Appendix B

Case Studies of Other Carrier Screening Programs

Carrier screening programs have historically beenfocused within a particular group---e.g., Tay-Sachs amongAshkenazic Jews and sickle cell anemia among AfricanAmericans. With cystic fibrosis (CF), the potential targetpopulation is larger and less defined, which may intro-duce both technical and organizational complexity notpresent in past carrier screening. This appendix describespast carrier screening programs for Tay-Sachs, sickle cellanemia, and ß-thalassemia. It also delineates the similari-ties and differences of these programs to reveal considera-tions for CF carrier screening.

SCREENING FORTAY-SACHS DISEASE

Tay-Sachs is a lethal genetic disorder that predominantlyaffects Jews of Eastern and Central European descent(Ashkenazic Jews) and populations in the United Statesand Canada descended from French Canadian ancestors;it also occurs infrequently in the general population. Thedisorder affects the central nervous system, resulting inmental retardation and death within the first 3 to 6 yearsof life. Unlike for CF, the means to screen for Tay-Sachscarrier and affected status have existed for more than twodecades.

Shortly after accurate tests were developed, a numberof large-scale carrier screening programs were initiated,first in the United States, and then throughout the world.Carrier screening programs for Tay-Sachs are frequentlyconsidered models for other genetic screening endeavors(54,64,66). While some of the experiences can begeneralized to other genetic disorders, other facets ofTay-Sachs carrier screening programs derive from spe-cific aspects of the condition and the populations targeted.

The Disease

TaY-Sachs (also called GM2 gangliosidosis, Type I) isa progressive, degenerative disorder of the central nerv-ous system. Due to the absence of a particular enzyme,hexosaminidase A (Hex A), fatty substances-speci-fically GM2 gangliosides—accumulate in cells throughoutthe central nervous system, eventually destroying them.The process begins prenatally, though the infant canappear normal for the first months of life. Symptomsusually begin between 4 and 12 months with an exagger-ated startle response, followed by increasing motorweakness. Blindness, seizures, and continual decline intoa vegetative state ensue until the child dies. No cure exists(19).

Genetics of Tay-Sachs Disease

Like CF, Tay-Sachs is a single gene disorder inheritedin an autosomal recessive pattern; that is, only a childreceiving a defective copy of the gene from each parentwill be affected; carriers have no clinical symptoms.Among the general population, Tay-Sachs mutations arerare, occurring with a carrier frequency of 1 in 167, givingrise to 1 in 112,000 affected births, The disease issignificantly more common, however, among AshkenazicJews: the carrier frequency is 1 in 31 and birth incidenceis 1 in 3,900 (77). Prevalence in Ashkenazic Jews is afunction of ethnic background, and is unrelated toreligious practice, Elevated incidence of variant alleles arealso found among Moroccan Jews (97), French-Canadians (l), and a distinct population of LouisianaFrench Acadians (41).

In 1969, scientists identified the lack of Hex A as theunderlying metabolic defect in Tay-Sachs disease (60). Ayear later, an enzymatic assay was developed to measureHex A activity. Application of this test to known carriersrevealed intermediate activity of the enzyme in theseindividuals, which led to the assay for carrier identifica-tion among those without family histories (59).

Tay-Sachs carrier screening is performed on bloodserum, although for pregnant women, women using oralcontraceptives, and persons with liver disease, the bloodserum test does not yield accurate results. Instead, whiteblood cells, platelets, or tears are used; such methods aremore time-consuming and costly. The biochemical assayalso can be used to detect affected fetuses through eitheramniocentesis (79) or chorionic villus sampling. Thisassay has had significant false positive carrier rates butlower false negative rates (80).

In the mid-1980s, characterization of the Hex A genestructure and mutations led to the possibility of DNA-based Tay-Sachs screening and diagnosis. Three distinctmutations account for 90 to 98 percent of Tay-Sachschromosomes in this population (28,62,94); one—a 4base pair insertion-is present in over 70 percent ofTay-Sachs Ashkenazic alleles. In contrast, among non-Ashkenazic carriers, the three mutations comprise about20 percent of defective mutations (28,62,94). For Moroc-can Jews, a single base pair deletion predominates (56),while in French-Canadians, multiple mutations are pre-sent (29). Preliminary results in the Imuisiana FrenchAcadian population indicate the presence of two altera-tions correlated with Ashkenazic carrier alleles (50).Additionally, one of the prevalent Ashkenazic mutationsresults in an “adult-onset” form of the disease (94).

–254-

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Appendix B-Case Studies of Other Carrier Screening Programs ● 255

DNA analysis is useful in confirmatory and familystudies and is being tested as a carrier screening methodin some centers. Currently, DNA assays allow confirma-tion of diagnosis, reducing levels of both false positivesand false negatives (62,94). In the future they mightreplace the enzymatic assay.

Screening Programs

Initial awareness of Tay-Sachs centered in Jewishcommunities; hence, screening programs (using biochem-ical assays) for carrier status originated there. After theseefforts were launched, similar programs spread to areaswhere French-Canadians clustered and, most recently, toparts of Louisiana, The almost immediate implementationof carrier screening programs among Ashkenazic Jewswas

●

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●

facilitated by a number of factors:

occurrence of the disease is concentrated in a definedpopulation;determination of the carrier state is easy and rela-tively inexpensive;at-risk pregnancies can be monitored through prena-tal diagnosis of the disease (34); andpublic funding or subsidies were available-e. g.,through the National Sickle Cell Anemia, Cooley’s

Anemia, Tay-Sachs, and Genetic Diseases Act(Public Law 94-278).

Tay-Sachs Carrier Screening Programs

Tay-Sachs carrier screening began in 1971 in theBaltimore, MD-Washington, DC Jewish populations atthe behest of the Jewish communities (34). The pilotprogram involved community outreach: 14 months oforganizational planning, technical preparation, and edu-cation of medical and religious leaders preceded massivepublic education campaigns. Every aspect was carried outwithin the community, from planning to sample collec-tions, which were held in synagogues, high schoolgymnasiums, and Jewish community centers (34). Eigh-teen hundred people showed up in one day for the firstscreening; in under a year, 5,600 individuals werescreened, and 245 carriers identified (34,35).

Following the success of this effort, Jewish communit-ies throughout the United States and Canada imple-mented similar endeavors. By 1976, 52 cities in theUnited States, and others in Canada, England, Israel,South Africa, and Japan were conducting carrier screen-ing programs (34). Many centers followed the initialprotocol, adapting specifics to individual locations. Mostchanges were made in the target population group and in

TAY-SACHS FACTS:● TAY-SACHS DISEASE IS AN INHERITED GENETIC

DISORDER OF INFANCY

● A CHILD WITH THE DISEASE CAN BE BORN TOHEALTHY PARENTS WHO ARE CARRIERS OF THETAY-SACHS GENE

● ANYBODY CAN BE A CARRIER – CARRIER RATE IS1 :150 IN THE GENERAL POPULATION AND 1:30 INTHE JEWtSH POPULATION

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Photo credit: Alpha Epsilon Pi

An advertisement for Tay-Sachs carrier screening.

256 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

emphasis on public or physician education. Three main and Jewish community centers advising them to referapproaches evolved: married couples, either pregnant or planning a pregnancy,

●

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to physicians for screening. In 1983, a unique program,educating and screening the entire community (mass Chevra Dor Yeshorirn, in New York City’s Orthodoxscreening); Jewish population began screening people prior totargeting couples of reproductive age, usually withthe involvement of physicians; and

arranged marriages to ensure that no marriages wouldoccur between carriers (box B-l).

screening high school and college students.Students. A different approach was launched in

Mass Screening. Mass screening programs essentiallyfollowed the prototype of the Baltimore, MD-Washington, DC endeavor. In a south Florida area with ahigh concentration of Ashkenazic Jews, for example, aprogram involving leaders of the local community,parents of children with Tay-Sachs, and the Departmentof Pediatrics at the University of Miami School ofMedicine was organized in 1973. In 1974, the steeringcommittee overseeing the Florida effort decided toreemphasize mass screening sessions, and establishedsmall, local clinics (including synagogues and colleges)where screening sessions could be coordinated with localblood banks’ visits to the community. Though screeningwas available to all individuals, young, single personswere counseled that it might be more effective to delayscreening until after marriage, when reproductive deci-sions would be more pertinent (93).

Couples of Reproductive Age. In 1977, clinicalchemists in Akron, OH designed a program that focusedon educating family physicians and minimizing publiceducation (63). Information was disseminated to rabbis

Montreal, Canada in 1974. -A school-based screeningprogram, operated by physicians and paramedical person-nel, garnered participation of 75 percent (48). An 8-yearfollowup study indicated that Canadians screened in highschool had largely positive attitudes toward geneticscreening long after the experience, and made appropriateuse of the results (82,83,106). Others criticize thefollowup study for underestimating the forgetfulness ofthe adolescents screened (91). Though voluntary geneticscreening of high school students is considered acceptableand successful by many in the Montreal community (83),some outside the community accuse the program ofcoercion (30).

Tay-Sachs Screening Today

Through 1987, 600,000 people had been screenedthrough voluntary programs in the United States (55).Almost 22,000 heterozygotes had been identified, andmore than 1,400 pregnancies were monitored. Over 200affected fetuses were detected and more than 1,000healthy babies were born from at-risk pregnancies (55).

Box B-1-Chevra Dor Yeshorim Tay-Sachs Program

Chevra Dor Yeshorim, which originated in New York City’s OrthCdox Jewish community, is a uniqueTay-Sachs screening program. The elevated incidence of Tay-Sachs in this population, combined with religiousbeliefs opposing abortion and contraception, led community leaders to conclude that preventing Tay-Sachs waspossible only by avoiding reproduction between carriers (52). Such reproduction could be avoided because thisOrthodox Jewish community arranges marriages through matchmakers.

In 1983, the Committee for Prevention of Jewish Genetic Diseases formed Chevra Dor Yeshorim, which stilloperates today. All marriageable people are assigned a number and screened for Tay-Sachs carrier status at a localcenter (52). No one is informed of his or her result, which is filed by numik only. When a marriage is proposed,the matchmaker calls the center with the prospective couple’s numbers and is informed whether the proposed matchinvolves two Tay-Sachs carriers; if the match does not, marriage plans proceed. If the match involves two carriers,the matchmaker tells the two families to contact the center, where the families are informed that both children arecarriers and referred to counseling. Carriers thus learn their status only if they match with another carrier familiescan report the match has failed for other reasons and look for new matches. This system of anonymity is employedbecause of historical stigmatization of carriers (52).

Chevra Dor Yeshorim has eventually become an adolescent rite of passage. Similar programs have beendeveloped in California, Tennessee, Michigan, Florida, Maryland, Massachusetts, Illinois, Montreal, Israel, Europe,and other communities (45). By 1992, more than 30,000 people have been screened through such programs. Morethan 7,000 inquiries have been made and 47 prospective matches between Tay-Sachs carriers identified and halted(45).

SOURCE: OffIce of Technology Assessment, 1992.

——. .

Appendix Mase Studies of Other Carrier Screening Programs ● 257

Today, the focus has changed somewhat from the earlymass education and screening approach, with over 100hospitals and clinics nationwide offering screening on acontinual basis. According to the National Tay-Sachs andAllied Diseases Association (NTSAD), a major aim“continues to be the promotion of genetic screeningprograms nationally through affiliated hospitals andmedical centers, and through [NTSAD’S] local chaptersand community organizations” (55).

A program in Toronto, Canada illustrates some generaltrends in Tay-Sachs carrier screening. Begun in 1972 asa community outreach program along the lines of theBaltimore, MD-Washington, DC prototype, it facedlagging community attendance by the end of the decade.By 1978, the orientation changed from mass screening toone of case finding, where physicians referred patients forscreening on an individual basis (14,15,47). In thismanner, 600 to 700 individuals are screened each year.Nearly two-thirds are pregnant at the time of screening,suggesting that determination of carrier status is beingviewed as part of prenatal care rather than preconceptionplanning.

Though outreach efforts are directed beyond the Jewishcommunity, knowledge of Tay-Sachs is generally con-fined to this population. When multiple cases of Tay -Sachs surfaced in a rural, Catholic community inLouisiana, NTSAD and Tulane University organized amass education and screening program (41). NTSADcontinues public education efforts through nationwidemailings to community and religious organizations and tocollege, high school, and grammar school libraries.

SCREENING FORSICKLE CELL ANEMIA

If Tay-Sachs screening is often held as an example ofa successful screening campaign, early sickle ceil screen-ing efforts are frequently cited as ‘‘screening gonewrong. Like Tay-Sachs, sickle cell anemia is anautosomal recessive condition generally affecting a par-ticular population—for sickle cell anemia, people ofAfrican descent. Sickle cell anemia impairs red blood cellflow through the circulatory system, causing complica-tions in organ systems throughout the body.

As for Tay-Sachs, massive screening programs forsickle cell were undertaken in the United States in the1970s. Sickle cell programs, however, differed im-mensely from the Tay-Sachs program in a variety of ways.Screening was mandatory in some States, and there wasneither treatment nor prenatal diagnosis. Early programsalso suffered from misinformation and discriminationagainst carriers.

Figure B-l—Normal and Sickled Red Blood Cells

In sickle cell anemia, many red blood cells are distorted from theirnormal round shape (top), into the shape of a crescent or sickle(bottom). These distorted cells can obstruct smaller blood vesselsor be removed too rapidly by the spleen.SOURCE: M. Murayama, National Institute of Arthritis, Musculoskeletal,

and Skin Diseases, National Institutes of Health, Bethesda, MD,1992.

The Disease

The sickle cell mutation affects hemoglobin (Hb), theoxygen-carrying molecule in the blood stream. Hb isfound in the red blood cells and can be of a variety oftypes. Fib A is found in healthy red blood cells; Hb Soccurs in the red blood cells of sickle cell anemia patients.Hb S causes the cells to become deformed and sickleshaped (figure B-l). Sickled red blood cells becometrapped, decreasing red blood cell survival and, therefore,oxygen transport. Individuals with sickle cell anemia aresusceptible to episodes of extreme pain in the limbs, backabdomen, or chest, which are thought to be caused byblockages of the deformed red blood cells in thecirculatory system, These crises occur as often as once amonth to once every other year and can last from 3 daysto more than 3 weeks. Lack of oxygen in the spleen,

258 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

kidneys, bones, and joints can also damage these organsand tissues. Eight to 30 percent of children with sickle cellanemia die in the first years of life from complications ofsevere bacterial infection (25). However, intensive antibi-otic treatment-if begun early enough-imparts someresistance to these conditions (25). No cure exists forsickle cell anemia. Unlike Tay-Sachs, sickle cell anemiadoes not involve mental retardation.

Genetics of Sickle Cell Anemia

Like CF and Tay-Sachs, sickle cell anemia is a geneticdisorder inherited in an autosomal recessive pattern. Aperson with two copies of the sickle cell mutation ishomozygous and has sickle cell anemia. A person with asingle copy is heterozygous and is said to be a sickle cellcarrier or to have sickle cell trait. The red blood cells ofpeople with the sickle cell trait contain both Hb A andHb S. These individuals do not have sickle cell anemiaand are considered to be healthy with a normal lifeexpectancy (88,101). Some clinical abnormalities havebeen found in people with sickle cell trait includingdefects in urine concentrating ability and occasional boutsof blood in the urine (88), Under extremely low-oxygen,high-exertion conditions, minimal sickling of red bloodcell can occur (36).

I I ,

Photo creadit: Howard University

Patient education brochures describing sickle cellanemia and sickle cell trait.

The precise difference between Hb A and Hb S waselucidated in 1956 (57); since then, the specific mutationcausing these mutations has been found. The genetic basisof sickle cell is rare: One base change accounts for allcases of the disorder (57). Abase change of an adenine fora thymine in the ß-globin gene produces a single aminoacid difference of the 146 amino acids in the ß-chain—one of the two protein components of Hb.

Although the incidence of the sickle cell mutation ishigh in Greeks, Italians (particularly Sicilians), Eti-Turks,Arabs, southern Iranians, and Asian Indians, the highestfrequency occurs in Africans and their descendants (7).One in 400 African American newborns has sickle cellanemia (32), and 1 in 10 or 11 has sickle cell trait(3,57,96).

Diagnostic procedures for sickle cell anemia evolved asknowledge of the biochemistry of Hb increased. Discov-ery of the differential electrophoretic mobility of Hb S andHb A permitted testing of blood samples. The presence ofonly Hb A indicated noncarrier status, only Hb Sindicated sickle cell anemia, and the combination ofHb A and Hb S in an individual indicated sickle cell trait.Restriction fragment length polymorphism analysis hashad an important impact on diagnosis of sickle celldisease and trait, especially in the prenatal diagnosis ofaffected fetuses by amniocentesis and chorionic villussampling. In the early 1980s, a restriction enzyme, Mst II,that recognizes a sequence at the site of the sickle cellmutation itself was found (61). Since 1982, researchershave performed this procedure with 100 percent informa-tiveness and rare errors (39). Diagnosis no longer dependson having informative family members. DNA diagnosisto detect sickle cell has been shown to be 100 percentinformative and 99 percent reliable (43). Additionally,polymerase chain reaction can now be used with nonradi-oactive, enzyme-labeled, allele-specific oligonucleotideprobes in dot-blot format (76).

Screening ProgramsIn the early 1970s, 16 States and the District of

Columbia enacted laws to identify people with sickle celltrait and sickle cell anemia so that carrier couples couldbe informed of their risks of having affected children.Most laws were drafted and promoted by AfricanAmerican legislators at the height of the civil rightsmovement. At first glance, they offered an inexpensivebenefit to African American citizens (65). Depending onthe States, screening was mandated for newborns, pre-school children, pregnant women, couples applying formarriage licenses, inmates of State institutions, or somecombination of these groups. Some States mandated thattests be offered, while others mandated screening.

Many aspects of State sickle cell screening lawsgenerated public critique. Statutes consistently contained

Appendix B--Case Studies of Other Carrier Screening Programs ● 259

blatant medical and scientific errors including calling forimmunization for sickle cell anemia. Some States classi-fied sickle cell carrier status with having sexuallytransmissible diseases on marriage licenses; others calledit a communicable disease (65). Almost every State lawfailed to insist on using the most sensitive assay available.Controversy also focused on the racial distribution ofsickle cell mutations and the target screening population.Sickle cell anemia was considered a “Black Disease”(32). The laws were seen by many citizens as racisteugenic measures aimed at reducing the number ofmarriages between carriers and decreasing the number ofpregnancies at risk for affected children of a minoritypopulation. The fact that the programs were largelydesigned and operated by Caucasians fueled proclama-tions of genocide.

Most State laws failed to provide adequate educationand counseling for persons with sickle cell anemia andtrait. The most common error conferred disease status onthose who were carriers. Those diagnosed with sickle celltrait were often told they could not have children, thatchildbirth would be hazardous, or other untruths. Only 4of 13 programs mentioned counseling of any sort. Peoplewere often confused about which condition they had—sickle cell disease or sickle cell trait—which led toincreased anxiety.

State laws also failed to provide public education toguard against discrimination and stigmatization. By 1972,for example, at least one flight attendant had beengrounded (32). Stories of job and insurance discrimina-tion multiplied as screening programs proliferated. Addi-tionally, too little concern was expressed over confidenti-ality of results, Some States required that positive testresults be filed with the State’s public health entity.

National Legislation

In 1971, President Nixon spoke of the problem of sicklecell anemia and the need for more research and education.The 1972 National Sickle Cell Anemia Control Actauthorized $85 million over 3 years for the ‘‘establish-ment and operation of voluntary sickle cell anemiascreening and counseling programs, ’ and to ‘‘developinformation and educational materials relating to sicklecell anemia and to disseminate such information andmaterials to persons providing health care and to thepublic generally” (Public Law 92-294). Some $30million was allocated for research on the disease and fordevelopment of educational, screening, and counselingprograms. Applicants for Federal funds were required tomeet certain standards and to ensure confidentiality of allmedical and counseling records. The law also promisedcommunity participation: African Americans deliveringthe service to African Americans.

Sickle Cell Screening Today

By 1973, laws in eight States had been repealed (57).By 1977, more than one-third of States had enacted lawsunder the National Sickle Cell Anemia Ccntrol Act (65).Mandatory screening was eliminated, and the need foradequate genetic counseling, public education, and confi-dentiality of test results was recognized (65). Neverthe-less, discrepancy between the ideal and actual practiceexisted, as criticism focused, in the late 1970s, on acontinued lack of ‘‘community participation’ and accu-sations of Federal money granted disproportionately towhite institutions (65),

Today, sickle cell screening is often done routinely onpregnant women as part of routine blood workup and onnewborns (3,23). Prenatal sickle cell screening infre-quently results in selective pregnancy termination (103).Forty States screen newborns for sickle cell anemia (103),detecting babies with sickle cell anemia and babies whoare carriers, Some States screen all newborns, some targeta particular population, and some have voluntary screen-ing that varies from hospital to hospital (103). Somenewborn screening is done without informed consent, butwith counseling of the parents if carrier status is detected(3).

SCREENING FORß-THALASSEMIA

ß-thalassemia, also known as Cooley’s anemia, thalas-semia major, target cell anemia, and Mediterraneananemia, is an autosomal recessive condition for whichcarrier screening has been undertaken. ß-thalassemiaclusters in particular ethnic groups—people of Mediterra-nean, Middle Eastern, Asian Indian, Chinese, SoutheastAsian, and African descent (7). Legislative action con-cerning ß-thalassemia has occurred both in the UnitedStates and abroad. Screening for a-thalassemia, a relateddisorder, was first introduced in 1975 and continues todayin some parts of the world (box B-2). Many Europeanprograms emphasize hemoglobinopathy screening en-compassing all clinically significant a and ß alleles andtheir combinations (103).

The Disease

ß-thalassemia is one of the most common geneticdisorders in the world (92). Like sickle cell anemia, thecondition affects the Hb of red blood cells. In ß-thalassemia, the amount of Hb is diminished, causing redblood cells to be smaller and have a‘ ‘target” appearance.Severe anemia, frequent infections, spleen enlargement,growth retardation, and marrow hypertrophy are allcharacteristics of the disorder (57). Death usually resultsfrom iron toxicity, most often in childhood. Therapy forß-halassemia includes transfusions, folic acid supple-mentation, and intensive treatment of infections. Transfu-

260 ● Cystic Fibrosis and DNA Tests: Implications of Carroer Screening

Box B-2---a-Thalassemia

a-thalassemia is another genetic condition often included in carrier screening programs. Like ß-thalassemi~it is an autosomal recessive disorder affecting hemoglobin (Hb) production. The level of a-globin, a component ofHb, is decreased, resulting in abnormal Hb molecules: Hb H and Hb Bart. It is the most common genetic diseasein some Chinese provinces and is found throughout Southeast Asia and the Mediterranean. According to the WorldHealth Organization, 10,000 babies are born with a-thalassemia each year in Asia (42). a-thalassernia also affectspeople of African descent (7).

a-thalassemia results from mutations in the a-globin genes (87). While there is one ß-globin gene in the humangenome, there are two a-globin genes. The most severe type of a-thalassemia is caused by homozygous deletionof both a-globin genes. This condition, called hemoglobin Bart’s hydrops fetalis, generally leads to intrauterinedeath (57,98) and is the primary cause of stillbirth in Southeast Asia (57). Three to five percent of African Americansare heterozygous carriers of mutations for both a-thalassemia genes, and about 26 percent are heterozygous carriersfor mutations in one of the a-thalassemia genes (6).

Prior to DNA analysis, diagnosis relied on assaying the presence of Hb Bart in cord blood of babies suspectedto have dmlassemia. Identifying carriers by determination of mean corpuscular volume (MCV) and globin chainelectrophoresis was inexact. Today, DNA technologies have increased the speed and efficacy of prenatal and carrierscreening for a-thalassemia (44).

Carrier screening for a-thalassemia occurs worldwide (100). One program is currently undenvay in HongKong, where 98 percent of the population are ethnic Chinese from South China, with a carrier frequency of 3 percent(12). Public education, and formal organization of screening, counseling, and referral were required to make theprogram successful (12). Today, both carrier screening and prenatal diagnosis appear to be well accepted in HongKong (12). A similar effort is advancing in Guangdong Province in southern China (107), where the carrierfrequency is about 5 percent.

a-thalassemia carrier screening has also been conducted in the United States. In the 1980s, researchers insouthern California educated a Southeast Asian population about screening through the community’s churches.Thalassemia screening was performed on a cross-section of the population and on newborns using MCV indicesand Hb electrophoresis. Approximately 8 percent of more than 600 individuals were found to be carriers.Today—although the program is no longer operating because Federal funding expired-overall awareness ofa-thalassemia appears to have been maintained among physicians, and screening now targets pregnant women inobstetricians’ offices (21).

One study in Hawaii assessed consumer attitudes towards thalassemia screening (105). As part of the HawaiiHereditary Anemia Project, 862 a- and ß-thalassemia carriers who were identified through the project weresurveyed about feelings of stigmatization and attitudes toward knowledge gained. Researchers concluded thatlearning carrier status provoked little anxiety (except in less educated populations) and provided meaningfulbenefits (105). Researchers in Rochester, NY have found that the percentages of people seeking an explanation ofthe test result, having the partner screened, and undergoing prenatal diagnosis are all higher among Southeast Asiansthan non-Southeast Asians (72).

SOURCE: Office of Technology Assessment 1992.

sions, however, can result in hemochromatosis (iron mutations, symptoms range from mild to severe (9). Someoverload), which can be improved slightly by usingchelating agents to reduce excess iron. Splenectomy—removal of the spleen—is indicated if signs of hyper-splenism exist and is performed preferably after age 5(57),

Genetics of ß- Thalassemia

Like sickle cell, ß-thalassem.ia is an autosomal reces-sive disease caused by mutations in the ß-globin gene.Unlike sickle cell, however, several mutations lead toß-thalassemia (37). Depending on the number and type of

Appendix B---Case Studies of Other Carrier Screening Programs ● 261

American, African American, or Asian American (74),those populations generally considered at high risk. Thisfinding argues in favor of screening all pregnant women,not only those usually regarded as at elevated risk basedon ethnicity or race. Eighty-six percent of women whowere counseled about their hemoglobinopathy carrierstatus said they wanted their partners screened, 55 percenthad their partners screened, and 47 percent of carriercouples identified underwent prenatal diagnosis. Thus,unselected patients in a primary care setting in theRochester region, even though pregnant, were receptive toand utilized genetic information (74). The researchersconcluded that genetic screening in such a setting hasmany advantages over that in non-health-care settings,including comprehensive coverage of the population,screening at a time appropriate or relevant for theindividual, and increased likelihood of appropriate medi-cal followup (69).

The Federal Government has also been involved withß-thalassemia screening. In 1972, the National Cooley’sAnemia Control Act (Public Law 92-414) was introducedand sponsored by legislators of Mediterranean heritage. Itauthorized $3 million for ß-thalassemia screening, treat-ment, and counseling programs, $3 million for publiceducation, and $5.1 million for disease research over a3-year period (65).

Canada

A program for ß-thalassemia prevention comprisingeducation, population screening for carriers, and repro-ductive counseling has been carried out in Canada (81). Ina 25-month period (1979-81), 6,748 persons, including5,117 high school students, were screened for ß-thalassemia trait using MCV indices; the participationrate was 80 percent(81 ). Researchers surveyed 60 carriersand 120 noncarriers among the high school studentpopulation, and most carriers told parents (95 percent) andfriends (67 percent) the test result. Most carriers (91percent) reported they would ascertain their spouses’genotype; 95 percent approved of the screening effort(81).

Sardinia

ß-thalassemia is a significant health problem. Onecouple in 80 is a carrier couple—i.e., at 1 in 4 risk of anaffected pregnancy. Prior to screening, 1 in 250 live birthshad ß-thalassemia. Most ß-thalassemia cases in Sardiniaare severe-i. e., ß-globin chains are absent. About 96percent of the ß-thalassemia mutations in this populationare of a single type, and another mutation accounts for 2.1percent of the remaining mutations (1 1).

In 1976, the region’s Department of Public Healthinitiated a voluntary program to control ß-thalassemia inSardinia based on carrier screening, genetic counseling,and prenatal diagnosis. General practitioners, obstetri-

262 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

cians, and paramedics were trained at specific educationalmeetings about the philosophical and technical aspects ofthe program. The program was targeted toward youngunmarried men and women, married couples, and preg-nant women. When a carrier was identified, the profes-sionals urged that other family members also considertesting (1 1).

Prior to implementing the program, a mass mediaeducational campaign geared to the general public waslaunched. About 47 percent of couples and 65 percent ofsingles screened said they learned of the program throughthis campaign. Screening was performed first on onemember of a couple. If that individual was positive, his orher partner was screened. Prenatal diagnosis was alsoperformed (1 1).

To date, 24 percent of Sardinia’s population has beenscreened, and 85 percent of the theoretical number ofcarrier couples (+/+) in the population have been identi-fied. In large part, this high efficiency results fromfollowup screening of carriers’ family members (1 1).Sixty-five percent of those screened in 1980 werepregnant women. By 1990, only 30 percent were preg-nant, demonstrating a trend in increased knowledge--i. e.,individuals came in for screening prior to conception. Theincidence of ß-thalassemia in Sardinia has declined from1 in 250 live births in 1974 to 1 in 1,200 in 1991, aneffective prevention of 90 percent of predicted cases (11).Of babies born with ß-thalassemia, 67 percent were bornto parents who were unaware of the disease and of carrierscreening, 20 percent were to parents who, for ethicalreasons, decided against abortion after prenatal diagnosis,and 13 percent were cases of false paternity (1 1).

An important early result of the program was theimpact on carriers. Many had difficulty finding jobs,chiefly because the national army is the predominantemployer in Sardinia and refuses to employ ß-thalassemiacarriers due to a misunderstanding about carrier status.Ongoing efforts to educate the army appear likely toreverse this practice in the near future (1 1). ß-thalassemiascreening in Sardinia is currently moving to encompassthe school-aged population (1 1).

Cyprus

In Cyprus, 1 in 7 individuals is a carrier, and 1 in 1,000Cypriots is a patient under treatment for ß-thalassemia(2). In the early 1970s, the realization that demand fortreating this single disease could outstrip resources for allhealth care led to the development of a national carrierscreening effort. Undertaken with World Health Organi-zation support, the program consisted of public education,population screening for carriers, genetic counseling forcarrier couples, prenatal diagnosis, and premarital screen-ing (2).

An unusual compliance mechanism is one facet of theCyprus program. The Greek Orthodox Church recognizedthe problems of the high incidence of ß-thalassemiabirths, but was reluctant to endorse pregnancy terminationto prevent such births. In 1983, however, the Churchagreed that, before the Church would bless a marriage orengagement, a couple would be required to present acertificate proving they had been screened and hadreceived genetic counseling. With the Church’s coopera-tion, the number of people screened skyrocketed from1,785 in 1977 to 18,202 in 1983. Today, 10,000 to 11,000people are screened annually. Since most couples ofreproductive age have been screened, attention nowfocuses on single people. Since 1985, a 20 percent fall inthe expected proportion of +/+ couples has been noted,perhaps indicating that carriers are avoiding marriage toother carriers (2).

As in Sardinia, the number of newborns with ß-thalassemia has fallen dramatically. In 1974,53 of 8,594births were affected: From 1986 through 1990, there werefive, for a prevention rate of 97 percent. Ninety percent ofthe 69 affected babies born between 1978 and 1980resulted from lack of knowledge among the public and themedical profession about the Cyprus carrier screeningeffort. Two births were due to refusal of prenataldiagnosis on religious grounds, two were laboratoryerrors, and one was parental choice after positive prenataldiagnosis.

The program’s success is attributed to several factors,including extensive and continuous public education,small population size, and homogeneity of the population(2). Time spent on counseling is much less today thanwhen the program was initiated-a direct result ofincreased public education. A newer program is underway in Turkish Cyprus.

Other ß-thalassemia Screening Programs

Screening programs for ß-thalassemia in the UnitedKingdom (58) incorporate treatment and prevention intogeneral health care. Primary health care, peripheralcenters, and reference centers coordinate the program’sefforts. Individuals learn about the screening throughschools and public information posters. Communityinvolvement, particularly through parents’ and patients’associations is an important component, and a detailededucation program provides effective information aboutgenetic risks and services. Fewer ß-thalassemia birthshave been avoided in the United Kingdom than in Cyprusor Sardinia, chiefly because of the large population size,the occurrence of ß-thalassernia in ethnic minoritiesscattered throughout an indigenous population, and thebeliefs of many of those at risk that prenatal diagnosis andabortion are socially and religiously unacceptable (58).Southeast Asia, Hong Kong, East Mediterranean coun-

Appendix B---Case Studies of Other Carrier Screening Programs ● 263

tries, and South China have ß-thalassemia carrier screen-ing programs (12,46,107).

LESSONS FOR CYSTIC FIBROSISCARRIER SCREENING

The Tay-Sachs, sickle cell anemia, ß-thalassemia, andß-thalassemia experiences offer lessons that might beapplicable to routine carrier screening for CF. Theselessons involve five principal aspects of the programsdescribed in this appendix:

nature of participation,setting and fiscal support,target population,public education, andcounseling carriers and at-risk couples.

Nature of Paticipation

Participation in the programs described in this appen-dix was voluntary or mandatory. The Tay-Sachs expedi-ence offers a model of voluntary participation, whichcontributed to its efficacy and success—both in reducingdisease and in avoiding stigmatization (54,66). It isnoteworthy, nonetheless, that one survey found thatnearly half of participants in one Tay-Sachs program feltscreening should be mandatory, although the breakdownof carriers and noncarriers expressing those opinions wasnot measured (13).

The sickle cell experience, on the other hand, includedsome mandatory State screening of people in schools orcorrectional institutions, or of couples applying formarriage licenses. Such mandatory participation wasviewed as a contributing factor in the widespread failureof these efforts (65,66). ß-thalassemia programs in theUnited States and abroad have used the voluntaryapproach and have been generally successful (2,11,74,105).ß-thalassemia programs in the Mediterranean that use aquasi-mandatory approach through the involvement ofthe Greek Orthodox Church also have been successful inreducing disease. Although stigmatization appeared to bean issue initially, it seems to now be obviated (2). Thesuccess of these mandatory programs, however, can beattributed mainly to the cultures of Cyprus and Sardiniaand is likely not applicable to carrier screening in theUnited States.

Thus, success of voluntary initiatives and the failure ofmandatory programs (excluding the Cyprus example)lead many to conclude that voluntary participation for CFcarrier screening is essential. The National Institutes ofHealth (NIH) Workshop on Population Screening for theCystic Fibrosis Gene recommended that screening bevoluntary (4).

Setting and Fiscal Support

The environment in which a genetic screening programis administered also affects its success and acceptance.Tay-Sachs carrier screening was community-based. Lead-ers within the Jewish community became leaders of thescreening programs, which were offered through syna-gogues, storefronts, and community centers. The commu-nity was involved in all aspects of the program. For CF,however, the target population is larger and more diffuse,with a wide range of religious beliefs. Thus, it would bean ill fit to organize CF carrier screening solely throughreligious centers.

In stark contrast, the sickle cell anemia programs wererun largely by the State and Federal governments, theircontractors, and grant recipients. During a time of tensionover civil rights, Caucasians from outside of the commu-nity generally controlled screening, which was viewedextremely negatively by the African American commu-nity. The resulting lack of support by the targetedpopulation doomed sickle cell screening programs tofailure.

ß-thalassemia programs in the United States have beenmore diverse, involving primary care physicians inneighborhood health centers, a large HMO, hospitalprenatal clinics, a family medicine program, and privatepractice. The particular setting seems less important tosuccess than other factors, (e.g., patient and providereducation> although a primary care clinical setting isdesirable (69)—and likely will prove most appropriate toCF carrier screening. (ß-thalassemia experiences in Eu-rope revolve around national health care systems, makingit difficult to compare setting and funding to U.S.experiences.)

Beyond the particular setting is the issue of funding fororganizing and maintaining the effort. Historical perspec-tives probably apply least in this area. Most effortslaunched in the 1970s and 1980s involved some degree ofpublic funding. With respect to routine CF carrierscreening in the United States, the funding issue iscomplex, but direct funding in the manner of Tay-Sachs,sickle cell, or the thalassemias is unlikely to materializebeyond the current NIH pilot projects (ch. 6). Thus, to theextent that direct public subsidy contributed to the successof past screening, routine CF carrier screening willunlikely realize such a benefit.

Target Population

Tay-Sachs programs targeted a narrow slice of the U.S.population. The population was easily identifiable, largelyurban, educated, and receptive to screening and reproduc-tive options; all are population characteristics often citedas beneficial to a program’s success (34). Sickle cellprograms targeted African American communities at the

264 ● Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

height of the civil rights movement, causing considerablecontroversy about segregation, discrimination, and stig-matization. Racial tensions created by singling out apopulation already historically discriminated againststress the importance of prior awareness of the implica-tions of focusing on members of a particular group andtheir potential reactions to screening.

The age and sex of the screened population also haveimplications for CF carrier screening. With the ability toperform prenatal diagnosis, much attention focuses onscreening pregnant women (95). Some argue that screen-ing during pregnancy offers the advantages of immediateinterest in knowledge of genetic information and compre-hensive coverage of the population (75). Disadvantages ofscreening during pregnancy include eliminating theoption to avoid conception, so that prenatal fetal testingmight be perceived as necessary. Or, it might be too latein a pregnancy for prenatal diagnosis even if desired.Some also believe that carrier identification can be tooanxiety-producing during pregnancy to be efficacious.Others argue that screening women first can be perceivedas eugenic screening for breeding fitness (102).

Many studies have attempted to ascertain the optimalgroup for carrier screening: newborns, students, primarycare recipients, pregnant women, couples planning tomarry, or married couples (13,16,17,99,106). The studiesoften conflict: Each group offers advantages and disad-vantages that vary by disease, available technology, andmanifestations of the disease (ch. 6). Thus, the optimalpopulation for CF carrier screening remains a topic ofdebate. Additionally, while CF mutations have a highprevalence in one racial group-Caucasians-the ethnicdiversity of this population in the United States poses achallenge that did not exist for previous screening efforts.Beyond diversity per se, many Americans do not knowspecifics of their ethnic backgrounds, knowledge whichmight assist in more precisely assigning risks (96).Further, CF also occurs, albeit less frequently, in AsianAmericans and African Americans. The extent to whichroutine screening within these two groups is appropriateis also an issue.

Public Education

Consumer knowledge--both about medical aspects ofthe specific genetic condition and the meaning of carrierstatus—is key. Conditions that affect mental function,such as Tay-Sachs, appear to have a greater acceptance ofcarrier screening and prenatal diagnosis (20,22,26). Thehigh acceptability of screening that resulted from publiceducation for Tay-Sachs might be less informative forroutine CF carrier screening, for example, although themechanism of providing the education could be illustra-tive. Likewise, CF carrier screening might not serve as agood indicator of future screening for disorders such asfragile X syndrome (box B-3).

Stigmatization of carriers, widely cited as a negativeoutcome of genetic screening (27,30,67), is largelyattributed to ignorance within both the community beingscreened and the general population. In contrast toacceptability, lessons about the importance of publiceducation to avoid stigmatization can be gleaned fromhistory. With Tay-Sachs screening, a concerted effort wasmade to educate community and religious leaders, whothen helped educate the public through outreach, mail-ings, media, and word of mouth before any screening tookplace. Educational efforts were adjusted over time, and ingeneral, data indicate the majority of carriers believe theywere not stigmatized, although a small percentage ofnoncarriers expressed attitudes of superiority (13,40),Similarly, the Mediterranean ß-thalassemiaprograrn dem-onstrates the effectiveness of massive public educationthrough the local media, although some contend themassive public education bordered on propaganda andcoercion (31). The sickle cell experience demonstrateshow poor public outreach and lack of knowledge amongprofessionals in the program lead to failure (54,66).

Regardless of the precise mechanism through whicheducation is achieved, implementation of CF carrierscreening can benefit from the knowledge that publiceducation has had a positive effect on previous screeningexperiences. Lessons learned from Tay-Sachs, sickle cell,and ß-thalassemia efforts can be applied to CF carrierscreening to increase public knowledge and decreasestigmatization.

Counseling Carriers and At-Risk Couples

CF carrier screening can be informed by the Tay-Sachs,sickle cell, and ß-thalassemia experiences with geneticcounseling. Lessons about informing patients, counselingcarriers, and counseling carrier couples can be applied toCF carrier screening. The sickle cell experience oftenomitted counseling, and so individuals with sickle celltrait became anxious, not only because they were givenincorrect information, but also because they had receivedinadequate counseling.

Tay-Sachs programs considered informed consent,counseling of carriers, and counseling carrier couples tobe high priorities. Such informed consent and counselingaided in the understanding and adjustment of individuals“who were identified as carriers. In contrast, with noapparent negative effect, ß-thalassemia carrier screeningin one pilot involving pregnant women was done on everyblood sample drawn, with no separate informed consent(since providers felt they had patients’ implicit consentfor relevant diagnostic blood tests) (74), As is acknowl-edged to be essential, carriers and carrier couples receivedpost-test counseling.

. . . —

Appendix B---Case Studies of Other Carrier Screening Programs . 265

Box B-3—Fragile X Syndrome

Recent advances elucidating the genetics of fragile X syndrome will have a great impact on future applicationsto screening. Fragile X syndrome is the most common form of inherited mental retardation. Its incidence is about1 in 1,500 male and 1 in 2,500 female live births (58). It includes minor dysmorphic features such as an elongatedFace, large ears, prominent jaw, and macroorchidism (78). The genetics of this disorder are different from themtosomal recessive disorders of cystic fibrosis, Tay-Sachs disease, sickle cell anemia, and the thalassernias. FragileX syndrome is an X-linked disorder-the gene for the disorder lies on the X chromosome, one of the two sexdetermining human chromosomes. (Females have two X chromosomes, while males have one X and one Ychromosome.)

Initially described in 1969, fragile X syndrome derives its name from the tendency for the tip of the Xchromosome to break off or appear fragile (figure B-2) (49). Its mode of inheritance, however, is unlike otherX-linked disorders such as hemophilia—it is neither recessive nor dominant. Unaffected men and women cantransmit a fragile X chromosome without manifesting any symptoms of the syndrome or expressing the fragile sitecytogenetically. Such transmitters, or carriers, can have children or grandchildren with fragile X syndrome (104).The mothers of all affected children are considered to be obligate carriers, and no affected offspring arise as a directresult of a new mutation (85). Among females, about half of the obligate carriers do not express the fragile Xchromosome. About 50 percent of heterozygous females express the disorder to some extent, and 30 percent arementally retarded. Approximately 20 percent of males who inherit the gene from their mothers are unaffectedcarriers. Furthermore, severity appears variable in different siblings even within the same family (58).

Physical signs of the disorder are neither specific nor constant, and generally appear after childhood, makingdiagnosis difficult. In the past, diagnosis generally occurred only after the birth of a second affected male (89), andinvolved expert, labor-intensive laboratory analysis (84). Once the X chromosome was shown to be fragile, linkageanalysis of other family members could be performed, with prenatal tests also possible (33,86),

In 1991, researchers elucidated the uninique inheritance of fragile X syndrome and developed a DNA probe todetect the fragile X site (58,104). Reliable and specific detection of all male or female carriers of a fragile X siteis now possible (58,68). Similarly, prenatal analysis can be performed (58,68,90). Moreover, results from DNAassays appear to correlate with disease severity, and so can be used to predict clinical outcome (58). Fragile Xsyndrome will likely be one of the first disorders for which the primary diagnosis is based on the direct analysisof a mutation at the DNA level (68,84)

The increased knowledge of the genetics of fragile X syndrome has applications to genetic screening. Mostfamilies with fragile X syndrome are presently unknown, because routine screening of the entire developmentallydisabled population has not been practical and because fragile X syndrome historically has been poorly diagnosed(89). Given the high sensitivity and specificity of the new fragile X assay—and the value of early diagnosis forgenetic counseling purposes-the next step to consider is selected population screening (18). Although suchscreening would initially focus on developmentally disabled males and females, if the frequency of normaltransmitting males is as high as the frequency of affected males, as one hypothesis predicts, an argument can be madefor general population screening, as has been proposed in the United Kingdom (18).

With respect to genetic counseling needs for fragile X syndrome, one study examined interest in prenataldiagnosis and attitudes towards termination of affected pregnancies (51). Surveyed prior to the advent of the DNAassay, 81 percent of women said they would seek prenatal diagnosis, and 28 percent indicated they would terminatean affected pregnancy. There was no significant difference in responses between women who had affected childrenand those who did not. Issues the subjects considered most important for discussion with a genetic counselorincluded the availability of treatment, risk for having an affected grandchild, and expectations for the futurefunctioning of children with fragile X syndrome (51).

SOURCE: Office of Technology Assessment, 1992.

266 . Cystic Fibrosis and DNA Tests: Implications of Carrier Screening

Figure B-2—Fragile X Chromosomes

The fragile X site appears as a break or separation at the distalend of the long arm of X chromosomes (arrows). Thiscomputer-enhanced photomicrograph shows a carrier female(top) and an affected male (bottom),SOURCE: The Denver Children’s Hospital, 1992.

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