mutations that are clearly pathogenic (clear clinical significance). At this time,

targeted genetic testing and analyses approaches are recommended.

3. Evidence: A solid evidence-based approach and follow up is necessary before initiating

carrier screening. This includes evidence about the understanding of the significance of the

screened mutations; information about the sensitivity and specificity of the tests;

information about the immediate and downstream costs related to the test and screening

offer; and information with regard to the psychological and social impact of a carrier

screening offer, as well as knowledge on the public acceptability of carrier screening. More

research on rare cases where carriers are affected themselves is needed.

4. Timing of carrier screening: Considering the primary aim, expanded carrier screening

should be offered preferentially in a preconception phase as this has the advantage that it


provides less time constraints, less pressure and less emotional distress than when a test is

performed during pregnancy.

5. Reproductive decision-making: As the primary objective is to strengthen reproductive

choices and decision-making of couples, the effectiveness of carrier screening programs

should be measured by assessing informed choice and not on a reduced birth rate of affected

children.

6. Informed consent: Pre-test information and post-test information and counseling has to be

an integral part of the carrier screening offer. Considering the fact that this offer is to be

provided to individuals with an initial low risk and limited awareness of the disorders

screened for, it is important to inform the public properly about these disorders, and the

issues related to the screening, including the purpose of testing, testing methods and their

reliability, the implications of both “positive” (unfavourable) and “negative” test results,

including residual risks and the alternative reproductive options, to the individual and

his/her near relatives, as well as the freedom to choose to participate. This may be achieved

using different methods, according to the individual needs of the screenee or couple,

including media, leaflets and programs in schools. Individual pre-test genetic counseling

should be made available for those who request it. In the context of screening for multiple

genetic disorders, new models of informed consent should be explored (e.g. generic consent)

in order to allow couples to be informed about the goal and concept of carrier screening,

without having to explain every disorder to be screened for individually. Potential clinical

consequences in heterozygous carriers should be adequately covered in the provision of

genetic information and in the informed consent before testing.

7. Voluntary participation: To facilitate autonomous choice, carrier screening should be

voluntary, with equal access of services, and avoiding risk of social pressure. The choice for

screening should be based on knowledge (of the benefits, disadvantages, and limitations of

testing), personal views and values, with sufficient time to decide.


8. Information and support: Attention should be given to psychological, social and

counseling-related aspects as more couples and intermediate risk couples (one partner tests

positive while the other tests negative) are detected with expanded carrier screening;

psychosocial support and pre-and posttest information should be available (with test-results

provided in a timely and sensitive manner). Post-test genetic counseling should be available

(and offered) to couples at increased risk for tested genetic disorder/s.

9. Quality of services: Genetic testing as well as provision of genetic information and

counseling should be provided by accredited institutions and appropriately trained

professionals.

10. Provision of care: Safeguards should ensure continuous quality of care for children born

with disease. If free reproductive informed decision making is the goal of carrier screening,

this is a prerequisite. In some cases, carrier screening could also contribute to the

identification of disorders that might lead to early therapeutic procedures in affected

offspring. This information should be adequately presented to the potential tested person.

11. Professionals and public education and dialogue: Attention should be paid to the

particular education and training needs of the potential health care professionals involved in

the provision of carrier screening, as well as the strengthening of public understanding on

genetics and carrier screening, including the benefits and limitations. The perception of the

harm and benefits of screening is very different among different stakeholders. For this

reason, it is important to have an open dialogue about the expected medical and social

benefits with all stakeholders, including patients and their representatives and the general

public. This would enable key frameworks to be developed, support decision making in

relation to the conditions for which screening could be offered.

CONFLICT OF INTEREST


Several of the authors are employed by university hospitals that perform carrier testing and/or

screening. The employer of LH, MC, CvE […]

ACKNOWLEDGEMENTS

This research was supported by the Netherlands Organisation for Health Research and Development

(ZonMw grant no. ) (LH), Clinical Research Fund UZ Ghent (SJ, DC) and the Research Fund Flanders

(PB). […]

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