Moira Mennie

Prenatal screening for cystic fibrosis

Screening for carriers of CF (cystic fibrosis) is now possible but the best way of delivering such a service is unknown. In one model 4348 women attending antenatal clinics in an Edinburgh maternity hospital were invited to participate in a trial of prenatal screening. Mouthwash samples were tested for six CF alleles (85% of mutant genes) and when a woman was found to be a CF carrier her partner was also tested. Heterozygous couples were offered prenatal diagnosis. 609 (14%) women declined to enter the trial and another 574 (13%) were not screened, usually because of late booking. Among the remaining 3165 women there were 111 carriers of a CF gene (1 in 29). 4 of these 111 had carrier partners and these couples opted for prenatal diagnosis, the 1 pregnancy with an affected fetus being terminated. The psychological impact of screening was assessed by the general health questionnaire. There was a significant increase in stress at the time of the test result among women identified as carriers. However, this disappeared when their male partners tested normal and did not reappear later in the pregnancy. By providing time for couples to discuss the possibility of screening and by offering the test at a point (the antenatal booking clinic) at which most pregnant women are seen, this approach has advantages, provided that counselling is readily available.

Antenatal screening for cystic fibrosis: a trial of the couple model

Abstract Objective : To assess the delivery and acceptability of antenatal couple screening for cystic fibrosis. Carrier status was notified only when both members of a partnership had cystic fibrosis alleles and therefore a one in four risk of having an affected child. Design: Mouthwash samples were tested when both partners participated. Results were returned only to positive couples. Setting : Two large maternity hospitals in Edinburgh. Subjects : Screening was offered to all couples who booked at one of the two hospitals. Main outcome measures :(a) The take up of screening, carriers and carrier couples identified, take up of prenatal diagnosis, and numbers of affected fetuses detected; (b) questionnaire measures of patient satisfaction and stress. Results : Screening was offered to 8536 couples. 714 (8.4%) were regarded as ineligible, usually because of late booking or absence of a partner. 1900 (24.3%) of the remainder declined screening. Among the 5922 screened couples, four tested positive - that is, both partners were cystic fibrosis heterozygotes. All four elected to have prenatal diagnosis. There were three terminations of pregnancy because of an affected fetus, one couple having two successive pregnancies with affected fetuses. The participation rate was 76% for eligible couples (5922/7822) and 69% for all couples (5922/8536). Only 89 screened couples (1.5%) requested information on individual carrier status. No anxiety was detected among a cohort of the screened population, and 99% of questioned participants expressed satisfaction with the concept of couple screening. Conclusions : Antenatal couple screening is a20satisfactory and acceptable way of screening for cystic fibrosis and has been adopted as routine in the two trial hospitals.

Predictive testing for Huntington disease : social characteristics and knowledge of applicants, attitudes to the test procedure and decisions made after testing

An investigation has been made of the social characteristics and knowledge and experience of Huntington disease (HD) for the first 80 individuals considering presymptomatic testing (applicants) at the medical genetics centres in Edinburgh and Glasgow and of attitudes to the test procedure and decisions made after testing for those who received a result. Sixty‐one percent of applicants were female and 31% were over 40 years old. Almost all had a symptomatic parent but 38% did not know HD was in their family until they were over 25 years old and 48% had never received genetic counselling. Thirty‐eight percent of applicants first heard of the test at the genetic clinic, 20% from a relative and 20% from the media, but none had received information from their GP. Thirty‐one applicants did not have the test because they voluntarily withdrew (17 individuals), their family structure was unsuitable or no informative result was possible (11 individuals), or they were diagnosed clinically as being affected (3 individuals). Those who voluntarily withdrew did not differ significantly from the 49 who received a result in social characteristics or knowledge and experience of HD. Twenty‐two individuals were found to be at increased risk (IR) (>50% of becoming affected) and 27 to be at decreased risk (DR) (< 50% of becoming affected). There was a median period of 9 months between entering the test procedure and receiving a result and the main criticism of the procedure was that it took too long to complete and several individuals experienced considerable anxiety while awaiting their result. One year after receiving their result, almost 40% of individuals had made major life decisions, mainly in the areas of personal relationships, career and financial matters and over a third of fecund individuals in both IR and DR groups had changed their decision about future childbearing. Eighty‐five percent of the IR group and 53% of the DR group requested continued follow up after the 1‐year follow‐up visit. The majority wanted follow up by the genetic clinician, but we have found that in practice many individuals do not attend when offered clinic appointments after this time.

Prenatal screening for cystic fibrosis: attitudes and responses of participants

Mennie M, Compton M, Gilfillan A, Axton RA, Liston WA, Pullen I, Whyte D, Brock DJH. Prenatal screening for cystic fibrosis: attitudes and responses of participants.

Attitudes of general practitioners to screening for cystic fibrosis.

Objective To ascertain the views of general practitioners (GPs) about screening for cystic fibrosis. To find out whether and under what conditions they might play a part in the delivery of such programmes. Setting All GP practices within the Lothian Health Board area. Methods A self administered questionnaire was sent to each of the 532 GPs in the area. Results 334 (63%) GPs participated in the study. Only 23% of these claimed to have no professional or personal experience of the disorder. 77% of GPs were aware of the existence of a programme of antenatal screening for cystic fibrosis (CF), which had been running in Edinburgh for the past six years, with only 2% unfavourably disposed to it. However, when asked to rank CF screening against antenatal screening for spina bifida and Downs syndrome, or cervical and breast screening, 55% gave it the lowest priority. There was fairly equal support for the screening site being an antenatal clinic, a genetic centre, a family planning clinic, or a GP surgery, but little enthusiasm for programmes in schools or the workplace. Surprisingly, only 13% of GPs thought that screening should be offered to those with a negative family history of the disorder. Although the idea of involvement in screening was favoured, GPs claimed that any aspect of delivery that they undertook would need to be supported. There were no significant differences between the responses of fundholding GPs and non-fundholders. Conclusions The low ranking by GPs of CF screening against other programmes, together with the need for support if they were to be involved, suggests that it is currently impractical to move the programme from its existing site in antenatal clinics.

Prenatal Screening for Cystic Fibrosis Carriers: does the method of testing affect the longer-term understanding and reproductive behaviour of women?

A comparative study of women who underwent prenatal cystic fibrosis (CF) carrier screening by either the ‘two‐step method’ or the ‘couple method’ was carried out 2–4 years after testing. Recall of the screening test and test result, understanding of the implications of the test result, and reproductive intentions and behaviour were compared. Women screened by the two‐step method were significantly better informed on the genetic implications of the test result and the significance of being a single gene carrier than their couple screen counterparts. Regardless of the method of screening, a majority of those who had received a negative test result erroneously believed that they were definitely not a carrier. However, women who intended having further children were significantly more likely to understand correctly that a negative test result meant that they were unlikely to be a CF carrier. The method of testing had no influence on reproductive intentions or behaviour. Differences in emphasis, content and presentation of pre‐screening information and counselling between the two methods of screening are identified. Reasons for variation in the long‐term understanding between women screened by the two methods are discussed.

Use of linkage disequilibrium data in prenatal diagnosis of cystic fibrosis.

SummaryParents at risk of bearing a child with cystic fibrosis, and who have no living affected child, often use prenatal diagnosis based on microvillar enzyme assay in second-trimester amniotic fluid samples. If enzyme levels are abnormal and the pregnancy is terminated, it is possible in principle to use the fetal tissues to establish the phase relationship of linked DNA markers for a subsequent first-trimester prenatal diagnosis. However, the probability of a fetus being affected after an abnormal microvillar enzyme test may be no greater than 80%. The strong linkage disequilibrium between haplotypes at the D7S23 locus and the cystic fibrosis gene may be used to increase this probability. If fetal tissues are homozygous for the 6.6-kb band defined by pKM.19 and PstI and also homozygous for the 2.1-kb band with pXV-2c and TaqI, the chance of being affected increases from 80% to between 95% and 97%. We regard this as being sufficiently certain for use in phase determination.

PREDICTIVE TESTING FOR HUNTINGTON'S DISEASE WITH LINKED DNA MARKERS

Availability of new DNA markers, more tightly linked to the Huntingtons disease (HD) locus than the original G8 (D4S10) probes, has improved predictive accuracy for both presymptomatic and prenatal exclusion testing. 50 predictive tests were carried out on high-risk individuals. 6 of these were on first-trimester chorionic villus biopsy specimens; in 2 cases the HD gene was not transmitted to the fetus while in 4 cases no exclusion could be made. The remaining 44 tests were on adults with either 25 or 50% risk of manifesting the disease; 19 had a greatly increased risk and 25 a substantially decreased risk of HD. Family structures in Scotland are suitable for testing about 75% of potentially affected individuals, and the new generation of DNA markers makes virtually all families fully informative.

Presymptomatic testing for Huntington's disease

SummaryPresymptomatic testing for Huntingtons disease (HD) is possible through the use of restriction fragment length polymorphisms (RFLPs) at the closely linked D4S10 locus. Recombination between the HD and D4S10 loci will occur in 4%–5% of meioses, and is a well-recognised complication of predictive testing. Recombination between RFLPs within the D4S10 locus is a rare event and can usually be ignored. We report a case where such an intra-locus recombination frustrated attempts to predict the chance of a high-risk individual inheriting the HD gene.

Genetic linkage between Huntington's disease and D4S10(G8) in Scottish families

Genetic linkage between Huntingtons disease (HD) and polymorphic DNA markers at the D4S10 locus has been investigated in 16 Scottish families. A maximum lod score of 3.499 at a recombination fraction of 0.07 was found, with 95% confidence limits of 0.02 and 0.22. Only one obvious recombinant was detected, and the wide confidence limits probably reflect the large number of unaffected individuals whose risk could only be estimated empirically.