Population Screening for Reproductive Risk for Single Gene Disorders in Australia: Now and the Future

Martin B. Delatycki1,2 1 Bruce Lefroy Centre for Genetic Health Research, Murdoch Childrens Research Institute, Australia 2 Genetic Health Services Victoria, Australia

s the results of the Human Genome Project are Carrier testing programs for genetic disorders began Arealized, it has become technically possible to formally in the early 1970s for Tay Sachs disease (TSD) identify carriers of numerous autosomal and X-linked by measurement of serum hexoseaminidase A (Kaback recessive disorders. Couples at risk of having a child et al., 1997). This was followed by carrier screening with one of these conditions have a number of repro- programs for β thalassaemia by measurement of mean ductive options to avoid having a child with the corpuscular volume and haemoglobin electrophoresis condition should they wish. In Australia the haemo- (Davies et al., 2000). This highlights the fact that globinopathies are the only group of conditions for genetic screening is not always by DNA testing. Indeed which population screening is widely offered and the genetic basis of TSD and β thalassaemia only which is government funded. In some Australian became known some years after screening programs states there are also population screening programs were introduced. If both members of a couple are carri- for and autosomal recessive conditions ers of the same autosomal recessive condition or a more common in Ashkenazi Jewish individuals which woman is a carrier of an X-linked condition there is a 1 are generally offered on a user pays basis. It is pre- in 4 (25%) chance of having a child with the condition. dicted that as consumer demand increases and The most often cited rationale for carrier screening testing becomes cheaper, that many people planning is to offer couples reproductive choice by identifying or in the early stages of pregnancy will have carrier those who are at high risk of having a child with a screening for multiple genetic conditions. This will genetic condition (Davies et al., 2000). The reduction have significant implications for genetic counseling, in incidence of genetic conditions through prenatal laboratory and prenatal testing resources. In addition diagnosis and pregnancy termination as well as preim- such screening raises a number of ethical issues plantation genetic diagnosis is often used to measure including the value of lives of those born with genetic conditions for which screening is available. the success of carrier screening (Marteau & Anionwu, 1996). Indeed if few couples identified by screening as Keywords: screening, carrier, cystic fibrosis, thalassaemia, being at high risk of having a child with a particular Tay Sachs disease genetic condition acted on the information, screening programs could not be justified on economic grounds (Haddow, 1997; Zeuner, 1997). Similarly, the uptake There are more than 2,000 autosomal, X-linked and of screening, whilst often used to measure the success mitochondrial disorders whose genetic basis is known of a program, is only one measure by which the value (McKusick, 2008). It is theoretically possible to offer of a program should be assessed (European Society testing for heterozygous status (so called of Human Genetics, 2003). Other important aspects carrier testing) for all autosomal recessive and X- to assess the success of programs are the level of linked disorders whose genetic basis is known and informed consent among those screened and those therefore to provide advice about the risk of any declining screening, the proportion of the target popu- couple having a child affected by these conditions. In lation offered screening, harms in those screened and reality it is only practical to offer population genetic economic outcomes (European Society of Human screening for few conditions largely because of the Genetics, 2003). cost of identifying carriers, the length of time it takes to do testing and the rarity of most genetic disorders in any community. Population screening refers to Received 27 April, 2008; accepted 7 May 2008. testing for carrier status in individuals who are not at Address for correspondence: Associate Professor Martin Delatycki, increased risk of being a carrier because of a family 10th Floor, Royal Children’s Hospital, Flemington Road, Parkville, history of the condition. 3052, Victoria, Australia. E-mail: [email protected]

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(Barlow-Stewart et al., 2003; Gason et al., 2005). These Table 1 will therefore be discussed in some detail. Reproductive Options Available to Couples Where Both are Carriers of the Same Autosomal Recessive Condition or the Female is a Carrier of Haemoglobinopathies an X-linked Condition The haemoglobinopathies are a group of autosomal Reproductive option Nonpregnant Pregnant recessive conditions that affect the function of haemo- Prenatal testing with pregnancy Yes Yes globin. They are the most common global recessive termination of affected fetuses conditions with about 270 million people (4.5% of the Pre-implantation genetic diagnosis Yes No world’s population) being carriers and at least 300,000 Donor gamete or embryo Yes No individuals are born each year who are affected by one Adoption Yes No of the haemoglobinopathies (Angastiniotis & Modell, Note: The pregnancy status refers to whether the female is pregnant at the time the 1998). Haemoglobinopathies can be divided into struc- couple’s carrier status is identified and whether the specific reproductive option tural variants, the commonest of which is sickle cell is available for that pregnancy. disease, and those that have quantitative effects on haemoglobin chains. The quantitative haemoglo- Couples may wish to know their carrier status to binopathies are the thalassaemias: the globin proteins be prepared for the birth of a child with a genetic are structurally normal but there are insufficient α- or condition or to avoid having a child affected by the β-globin chains (Old, 2007). condition. Couples at high risk have a number of The two main forms of thalassaemia, α and β, reproductive options to enable them to avoid having a result from in the α- and β-globin genes, child affected by the condition. These are outlined in respectively. The genetics of α-thalassaemia is compli- Table 1. cated by the fact that there are four rather than two α-globin genes. Thalassaemia is most common in Criteria for the Introduction people from Mediterranean countries, including the of Carrier Screening Middle East, India, Africa and south-east Asia (Davies The decision to offer population carrier screening for et al., 2000). a genetic condition is generally arrived at because the β thalassaemia major results in chronic anaemia condition fulfils a number of criteria. The basic prin- requiring regular blood transfusions and iron chela- ciples of population screening were developed by tion therapy (Birgens & Ljung, 2007). Because there Wilson and Junger in 1968 (Wilson & Junger, 1968). are four α-globin genes, an individual may have 0–4 A significant recent addition to the principles of popu- functioning α-globin genes. If a fetus has no func- lation screening is that appropriate education should tional α-globin genes, they will have haemoglobin be provided so that individuals can make informed Bart’s hydrops fetalis syndrome and will usually not decisions about having testing and that the individ- survive (Birgens & Ljung, 2007). The presence of a ual’s decision is respected and they are protected from single functional α-globin gene results in haemoglobin stigmatisation and discrimination (Andermann et al., H disease and may require regular blood transfusions 2008). The principles of population genetic screening and iron chelation if the affected individual has a are listed in Table 2. moderately severe haemolytic condition. Individuals with two or three functional α-globin genes are Cascade Testing healthy carriers of α-thalassaemia. Their partner Cascade testing refers to testing for carrier status of relatives of individuals with a genetic condition or where an individual is identified as a carrier of such a condition (Barlow-Stewart et al., 2007). The rationale Table 2 is that genetic relatives are at much higher than back- The Principles of Population Genetic Screening (Khoury et al., 2003; ground risk of being a carrier of a genetic condition in Wilson & Junger, 1968) their family. If the causative mutation(s) is known in Principle the family, carrier testing is available and can be 1 It screens for an important problem offered to relatives irrespective of the population fre- 2 There is acceptable treatment quency of the condition. 3 There are facilities for diagnosis and treatment Population Genetic Screening in Australia 4 There is a recognized latent or early symptomatic stage 5 The natural history is understood Population genetic carrier screening is widely conducted 6 There is a suitable test acceptable to population in Australia for haemoglobinopathies (Metcalfe et al., 2007). Population screening is offered in some places 7 There is an agreed policy on who to treat for cystic fibrosis (Barlow-Stewart et al., 2003; Christie 8 The cost of case finding is balanced against total expenditure et al., 2006; Massie et al., 2005) and autosomal reces- 9 There is a continuous process of case finding sive conditions more common among Ashkenazi 10 Appropriate education should be provided

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should be offered DNA testing to ascertain if they are of Medical Genetics recommend that mutations which a carrier of α-thalassaemia. occur with a frequency of greater than 0.1% in the CF In considering screening for thalassaemia, the prac- population should be tested meaning screening for 23 titioner should establish whether there is a family mutations is currently recommended in the USA history of a haemoglobinopathy, the ancestry of the (Watson et al., 2004). In Australia, current programs individual and arrange a full blood examination (FBE) vary in the mutations tested for. In the Hunter Region, (Old, 2007). Further testing is indicated when: NSW, screening is initially for p.F508del alone and if • there is a positive family history one member of a couple is found to carry this muta- tion, the other member of the couple is tested for a • the individual is from one of the high-risk ethnic panel of 28 other mutations (Christie et al., 2006). By groups contrast, in Victoria, 12 mutations are tested which • there is a low mean corpuscular volume (MCV) will identify about 83% of carriers (Massie et al., and/or mean corpuscular haemoglobin (MCH). 2005). Currently there is no government funding for Further testing includes haemoglobin electrophoresis, population screening for CF in Australia. iron studies and, if indicated, DNA studies (Old, 2007). In β-thalassaemia carriers (so-called β-thalas- Screening in the Ashkenazi Jewish Community saemia minor) the FBE generally shows a low MCV/ are those whose ancestors originated MCH and there are elevated levels of HbA2 in the in Eastern Europe. The majority of Jews in Australia haemoglobin electrophoresis. are Ashkenazim. There are a number of autosomal In carriers of α-thalassaemia haemoglobin electro- recessive conditions that are more common in this phoresis is normal (American College of Obstetricians community (Leib et al., 2005). These include Tay and Gynecologists, 2007). Therefore, specific genetic Sachs disease, , Niemann Pick disease testing should be carried out if a person has low type A, , Fanconi anaemia, familial MCV or MCH and/or is from one of the high-risk dysautonomia, mucolipidosis type IV and Gaucher ethnic groups to identify whether they are a carrier of disease (Table 3). In addition, CF occurs with about α-thalassaemia. the same frequency in Ashkenazi Jews as it does Thalassaemia screening is done in the majority of among the broader Caucasian community. Testing for pregnant women because the initial investigation is the most common mutations for all of these condi- an FBE, a test undertaken on most women early in tions is available to individuals of Ashkenazi Jewish pregnancy. Further testing with haemoglobin elec- ancestry and formal programs exist in Sydney (Burnett trophoresis and/or is carried out if the et al., 1995) and Melbourne (Gason et al., 2003). result of the FBE dictates that this is appropriate or Screening for Tay Sachs disease can be by mutation if the woman is from a high-risk ethnic background. detection or measurement of hexoseaminidase A. Both An FBE is done in pregnant women for a number of will identify > 97% of carriers (Bach et al., 2001). The reasons in addition to screening for thalassaemia enzymatic assay is technically more complex in preg- including assessing for anaemia. It is doubtful that nant women and can only be done on blood samples many women are aware they are screened for thalas- whereas the genetic test is the same irrespective of the saemia until they are found to be a carrier. individual’s pregnancy status and can be done on cheek cells as well as blood (Gason et al., 2005). Cystic Fibrosis The ultra-orthodox Jewish Community have devel- Cystic fibrosis (CF) is the commonest severe autosomal oped a unique program to meet their specific cultural recessive condition in childhood among Caucasian needs. The Dor Yeshorim program tests young people individuals. About 1 in 25 people from this ethnic for carrier status for nine conditions (Ekstein & background are carriers with about 1 in 2,500 being Katzenstein, 2001). The test result is not released to affected by the condition (Massie et al., 2000). CF the individual but rather they are issued with a per- results in affected individuals having some or all of sonal identification number (PIN). In this community suppurative lung disease, malabsorption, reduced fer- pregnancy termination is problematic and marriages tility, liver disease and meconium ileus and generally are generally arranged. The PINs of a prospective results in a significantly reduced life span. couple are presented to the central laboratory and CF results from mutations in the CFTR gene only if at least one of the couple is not a carrier for (Rommens et al., 1989). More than 1500 different each of the conditions does the marriage proceed. alterations have been identified in this gene (Cystic Screening for Gaucher disease is somewhat contro- Fibrosis Consortium, 2007). The p.F508del mutation versial. Although mutations that underlie Gaucher accounts for about 70% of mutations among disease are the commonest of the autosomal recessive Caucasians. Because so many different mutations can conditions amongst Ashkenazi Jews, only about one result in CF, screening programs test for the most third of individuals who are homozygous or com- common mutations in the community where the pound heterozygous for the commonest mutations program is being offered. The American College of have symptomatic disease (Beutler, 2006). In addition, Obstetricians and Gynecology and American College there is an effective, albeit expensive treatment,

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overcome, paving the way for the introduction of Table 3 widespread screening (Tassone et al., 2008). Screening Autosomal Recessive Disorders More Common in the Ashkenazi for fragile X syndrome has been undertaken for a Jewish Population, Mutation Frequencies and the Sensitivity number of years in (Berkenstadt et al., 2007) of Carrier Testing with an uptake of about 24% (Sher et al., 2003). Disease Carrier rate Test sensitivity A significant issue to consider related to popula- Gaucher disease 1 in 15 96% tion screening for fragile X syndrome carrier status is that individuals with an FMR1 premutation may Cystic fibrosis 1 in 25 97% develop the fragile X-associated tremor/ ataxia syn- Tay Sachs disease 1 in 28 98% drome (FXTAS) (Jacquemont et al., 2007). Features of 1 in 30 99% FXTAS include cognitive decline, tremor, ataxia and Canavan disease 1 in 40 98% autonomic dysfunction. FXTAS affects over 50% of Mucolipidosis type IV 1 in 80 95% male premutation carriers over the age of 70 years Fanconi anaemia 1 in 90 99% (Jacquemont et al., 2004) and about 8% of female Niemann-Pick disease type A 1 in 90 92% premutation carriers over 40 years (Coffey et al., Bloom syndrome 1 in 100 99% 2008). Population screening will identify women who will go on to develop this neurological syndrome and such screening is thus a form of presymptomatic enzyme replacement therapy, for those who are symp- testing. It is therefore important that woman are made tomatic (Brady, 2006). A study in Israel revealed that aware of this risk prior to screening. few couples identified as both being carriers of muta- tions that underlie Gaucher disease, choose prenatal Spinal muscular atrophy (SMA) is an autosomal reces- testing and pregnancy termination when an affected sive condition that affects about one in 10,000 fetus is identified (Zuckerman et al., 2007). An individuals meaning about one in 50 people are carri- accompanying editorial recommended against routine ers (Pearn, 1980). The most severe form referred to as screening for Gaucher disease (Beutler, 2007). type I SMA or Werdnig Hoffman disease, results in an Screening for Gaucher disease is not routinely offered infant having progressive muscle weakness, never by either of the two formal programs in Australia. being able to walk and results in death before two years. Almost all SMA is due to deletions involving Other Genetic Diseases for Which Screening the SMN gene (Lefebvre et al., 1995). Carriers can be is Possible diagnosed by dosage studies. There are complexities There are a number of other conditions that are con- with carrier testing due to the possibility of point sidered common enough that population genetic mutations that cannot be diagnosed by dosage studies screening is being considered. These include fragile X and the fact that people can have two normal SMN syndrome and spinal muscular atrophy. genes on one chromosome and none on the other Fragile X Syndrome (Ogino et al., 2004). In this situation, the individual is a carrier as they can pass on a chromosome with a Fragile X syndrome is the commonest inherited cause deleted SMN gene but dosage studies reveals two of intellectual disability with around one in 4,000 copies of the gene. The frequency of this occurrence males and one in 8000 females affected (Murray et al., has been studied enabling the residual risk to be cal- 1997). It is virtually always due to an expansion of a culated (Ogino et al., 2004). There are no studies CCG trinucleotide repeat at the 5’ end of the FMR1 reported in the literature of formal population screen- gene on the X-chromosome. About one in 150 females ing programs for SMA. carry a so called premutation meaning they are at risk of having a child with a full mutation (Berkenstadt et Timing of Testing al., 2007). Essentially all males and some females with a full mutation have intellectual disability often In theory, carrier testing can be done at any time from accompanied by severe behavioral problems with preimplantation onwards. In practice, such screening is generally offered in high school, pre-pregnancy or in autistic features being prominent (Reiss & Hall, early pregnancy. As discussed above, the first two of 2007). One of the challenges of offering population these result in more reproductive options being avail- genetic screening for fragile X syndrome is that identi- able than the third (Table 1). fying full mutations in a timely fashion has been technically difficult as Southern blotting is often High School Screening required. These technical issues can mean that provid- High school screening for Tay Sachs disease and thalas- ing pregnant women with a result in time to enable saemia have been offered since the mid-1970s in prenatal diagnosis and, if necessary, pregnancy termi- Montreal, Canada (Mitchell et al., 1996). High school nation, may not always be possible. New technology screening for Tay Sachs disease has more recently using a rapid polymerase chain reaction based screen- been introduced in Sydney (Burnett et al., 1995) and ing method may mean that these problems can be Melbourne (Gason et al., 2003). The advantage of this

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approach is that a large percentage of the population • perceived benefits — effectiveness of various actions can be offered education about screening and be in reducing disease threat or reducing anxiety offered screening with relative ease. In addition, stu- • perceived barriers — potential negative aspects of dents who are educated about screening have much the action. better knowledge at the time of screening than adults screened in other settings (Barlow-Stewart et al., 2003; A screening program should aim to have as many Gason et al., 2003; Gason et al., 2005; Mitchell et al., people as possible aware of the availability of screen- 1996). Concerns that individuals will forget their test ing so as to make an informed choice about having result by the time reproduction occurs have not gener- testing and remove as many barriers as possible. Given ally been borne out for carriers (Mitchell et al., 1996). the issues with each of the three major times for offer- Similarly, long term negative psychological sequelae are ing screening outlined above, it is appropriate to give rare. Critics nevertheless have raised concerns about individuals the opportunity for screening at a number whether high school students are sufficiently mature to of life stages and in a number of settings. provide fully informed consent for such screening (Frumkin & Zlotogora, 2008) and that peer pressure Evolution of a Screening Program: may result in individuals having screening when they A Case Study may otherwise not choose to do so (Ross, 2006). The Melbourne Tay Sachs Disease Prevention Program began in 1998. It has three main arms: (a) a high Prepregnancy school screening program where screening is free, (b) Prepregnancy adulthood is considered an ideal time for biannual community screening days where screening is testing (Frumkin & Zlotogora, 2008). At this time offered at a discount rate and (c) promotion of the individuals are often already in a relationship with a program through religious leaders and obstetricians. A person with whom they plan to have children. number of research studies have been done to gauge Therefore if one is found to be a carrier of a genetic the views of users and potential users with the results condition, the other can be quickly tested to define being used to improve the program (Gason et al., their risk of having a child with the condition in ques- 2003; Gason et al., 2005). For example, in the high tion. If both are carriers, all reproductive options are school program, where testing was initially through a open to them (Table 1). The practical barrier to screen- blood sample, a significant minority of students ing at this time is that individuals/ couples often do not wanted screening but did not have it due to needle consider screening until a pregnancy ensues. If screen- phobia. Testing was therefore changed to cheek brush ing is offered on a user-pays basis, such testing may not sampling. The uptake increased from 85% to 96% be a financial priority until a pregnancy occurs. (p < .0001). Testing packs were developed whereby the Pregnancy individual can self-administer the cheek swab test and Pregnancy is the time when screening is most com- post it to the laboratory, meaning they do not need to monly done. The reasons are that this may be that the attend a pathology collection facility. Major commu- first contact with a health professional does not occur nity awareness campaigns were conducted including until the woman is pregnant or that screening does not newspaper articles and flier distribution. Outside the become a priority until this time. In addition couples school program, awareness of the program has esca- may not believe they need to consider screening until lated and uptake is slowly increasing. pregnant. There are two major disadvantages to screening in pregnancy. The first is that the only Genetic Screening: Harms and Benefits option where a couple are both found to be carriers of It is very important that screening programs are cultur- a condition and wish to not have a child with that ally sensitive if they are to succeed. The introduction of condition, is to have prenatal diagnosis and termina- screening for carrier status of sickle cell disease in the tion of an affected pregnancy. Secondly, the couple United States in the 1970s resulted in discrimination often needs to make major decisions in a short space due to misunderstanding that being a carrier of this of time during a period that is often already emotion- disorder caused illness (Beutler et al., 1971). The Dor ally charged. Yeshorim program described above is an excellent The Health Belief Model example of where a community has designed a screen- ing program that is culturally acceptable and widely The Health Belief Model (HBM) was designed to utilized as a result (Ekstein & Katzenstein, 2001). explain the relationships between health beliefs and Carrier testing should have no implications for life health behavior (Sheeran & Abraham, 1996). The and disability insurance (health insurance is commu- HBM has four dimensions: nity rated in Australia meaning all pay the same rates • perceived susceptibility — subjective perception of irrespective of their health and family history). All risk of being a carrier/having a child with the con- individuals have heterozygous mutations, the majority dition in question of which have no implications for their health and • perceived severity — medical and social conse- some of which reduce the risk of disease such as the quences of the condition carrier status for haemoglobinopathies which reduce

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the risk of falciparum malaria. Nevertheless there is programs generally are, are less inclined to access some evidence that people are concerned about the information than people at higher risk such as those insurance implications of being identified as a carrier with disease symptoms or those with a family history. by population screening (Quinlivan & Suriadi, 2006; It is nevertheless critical that individuals have access to Williams & Schutte, 1997). accurate unbiased information upon which to base A number of studies have examined the psycholog- screening decisions. A review of brochures related to ical impact of being identified as a carrier. In general CF carrier screening in the USA and UK found signifi- these studies have found minimal impact from this cant variability in the information presented including in cystic fibrosis (Denayer et al., 1996; Gordon et al., how the condition was portrayed (positive, neutral and 2003; Marteau et al., 1997) and Tay Sachs disease negative statements) and whether or not termination of (Childs et al., 1976; Mitchell et al., 1996). The anxiety pregnancy is discussed (Loeben et al., 1998). However, levels are generally higher when carriers are identified people cannot be forced to access education and it in pregnancy than when not pregnant. Unsurprisingly, must be accepted that many will be screened or refuse anxiety is highest when both members of a couple screening without being fully informed. are found to be carriers particularly if the female is pregnant. There is a negative correlation between Health Economic Considerations knowledge level and anxiety of those screened. That As noted above, screening criteria state that for a is, those who are more knowledgable about screening screening program to be introduced, it needs to be cost and the condition being screened for are less anxious effective (Wilson & Junger, 1968). It is generally agreed about the prospect of being found to be a carrier than that economic considerations should not be the ultimate those less knowledgable (Gason et al., 2005). Concerns have been raised that by offering screen- arbiter of whether screening programs for a condition ing for carrier status with the option of carrier couples should be introduced, but nevertheless economic con- utilizing technology to prevent the birth of children siderations are important in deciding whether or not to with specific genetic disorders, that the value of the introduce a program. Governments are unlikely to fund lives of those with genetic disorders is diminished programs that are not cost effective. (Knoppers et al., 2006). Indeed there is evidence that A review of the literature regarding economic eval- where children are born with Down syndrome in the uation of CF screening found much heterogeneity in current era of widespread screening, that some parents study design, modeling and reporting (Radhakrishnan are questioned about why the condition wasn’t picked et al., 2008). Nevertheless, the majority of studies up in pregnancy and the birth of the child prevented reported that the cost of a screening program is less (Marteau & Drake, 1995). Others believe that it is than the potential healthcare costs averted through the possible for society to both accept prevention of birth of fewer individuals with CF. This was by no genetic conditions and respect and care for those with means universal, however. One study compared CF disabilities. It has also been argued that when some screening to other established screening programs, individuals choose to use preventive reproductive tech- including newborn screening for PKU and mammogra- nologies, more resources are available for those in phy, and concluded that CF screening represents good society with disabilities (Soini et al., 2006). value for money by comparison (Rowley et al., 1998). There are fewer economic data for TSD screening Is Informed Consent Always Possible? (Nelson et al., 1978; Warren et al., 2005). The cost of As noted above, it is considered essential that individu- screening for TSD is similar to CF screening but the als are given sufficient information upon which to lifetime medical costs of a child with TSD is consider- base an informed decision on whether or not to have ably less than for an individual with CF (Warren et al., screening (Andermann et al., 2008). How informed is 2005). Nevertheless an argument has been mounted decision making in screening? In high school screening that the emotional (to the family) and physical (to the programs where students are exposed to detailed edu- affected child) costs are greater for TSD than CF and cation by oral or CD ROM education, knowledge this makes the value of preventing the birth of child levels are very high and consent, at least in terms of with TSD much higher than preventing the birth of a knowledge, is generally well informed (Gason et al., child with CF (Warren et al., 2005). 2005). Where education is by brochure with or with- Studies have consistently shown screening for out information from a health practitioner, knowledge haemoglobinopathy carrier status to be cost effective levels are generally lower (Gordon et al., 2003; Mennie (Cronin et al., 2000; Ostrowsky et al., 1985). et al., 1997). It is common for individuals to prefer to There are limited economic data for single gene obtain detailed knowledge only if they are found to reproductive screening in Australia and such data are be a carrier of the condition being tested for. In addi- very important to inform government decisions tion as more conditions become available for carrier regarding funding screening programs. Calls have testing the challenge of providing sufficient informa- been made to collect such data and indeed, a health tion becomes even more demanding (Chadwick et al., economic evaluation of CF screening in Australia is 1998). People at low risk, as participants in screening currently underway (Radhakrishnan et al., 2008).

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The Future tion: DNA testing is the preferred procedure. American Journal of Medical Genetics, 99, 70–75. Genetic screening for reproductive risk is largely in its infancy in Australia. The only single gene disorders Barlow-Stewart, K., Burnett, L., Proos, A., Howell, V., for which screening is government funded are the Huq, F., Lazarus, R., & Aizenberg, H. (2003). A haemoglobinopathies. Other programs have been set genetic screening programme for Tay-Sachs disease up by individuals interested in providing couples and cystic fibrosis for Australian Jewish high school with more options. Peak bodies including the Royal students. Journal of Medical Genetics, 40, e45. Australian and New Zealand College of Obstetrics Barlow-Stewart, K., Gaff, C., Emery, J., & Metcalfe, S. A. and Gynaecology and the Human Genetics Society of (2007). Family genetics. Australian Family Physician, Australasia do not have policies regarding when and 36, 802–805. for which single gene disorders screening should be Berkenstadt, M., Ries-Levavi, L., Cuckle, H., Peleg, L., & offered. These bodies need to take the lead in this Barkai, G. (2007). Preconceptional and prenatal area as governments are unlikely to fund screening screening for fragile X syndrome: experience with unless the leaders in these fields make recommenda- 40,000 tests. Prenatal Diagnosis, 27, 991–994. tions that screening should be offered and in the Beutler, E. (2006). Gaucher disease: Multiple lessons from interests of equity that it is freely available to all. a single gene disorder. Acta Paediatrica, 95(Suppl.), The laboratory costs of screening have decreased 103–109. rapidly and are likely to continue to do so as technol- ogy improves. In addition, it is likely that there will be Beutler, E. (2007). Carrier screening for Gaucher disease: increased consumer demand for testing. In Israel for More harm than good? Journal of the American Medical example, where screening for Tay Sachs disease has Association, 298, 1329–1331. been widely taken up since the 1970s, screening for up Beutler, E., Boggs, D. R., Heller, P., Maurer, A., Motulsky, to 14 conditions is commonly requested (Professor E A. G., & Sheehy, T. W. (1971). Hazards of indiscrimi- Levy-Lahad, pers. comm.). Apart from the test for Tay nate screening for sickling. New England Journal of Sachs disease which is government funded, individuals Medicine, 285, 1485–1486. pay for testing. The more conditions that are screened Birgens, H., & Ljung, R. (2007). The thalassaemia syn- for the more carriers that will be identified. Funding dromes. Scandinavian Journal of Clinical and Laboratory for genetic counseling of carriers and prenatal testing Investigation, 67, 11–25. for carrier couples therefore needs to be included in costing whether programs are funded by payment by Brady, R. O. (2006). Enzyme replacement for lysosomal those tested or by government. diseases. Annual Review of Medicine, 57, 283–296. It is possible that in the not too distant future, Burnett, L., Proos, A. L., Chesher, D., Howell, V. M., screening will be cheap enough to test for carrier status Longo, L., Tedeschi, V., Yang, V. A., Siafakas, N., & for over 100 single gene autosomal and X-linked dis- Turner, G. (1995). The Tay-Sachs disease prevention orders. Pre-test knowledge of all conditions will be program in Australia: Sydney pilot study. Medical essentially impossible making post-test counseling Journal of Australia, 163, 298–300. of carriers of even greater importance (Chadwick et Chadwick, R., ten Have, H., Husted, J., Levitt, M., al., 1998). McGleenan, T., Shickle, D., & Wiesing, U. (1998). Genetic screening and ethics: European perspectives. Acknowledgments Journal of Medicine and Philosophy, 23, 255–273. Martin Delatycki is a National Health and Medical Childs, B., Gordis, L., Kaback, M..M., & Kazazian, H. Research Council Practitioner Fellow. H., Jr. (1976). Tay-Sachs screening: Social and psycho- logical impact. American Journal of Human Genetics, References 28, 550–558. American College of Obstetricians and Gynecologists. Christie, L. M., Zilliacus, E. M., Ingrey, A. J., & Turner, (2007). ACOG Practice Bulletin No. 78: Hemoglobino- G. (2006). Screening couples for cystic fibrosis carrier pathies in pregnancy. Obstetrics and Gynecology, 109, status: Why are we waiting? Medical Journal of 229–237. Australian, 184, 477. Andermann, A., Blancquaert, I., Beauchamp, S., & Dery, Coffey, S. M., Cook, K., Tartaglia, N., Tassone, F., V. (2008). Revisiting Wilson and Junger in the Nguyen, D. V., Pan, R., Bronsky, H. E., Yuhas, J., genomic era: A review of screening criteria over the Borodyanskaya, M., Grigsby, J., Doerflinger, M., past 40 years. Bulletin of the World Health Organiza- Hagerman, P. J., & Hagerman, R. J. (2008). Expanded tion, 86, 317–319. clinical phenotype of women with the FMR1 premuta- Angastiniotis, M., & Modell, B. (1998). Global epidemi- tion. American Journal of Medical Genetics, 146, ology of hemoglobin disorders. Annals of the New 1009–1016. York Academy of Sciences, 850, 251–269. Cronin, E. K., Normand, C., Henthorn, J. S., Graham, V., Bach, G., Tomczak, J., Risch, N., & Ekstein, J. (2001). & Davies, S. C. (2000). Organisation and cost-effec- Tay-Sachs screening in the Jewish Ashkenazi popula- tiveness of antenatal haemoglobinopathy screening

428 Twin Research and Human Genetics August 2008 Downloaded from https://www.cambridge.org/core. IP address: 170.106.33.42, on 01 Oct 2021 at 12:06:06, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1375/twin.11.4.422 Reproductive Screening for Single Gene Disorders

and follow up in a community-based programme. Kaback, M., Nathan, T., & Greenwald, S. (1997). Tay- British Journal of Obstetrics and Gynaecology, 107, Sachs disease: heterozygote screening and prenatal 486–491. diagnosis. U.S. experience and world perspective. In M. Kaback (Ed.), Tay-Sachs Disease, Screening and Cystic Fibrosis Consortium. (2007). Cystic fibrosis muta- Prevention (pp. 13–36). New York: Alan R. Liss. tion database statistics. Retrieved from http://www. genet.sickkids.on.ca/cftr/StatisticsPage.html Khoury, M. J., McCabe, L. L., & McCabe, E. R. (2003). Population screening in the age of genomic medicine. Davies, S. C., Cronin, E., Gill, M., Greengross, P., New England Journal of Medicine, 348, 50–58. Hickman, M., & Normand, C. (2000). Screening for sickle cell disease and thalassaemia: A systematic review Knoppers, B. M., Bordet, S., & Isasi, R. M. (2006). with supplementary research. Health Technology Preimplantation genetic diagnosis: An overview of Assessment, 4, 1–99. socio-ethical and legal considerations. Annual Review of Genomics and Human Genetics, 7, 201–221. Denayer, L., Welkenhuysen, M., Evers-Kiebooms, G., Cassiman, J. J., Van den Berghe, H. (1996). The CF Lefebvre, S., Burglen, L., Reboullet, S., Clermont, O., carrier status is not associated with a diminished self- Burlet, P., Viollet, L., Benichou, B., Cruaud, C., concept or increased anxiety: Results of psychometric Millasseau, P., Zeviani, M., Le Paslier, D., Frézal, J., testing after at least 1 year. Clinical Genetics, 49, Cohen, D., Weissenbach, J., Munnich, A., & Melki, J. 232–236. (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell, 80, 155–165. Ekstein, J., & Katzenstein, H. (2001). The Dor Yeshorim Leib, J. R., Gollust, S. E., Hull, S. C., & Wilfond, B. S. story: community-based carrier screening for Tay- (2005). Carrier screening panels for Ashkenazi Jews: is Sachs disease. Advances in Genetics, 44, 297–310. more better? Genetics in Medicine, 7,185–190. European Society of Human Genetics. (2003). Population Loeben, G. L., Marteau, T. M., & Wilfond, B. S. (1998). genetic screening programmes: Technical, social and Mixed messages: Presentation of information in cystic ethical issues. European Journal of Human Genetics, fibrosis-screening pamphlets. American Journal of 11, 903–905. Human Genetics, 63, 1181–1189. Frumkin, A., & Zlotogora, J. (2008). Genetic screening for Marteau, T., & Anionwu, E. (1996). Evaluating carrier reproductive purposes at school: Is it a good strategy? testing: objectives and outcomes. In T. Marteau & M. American Journal of Medical Genetics, 146, 264–269. Richards (Eds.), The troubled helix: Social and psycho- Gason, A. A., Metcalfe, S. A., Delatycki, M. B., Petrou, logical implications of the new human genetics. (pp. V., Sheffield, E., Bankier, A., & Aitken, M. (2005). 123–139). Cambridge: Cambridge University Press. Tay Sachs disease carrier screening in schools: Educa- Marteau, T. M., & Drake, H. (1995). Attributions for tional alternatives and cheekbrush sampling. Genetics disability: The influence of genetic screening. Social in Medicine, 7, 626–632. Science and Medicine, 40, 1127–1132. Gason, A. A., Sheffield, E., Bankier, A., Aitken, M. A., Marteau, T. M., Dundas, R., & Axworthy, D. (1997). Metcalfe, S., Barlow-Stewart, K., & Delatycki, M. B. Long-term cognitive and emotional impact of genetic (2003). Evaluation of a Tay-Sachs disease screening testing for carriers of cystic fibrosis: The effects of test program. Clinical Genetics, 63, 386–392. result and gender. Health Psychology, 16, 51–62. Gordon, C., Walpole, I., Zubrick, S. R., & Bower, C. Massie, R. J., Delatycki, M. B., & Bankier, A. (2005). (2003). Population screening for cystic fibrosis: Screening couples for cystic fibrosis carrier status: Knowledge and emotional consequences 18 months Why are we waiting? Medical Journal of Australia, later. American Journal of Medical Genetics, 120, 183, 501–502. 199–208. Massie, R. J., Olsen, M., Glazner, J., Robertson, C. F., & Haddow, J. E. (1997). Why the term ‘carrier screening’ Francis, I. (2000). Newborn screening for cystic fibro- should be abandoned. Journal of Medical Screening, sis in Victoria: 10 years’ experience (1989–1998). 4, 1. Medical Journal of Australia, 172, 584–587. Jacquemont, S., Hagerman, R. J., Hagerman, P. J., Leehey, McKusick, V. (2008). Online in M. A. (2007). Fragile-X syndrome and fragile X-asso- Man. Available at http://www.ncbi.nlm.nih.gov/sites/ ciated tremor/ataxia syndrome: two faces of FMR1. entrez?db=omim Lancet Neurology, 6, 45–55. Mennie, M. E., Axworthy, D., Liston, W. A., & Brock, D. Jacquemont, S., Hagerman, R. J., Leehey, M. A., Hall, D. J. (1997). Prenatal screening for cystic fibrosis carri- A., Levine, R. A., Brunberg, J. A., Zhang, L., Jardini, ers: does the method of testing affect the longer-term T., Gane, L. W., Harris, S. W., Herman, K., Grigsby, understanding and reproductive behaviour of women? J., Greco, C. M., Berry-Kravis, E., Tassone, F., & Prenatal Diagnosis, 17, 853–860. Hagerman, P. J. (2004). Penetrance of the fragile X- Metcalfe, S. A., Barlow-Stewart, K., Campbell, J., & associated tremor/ataxia syndrome in a premutation Emery, J. (2007). Genetics and blood: Haemoglobino- carrier population. Journal of the Americal Medical pathies and clotting disorders. Australian Family Association, 291, 460–469. Physician, 36, 812–819.

Twin Research and Human Genetics August 2008 429 Downloaded from https://www.cambridge.org/core. IP address: 170.106.33.42, on 01 Oct 2021 at 12:06:06, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.1375/twin.11.4.422 Martin B. Delatycki

Mitchell, J. J., Capua, A., Clow, C., & Scriver, C. R. Sheeran, P., & Abraham, C. (1996). The health belief (1996). Twenty-year outcome analysis of genetic model. In M. Connor PN (Ed.). Predicting health screening programs for Tay-Sachs and beta-tha- behaviour: Research and practice with social cognitions lassemia disease carriers in high schools. American models (pp. 23–61). Buckingham: Oxford University Journal of Human Genetics, 59, 793–798. Press. Murray, J., Cuckle, H., Taylor, G., & Hewison, J. (1997). Sher, C., Romano-Zelekha, O., Green, M. S., & Shohat, Screening for fragile X syndrome: information needs T. (2003). Factors affecting performance of prenatal for health planners. Journal of Medical Screening, 4, genetic testing by Israeli Jewish women. American 60–94. Journal of Medical Genetics, 120, 418–422. Nelson, W. B., Swint, J. M., & Caskey, C. T. (1978). An Soini, S., Ibarreta, D., Anastasiadou, V., Ayme, S., Braga, economic evaluation of a genetic screening program S., Cornel, M., Coviello, D. A., Evers-Kiebooms, G., for Tay-Sachs disease. American Journal of Human Geraedts, J., Gianaroli, L., Harper, J., Kosztolanyi, G., Genetics, 30, 160–166. Lundin, K., Rodrigues-Cerezo, E., Sermon, K., Ogino, S., Wilson, R.B., & Gold, B. (2004). New insights Sequeiros, J., Tranebjaerg, L., & Kaariainen, H. on the evolution of the SMN1 and SMN2 region: sim- (2006). The interface between assisted reproductive ulation and meta-analysis for allele and haplotype technologies and genetics: Technical, social, ethical and frequency calculations. European Journal of Human legal issues. European Journal of Human Genetics, 14, Genetics, 12, 1015–1023. 588–645. Old, J. M. (2007). Screening and genetic diagnosis of Tassone, F., Pan, R., Amiri, K., Taylor, A. K., & haemoglobinopathies. Scandinavian Journal of Clinical Hagerman, P. J. (2008). A rapid polymerase chain and Laboratory Investigation, 67, 71–86. reaction-based screening method for identification of Ostrowsky, J. T., Lippman, A., & Scriver, C. R. (1985). all expanded alleles of the fragile X (FMR1) gene in Cost-benefit analysis of a thalassemia disease preven- newborn and high-risk populations. Journal of tion program. American Journal of Public Health, 75, Molecular Diagnostics, 10, 43–49. 732–736. Warren, E., Anderson, R., Proos, A. L., Burnett, L. B., Pearn, J. (1980). Classification of spinal muscular atro- Barlow-Stewart, K., & Hall, J. (2005). Cost-effective- phies. Lancet, 1, 919–922. ness of a school-based Tay-Sachs and cystic fibrosis genetic carrier screening program. Genetics in Quinlivan, J. A., & Suriadi, C. (2006). Attitudes of new Medicine, 7, 484–494. mothers towards genetics and newborn screening. Journal of Psychosomatic Obstetrics and Gynaecology, Watson, M. S., Cutting, G. R., Desnick, R. J., Driscoll, D. 27, 67–72. A., Klinger, K., Mennuti, M., Palomaki, G. E., Popovich, B. W., Pratt, V. M., Rohlfs, E. M., Strom, Radhakrishnan, M., van Gool, K., Hall, J., Delatycki, M., C. M., Richards, C. S., Witt, D. R., & Grody, W. W. & Massie, J. (2008). Economic evaluation of cystic (2004). Cystic fibrosis population carrier screening: fibrosis screening: A review of the literature. Health Policy, 85, 133–147. 2004 revision of American College of Medical Genetics mutation panel. Genetics in Medicine, 6, Reiss, A. L., & Hall, S. S. (2007). Fragile X syndrome: 387–391. assessment and treatment implications. Child and Adolescent Psychiatric Clinics of North America, 16, Williams, J. K., & Schutte, D. L. (1997). Benefits and 663–675. burdens of genetic carrier identification. Western Journal of Nursing Research, 19, 71–81. Rommens, J. M., Iannuzzi, M. C., Kerem, B., Drumm, M. L., Melmer, G., Dean, M., Rozmahel, R., Cole, J. L., Wilson, J., & Junger, G. (1968). The principles and prac- Kennedy, D., Hidaka, N., Zsiga, M., Buchwald, M., tice of screening for disease. In World Health Riordan, J. R., Tsui, L. C., & Collins, F. S. (1989). Organisation. Public Health Paper 34. Geneva: World Identification of the cystic fibrosis gene: Chromosome Health Organization. walking and jumping. Science, 245, 1059–1065. Zeuner, D. (1997). Why the term ‘carrier screening’ should Ross, L. F. (2006). Heterozygote carrier testing in high not be abandoned. Journal of Medical Screening, 4, schools abroad: What are the lessons for the U.S.? 176. Journal of Law, Medicine and Ethics, 34, 753–764. Zuckerman, S., Lahad, A., Shmueli, A., Zimran, A., Peleg, Rowley, P. T., Loader, S., & Kaplan, R. M. (1998). L., Orr-Urtreger, A., Levy-Lahad, E., & Sagi, M. Prenatal screening for cystic fibrosis carriers: an eco- (2007). Carrier screening for Gaucher disease: Lessons nomic evaluation. American Journal of Human for low-penetrance, treatable diseases. Journal of the Genetics, 63, 1160–1174. American Medical Association, 298, 1281–1290.

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