Lack of interest by nonpregnant couples in population-based cystic fibrosis carrier screening.

We used signs and letters to offer free cystic fibrosis (CF) carrier screening to nonpregnant adults in stable relationships who visited numerous clinical and nonclinical sites in Nashville. A total of 179 individuals (<<1% of those eligible) elected to be tested. To understand this observation, we used questionnaires to assess individuals' attitudes about genetic testing in general and about CF carrier screening in particular (n=873). Participants expressed conflicting views about carrier screening. More than 90% of people thought that genetic testing should at least be available. Most respondents said that the views of their partners and physicians were important in their decision making, and most believed that these others favored genetic testing. Yet, more than two-thirds indicated that such factors as insurability, being "at risk," what they would need to learn, abortion, and religious beliefs were important in their decision making, opinions that mitigated against genetic testing. In particular, one-third feared that carriers would lose their health insurance, one-quarter said that they would have been more interested had they been able to provide DNA by buccal swab rather than by finger stick, and less than one-sixth believed that genetic testing was meddling in God's plan. In the face of both the low level of use of free CF carrier screening by nonpregnant couples when it was not offered in person by health-care professionals and the wide variety of concerns demonstrated, we believe that clinicians should not routinely offer carrier screening to nonpregnant individuals who do not have a family history of CF.     

Cystic fibrosis carrier population screening in the primary care setting.

To determine the receptivity of prenatal care providers and their patients to carrier testing for cystic fibrosis (CF), we offered free carrier screening, followed by genetic counseling of carriers, to all prenatal care providers in Rochester, NY, for all their female patients of reproductive age, pregnant or not. Of 124 prenatal care providers, only 37 elected to participate, but many of these offered screening only to pregnant women. The acceptance rate among pregnant women was approximately 57%. The most common reasons for accepting screening were to obtain reassurance (50.7%) and to avoid having a child with CF (27.8 %). The most common reasons for declining screening were not intending to terminate a pregnancy for CF (32.4%) and believing that the chance of having a CF child was very low (32.2%). Compared with decliners, acceptors were more likely to have no children, regarded having a child with CF as more serious, believed themselves more susceptible to having such a child, knew more about CF, would be more likely to terminate a pregnancy if the fetus were shown to have CF, and more strongly supported offering CF screening to women of reproductive age. Of 4,879 women on whom results were obtained, 124 were found to be carriers. Of these 124 carriers, the partners of 106 were tested. Of the five at-risk couples, four requested prenatal diagnosis and one requested neonatal diagnosis. No woman found to be a carrier whose partner tested negative requested prenatal diagnosis. Except for the imperfect knowledge of those testing negative, none of the adverse outcomes predicted for CF carrier testing in the general population were observed in this study.     

Prenatal screening for cystic fibrosis carriers: an economic evaluation.

The cloning of the CFTR gene has made it technically possible to avert the unwanted birth of a child with cystic fibrosis (CF). Several large trials offering prenatal CF carrier screening suggest that such screening is practical and that identified carriers generally use the information obtained. Therefore, a critical question is whether the cost of such screening is justified. Decision analysis was performed that used information about choices that pregnant women were observed to make at each stage in the Rochester prenatal carrier-screening trial. The cost of screening per CF birth voluntarily averted was estimated to be $1,320,000-$1,400,000. However, the lifetime medical cost of the care of a CF child in today's dollars was estimated to be slightly>$1,000,000. Therefore, despite both the high cost of carrier testing and the relative infrequency of CF conceptions in the general population, the averted medical-care cost resulting from choices freely made are estimated to offset approximately 74%-78% of the costs of a screening program. At present, if it is assumed that a pregnancy terminated because of CF is replaced, the marginal cost for prenatal CF carrier screening is estimated to be $8,290 per quality-adjusted life-year. This value compares favorably with that of many accepted medical services. The cost of prenatal CF carrier screening could fall to equal the averted costs of CF patient care if the cost of carrier testing were to fall to $100.     

The deletion F508 is the major gene mutation in a representative Belgian cystic fibrosis population

Summary The cystic fibrosis (CF) gene deletion F508 was studied in a Belgian population of 74 families and their 83 CF children. The haplotypes for CF and normal chromosomes had previously been determined with several linked DNA probes. In our CF population, the gene deletion F508 was found in 76% of the mutant alleles. Of the deletion F508, 97% segregated with the highest risk haplotype for the CF carrier status. Some 61% of our families were found to be homozygous for this major CF mutation. Each of our three pancreatic sufficiency patients (two of whom were siblings) was heterozygote for the F508 deletion.     

CFTR mutations and reproductive outcomes in a population isolate

Multiple hypotheses have been proposed to explain the high incidence of cystic fibrosis in Caucasian populations. Most rely on a fitness advantage to carriers of CF mutations, either through increased resistance to infectious disease, such as cholera, or through increased fertility. In this study we tested the latter hypothesis in the Hutterites of South Dakota, a genetic isolate with a relatively high CF carrier frequency. Following a population-wide screen for the only two mutations present in the Hutterites (M1101K, ΔF508), we tested for associations between carrier status and measures of fertility. There was no evidence of nonrandom transmission of mutations (P = 0.409) or skewed sex ratios (P = 0.847) in children of carrier parents. Moreover, carrier status was not associated with overall fertility (P = 0.597 for carrier fathers and 0.694 for carrier mothers). Although carrier males’ sibship sizes were larger than carrier females’ sibship sizes (P = 0.049), this was not significant after accounting for multiple testing. Overall, our results suggest that if there is a fertility advantage among CF carriers, it is too small to be detected in our sample (85 carriers out of ∼950 screened), or the effects are confined to ΔF508 carriers, for which there are too few in our sample to test this specific hypothesis.     

Teaching about cystic fibrosis carrier screening by using written and video information.

We performed two studies using only written and video materials to educate people about cystic fibrosis (CF) and carrier screening. Participants were randomized to receive written or video materials. All received a brief questionnaire. Subjects in group I (n = 238) were (1) individuals in steady relationships and their partners, (2) > or = 18 years old, and (3) not pregnant. Those who accepted free screening and were not demonstrable carriers were sent a letter explaining their results and another questionnaire. Subjects in group II (n = 108) were parents seeking well child care in a university clinic. The main outcome measures were ability to answer questions correctly about (1) health status of CF carriers and people with CF, (2) the possibility of false-negative results, and (3) for those who had screening, the implications of their own results. Written and video materials were equally effective in conveying information. Prior to screening, subjects answered an average of 86% of questions correctly. Subjects with less formal education answered fewer questions correctly; 60% of those with less than a high school education had adequate knowledge of the health consequences of having CF or being a carrier, compared with > or = 94% of college graduates. Performance improved after screening. Where neither partner was a demonstrable carrier, 88% knew their own and their partner's test results, and 90% indicated that their risk of having a child with CF was not zero. Written and video educational materials can be used without face-to-face counseling to inform most people about carrier screening and their test results. These materials may be less effective for those with lower educational backgrounds.     

Application of carrier testing to genetic counseling for X-linked agammaglobulinemia.

Bruton X-linked agammaglobulinemia (XLA) is a phenotypically recessive genetic disorder of B lymphocyte development. Female carriers of XLA, although asymptomatic, have a characteristic B cell lineage-specific skewing of the pattern of X inactivation. Skewing apparently results from defective growth and maturation of B cell precursors bearing a mutant active X chromosome. In this study, carrier status was tested in 58 women from 22 families referred with a history of agammaglobulinemia. Primary carrier analysis to examine patterns of X inactivation in CD19+ peripheral blood cells (B lymphocytes) was conducted using quantitative PCR at the androgen-receptor locus. Obligate carriers of XLA demonstrated > 95% skewing of X inactivation in peripheral blood CD19+ cells but not in CD19- cells. Carrier status for mothers of isolated affected males could be assessed in 10 of 11 families: 7 women showed skewing, and 3 did not. Five carriers were found in six families in which there were no living affected males. Among all those tested, one individual's carrier status was considered to be indeterminate and five women were noninformative for the carrier test. Results obtained by the carrier test were congruent with linkage analysis (where applicable) using the RFLPs DXS178 and DXS94 and two newly developed polymorphic microsatellite markers, DXS178CA and DXS101AAT. Refinements in techniques for primary carrier testing and genetic mapping of XLA now make possible an ordered approach to diagnosis, prenatal diagnosis, and genetic counseling.     

Active cascade testing for carriers of cystic fibrosis gene.

OBJECTIVE--To examine the acceptability, practicability, efficiency, and application of active screening for carriers of the cystic fibrosis gene in the extended families of those in whom the disease is present (Cascade screening). DESIGN--Paediatricians and physicians provide details of their affected patients, pedigrees are drawn up, and relatives offered tests after initial contact by the affected nuclear families. Affected patients are genotyped in a laboratory with a special interest in the genetics of cystic fibrosis. SETTING--North Western health region. SUBJECTS--Relatives and partners of 607 people with cystic fibrosis. INTERVENTIONS--Genetic counselling by letter for people found to be carriers; formal genetic counselling and when indicated arrangements for prenatal diagnosis for couples discovered to be carriers. MAIN OUTCOME MEASURES--Number of carrier couples detected; action in pregnancy of detected carrier couples; extent of the uptake of screening by relatives. RESULTS--Of 1563 relatives or partners tested, 15 carrier couples were detected; of nine pregnancies undertaken by these 15, eight had prenatal tests and three terminated pregnancies. An average of 16 people per family have come forward for testing so far. CONCLUSIONS--Cascade screening for carriers of cystic fibrosis is well accepted by relatives, especially on the mother''s side of the family; it is 10 times more efficient in detecting carrier couples than unfocused screening. Detected carrier couples make practical use of the information in pregnancy. Active cascade screening for carriers is effective in cystic fibrosis and widespread application is recommended. These principles could be applied to other recessive disorders.     

Carrier detection and prenatal diagnosis of cystic fibrosis using an intragenic TA-repeat polymorphism

Summary We have analysed the segregation of a TA-repeat polymorphism in intron 17b of the cystic fibrosis transmembrane conductance regulator gene responsible for cystic fibrosis (CF) in 23 French CF families non-informative for the F508 mutation (i.e. with at least one parent not carrying F508) or closely linked DNA markers. At least 13 different alleles ranging from 7 to 45 repeats were observed and the detected heterozygosity was 89%. Of the 23 families studied, 19 were fully informative for prenatal diagnosis or carrier detection, 3 were partially informative and one was not informative. In 6 families, prenatal diagnosis for CF or carrier detection in siblings of CF cases were performed using this polymorphism.     

Cystic fibrosis typing with DNA probes and screening for ΔF508 deletion in families from Southern France

Summary A sample of 235 individuals from 49 French cystic fibrosis (CF) families with at least one living affected child was typed with probes for restriction fragment length polymorphisms (RFLPs) known to be linked to the CF gene, and was screened for the ΔF508 mutation. Using a combination of six probes, 44 out of the 49 families were sufficiently informative to enable prenatal diagnosis or carrier determination. As in many other populations, linkage disequilibrium was found between the CF locus and the haplotype B (XV2c: allele 1; KM19: allele 2), which accounts for about 78% of CF chromosomes in our families. The ΔF508 deletion was present in 64.3% of CF chromosomes.     

Adaptation of children to a chronically ill or mentally handicapped sibling.

The presence of a chronically ill or mentally handicapped child in a family can be a stress for the child''s siblings, who often are ill informed about the nature and prognosis of the illness, may be uncertain what is expected of them in the caregiving role, may feel their own identities threatened, and may experience ostracism by their friends and misunderstanding at school. Although individual reactions vary widely, feelings of anger, guilt, resentment and shame are commonly reported. Excessive responsibility and concern about one''s identity may add to these feelings and culminate in psychologic problems in the sibling. The physician caring for the family must be alert for symptoms of emotional disturbance or social maladjustment among the siblings of chronically ill or mentally handicapped children and should be prepared to counsel the family or refer them to a counsellor experienced in this area. In general, the first step is to be sure that the sibling is fully informed about the condition and to encourage frank discussion between the parents and the handicapped child''s siblings.     

Involving consumers in the development of an educational program for cystic fibrosis carrier screening.

Input from consumers of health care was sought in developing an educational program to be provided to individuals who are considering carrier testing for cystic fibrosis (CF). In addition, we assessed the ability of health professionals to predict consumers' priorities with regard to such information. A focus group of six middle school teachers formulated questions that they would ask in trying to decide whether they wanted carrier screening for CF. Then, other adults with (n = 39) and without (n = 60) a family history of CF were presented with the questions and were asked to select the questions in the order in which they would want them answered if offered the carrier test. After each question was answered, they were asked whether they would want the carrier test if it were offered to them. CF clinic staff, clinical geneticists, and genetic counselors (n = 31) were asked to select the questions in the order in which they believed that an adult from the general population would want them answered. There were no differences in the order in which adults with and without a family history of CF would want questions answered. Consumers would want to learn about the carrier test as well as their risk of being a carrier and of having a child with CF, before receiving information on reproductive options and the effect that a child with CF would have on the family. Of the 44% of consumers who changed their mind about wanting screening during the course of selecting questions, 52% did so after the first question that they selected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Offering cystic fibrosis carrier screening to an HMO population: factors associated with utilization.

We offered cystic fibrosis (CF) carrier testing to reproductive-age enrollees in an HMO, in order to determine factors associated with test utilization in a primarily nonpregnant population. Male and female enrollees either were mailed an invitation to have the test after attending an educational session (N = 2,713) or were approached in waiting rooms at the HMO sites and given the opportunity to have the test without making an additional visit (N = 608). Uptake was considerably higher when testing could be obtained without making an additional visit (23.5%) than when attendance at an educational session was required as a prerequisite for having the test (3.7%). Utilization was higher among respondents who were planning children. Caucasians, and those with higher educational attainment. Among respondents planning to have children, individuals with higher tolerance for test uncertainty, lower fear of stigma, and higher perceived risk of being a carrier were significantly more likely to have the test. Testing decisions were not associated with the perceived burden of a child with CF or with the likelihood of aborting for CF. Although utilization of CF carrier testing is relatively low among nonpregnant individuals, uptake is significantly higher when testing can be obtained with minimal effort. Factors associated with the decision to be tested had more to do with implications of being a carrier per se than with the concerns of having a child with CF.     

Direct and indirect mutation analyses in patients with ornithine transcarbamylase deficiency.

Ornithine transcarbamylase (OTC) is one of 5 enzymes in the detoxification of ammonia to urea, and its deficiency, an X-linked disease, is the most common inborn error of urea genesis in humans. Because of the devastating nature of the disease there is a strong demand for reliable and rapid molecular analyses in OTC families in order to offer carrier detection and prenatal diagnosis. This paper presents the efficiency of direct and indirect mutation analyses in 22 OTC families using Southern blotting and polymerase chain reaction (PCR) amplification. For 89% of the mothers with an affected child, at least 1 RFLP of the OTC locus was informative concerning prenatal diagnosis. 100% informativity was reached by using the additional flanking markers 754 and LI.28. In total, 3 deletions (14%) and 1 TaqI site mutation (4.5%) in exon 3 were detected. 13 (60%) of our 22 mothers were found to be carriers, 9 of them being obligate carriers and 4 detected by biochemical testing. 4 mothers were excluded as carriers by DNA analyses, and in 5 mothers the carrier status could not be assessed positively. DNA analyses permitted carrier detection in 32% and carrier exclusion in 55% of 22 female relatives. Prenatal diagnosis was performed in 4 families: in 1 family by direct mutation detection and in 3 families by linkage analyses. It was possible to determine the mutation origin in 6 families, all of them with male probands. In 4 families the mutation had occurred during grandpaternal spermiogenesis, suggesting higher mutation rates in males, but in 2 cases it was the result of an event during maternal oogenesis, proving that new mutations in the OTC gene do also occur in eggs. Our recommended strategy for carrier detection and prenatal diagnosis in OTC deficiency is to examine routinely Southern blots of BamHI, EcoRI, HindIII, MspI, PstI and TaqI digestions using the OTCcDNA probe pH0731 and the flanking markers 754 and LI.28, as well as the TaqI-digested PCR products of exons 3, 5 and 9.     

Effects of childhood cancer on long-term survivors and their families.

Problems experienced by families of long-term survivors of acute lymphatic leukaemia and Wilms''s tumour were investigated to find out the best way of using limited resources to improve management of such patients. All patients had received treatment at Alder Hey Children''s Hospital, and all had completed treatment at least two years before the study. A social worker interviewed the parents of each child. The results showed that various aspects of management needed improvement, including: information given to parents at diagnosis of their child''s illness and during subsequent treatment; continuity of care and multidisciplinary teamwork among those caring for the child; greater understanding by school teachers that such children have the same educational needs as others; wider communication by hospital staff with the child''s other relatives, particularly grandparents; financial help for parents; and marital counselling. To help implement these proposals full-time social workers were attached to the hospital. Preliminary results were encouraging, though it is too early to evaluate the long-term effects of the changes.     

Antenatal screening for carriers of cystic fibrosis: randomised trial of stepwise v couple screening.

OBJECTIVE--To perform a rigorous comparative evaluation of stepwise and couple approaches to antenatal carrier screening for cystic fibrosis. DESIGN--Pragmatic randomised trial. SETTING--Hospital antenatal clinic serving a regional population. SUBJECTS--2002 women (couples) attending for booking antenatal visit at less than 17 weeks'' gestation with no family history of cystic fibrosis. INTERVENTIONS--Offering counselling and carrier testing for cystic fibrosis, either to women in the first instance (stepwise) or to couples (couple screening). MAIN OUTCOME MEASURES--Uptake rates; anxiety; knowledge of cystic fibrosis and carrier status (both partners); attitudes to health, pregnancy, the baby, and screening (both partners); and uptake of carrier testing by relatives. RESULTS--Uptake of screening was the same for both approaches (90%). After delivery most women remembered test results and their meaning, but 53/253 (21%) of those with negative results of couple testing had forgotten that repeat testing would be advisable if they had a pregnancy with a new partner. With stepwise screening women identified as carriers had high levels of anxiety when results were received (mean anxiety score 52.3). This dissipated with a reassuring partner''s result (carriers'' mean anxiety score 36.1) to levels similar to those receiving negative results from couple screening. Of those receiving negative results, women who had stepwise screening were significantly less anxious than those who had couple screening (mean score with result 32.1 v 35.4, 95% confidence interval for difference -4.7 to -2.1). CONCLUSIONS--Couple screening allows carriers to avoid transient high levels of anxiety, but is associated with more anxiety and false reassurance among most screenees who will test negative. Stepwise screening gives carriers and their relatives genetic information and is, in our opinion, the better method.     

Linkage disequilibrium and CF allele segregation analysis in cystic fibrosis families in Northern Ireland

Summary Linkage disequilibrium and cystic fibrosis (CF) allele segregation were analysed in 46 CF families in Northern Ireland. The smaller (+) allele of the KM19/PstI polymorphism and the larger (-) allele of the XV-2c/TaqI polymorphism showed marked linkage disequilibrium with CF. This information can be used to alter the risk of an individual being a carrier of CF away from the expected population risk of 1 in 20. The high-risk genotypes K+K+ or X-X- have a risk of 1 in 10 and the low-risk genotypes K-K- or X+X+ have a risk of 1 in 50. A study of the segregation of CF alleles in the 46 families, using KM19 and Xv-2c, showed preferential inheritance of the paternal (79%), as opposed to the maternal (21%), CF allele by the heterozygous carriers. A mechanism that might explain this observation is discussed.     

Screening for carriers of cystic fibrosis--a general practitioner's perspective.

The identification of the gene for cystic fibrosis has led to the possibility of population based screening for carriers of cystic fibrosis to identify couples at risk of having an affected child. Pilot studies have shown that screening is feasible and does not cause untoward anxiety, though the uptake of testing varies considerably with the setting and method of invitation. Screening offered at times when individuals (and health professionals) perceive it as directly relevant will probably gradually become established in the United Kingdom. This review examines the role of general practice in genetic carrier screening as exemplified by cystic fibrosis. General practice has a pivotal role from the beginning in providing individuals and couples with information, facilitating testing of patients'' relatives and of carriers identified by screening elsewhere (such as antenatal clinics), and offering testing in the context of reproduction. Screening for the cystic fibrosis gene will probably be followed by other genetic screening programmes.     

The Winnipeg Children's Hospital child protection centre: a provincial medical initiative.

The Winnipeg Children''s Hospital child protection centre is a hospital-based provincial protection program that focuses on the diagnosis, treatment and prevention of child abuse and neglect in Manitoba. The multidisciplinary group of professionals working in the centre differs from most hospital-based teams in that it has a strong government liaison both functionally and financially, has strong ties to the welfare system and has legal counsel relating to the court system. The centre represents the philosophy that medical participation in welfare matters relating to children need not be relegated to the sidelines. This paper describes the centre''s history and structure, and it outlines some of its research projects.     

Cystic fibrosis heterozygote screening in 5,161 pregnant women.

A screening program for cystic fibrosis (CF) heterozygotes was conducted in a large HMO prenatal population, to evaluate the level of interest among eligible patients, the effectiveness of prescreening education, attitudes toward the screening process, psychological effects, and utilization of prenatal diagnosis and its outcomes. The heterozygote identification rate and frequency of specific CFTR mutations were also assessed. Identified carriers were offered genetic counseling and testing of male partners. Prenatal diagnosis was offered if both parents were identified as carriers. A total of 5,161 women underwent carrier testing; 947 others completed survey instruments only. The acceptance rate of screening was high (78%), and pretest education by videotape was generally effective. Adverse psychological effects were not reported. Participants generally found screening to be desirable and useful. Screening identified 142 female heterozygotes, 109 couples in which the male partner was not a carrier, and 7 high-risk couples. The incidence of R117H mutations was much higher than expected. The number of identified carriers was much lower in Hispanics than in Caucasians. We conclude that large-scale prenatal screening for CF heterozygotes in the absence of a family history of CF is an acceptable method for identifying couples at risk for affected fetuses. Sufficient pretest education can be accomplished efficiently, test insensitivity is well accepted, adverse psychological events are not observed, and general patient satisfaction is high.