Sylvia A. Metcalfe

Use of community genetic screening to prevent HFE-associated hereditary haemochromatosis

HFE-associated hereditary haemochromatosis is a recessive, iron-overload disorder that affects about one in 200 north Europeans and that can be easily prevented. However, genetic screening for this disease is controversial, and so we assessed whether such screening was suitable for communities. Cheek-brush screening for the Cys282Tyr HFE mutation was offered to individuals in the workplace. Outcomes were assessed by questionnaires before and after testing. 11,307 individuals were screened. We recorded no increase in anxiety in individuals who were homozygous for the Cys282Tyr mutation or non-homozygous. Self-reported tiredness before testing was significantly higher in homozygous participants than in non-homozygous participants (chi2 test, p=0.029). Of the 47 homozygous individuals identified, 46 have taken steps to treat or prevent iron accumulation. Population genetic screening for HFE-associated hereditary haemochromatosis can be practicable and acceptable.

Carrier screening for Beta-thalassaemia: a review of international practice

β-thalassaemia is one of the most common single-gene inherited conditions in the world, and thalassaemia carrier screening is the most widely performed genetic screening test, occurring in many different countries. β-thalassaemia carrier screening programmes provide a unique opportunity to compare the delivery of carrier screening programmes carried out in different cultural, religious and social contexts. This review compares the key characteristics of β-thalassaemia carrier screening programmes implemented in countries across the world so that the differences and similarities between the programmes can be assessed. The manner in which thalassaemia carrier screening programmes are structured among different populations varies greatly in several aspects, including whether the programmes are mandatory or voluntary, the education and counselling provided and whether screening is offered pre-pregnancy or antenatally. National and international guidelines make recommendations on the most appropriate ways in which genetic carrier screening programmes should be conducted; however, these recommendations are not followed in many programmes. We discuss the implications for the ethical and acceptable implementation of population carrier screening and identify a paucity of research into the outcomes of thalassaemia screening programmes, despite the fact that thalassaemia screening is so commonly conducted.

A systematic review of population screening for fragile X syndrome.

Purpose: To conduct a systematic review of literature regarding population-based screening for fragile X syndrome in newborns and women of reproductive age, either before or during pregnancy.Methods: Seven electronic databases were searched for English language studies published between January 1991 and November 2009. Data extraction was performed for all included studies. Results were synthesized using a narrative approach.Results: One article that examined offering newborn screening for fragile X syndrome and 10 that examined the offer of fragile X syndrome screening to women of reproductive age were identified. Two of these articles also addressed psychosocial aspects of population screening for fragile X syndrome such as attitudes to screening and experiences of screening, and a further nine addressed these issues alone. Studies exploring psychosocial issues demonstrated challenges for counseling arising from a lack of awareness or personal experience with fragile X syndrome in the general population.Conclusions: Targeted counseling and educational strategies will be essential to support women from the general population. It is crucial that future studies offering screening for fragile X syndrome explore a range of psychosocial aspects in addition to looking at uptake of testing and mutation frequency.

Use of a decision aid for prenatal testing of fetal abnormalities to improve women's informed decision making: a cluster randomised controlled trial [ISRCTN22532458].

Objective  To evaluate the effectiveness of a decision aid for prenatal testing of fetal abnormalities compared with a pamphlet in supporting women’s decision making.

Responsible implementation of expanded carrier screening

This document of the European Society of Human Genetics contains recommendations regarding responsible implementation of expanded carrier screening. Carrier screening is defined here as the detection of carrier status of recessive diseases in couples or persons who do not have an a priori increased risk of being a carrier based on their or their partners’ personal or family history. Expanded carrier screening offers carrier screening for multiple autosomal and X-linked recessive disorders, facilitated by new genetic testing technologies, and allows testing of individuals regardless of ancestry or geographic origin. Carrier screening aims to identify couples who have an increased risk of having an affected child in order to facilitate informed reproductive decision making. In previous decades, carrier screening was typically performed for one or few relatively common recessive disorders associated with significant morbidity, reduced life-expectancy and often because of a considerable higher carrier frequency in a specific population for certain diseases. New genetic testing technologies enable the expansion of screening to multiple conditions, genes or sequence variants. Expanded carrier screening panels that have been introduced to date have been advertised and offered to health care professionals and the public on a commercial basis. This document discusses the challenges that expanded carrier screening might pose in the context of the lessons learnt from decades of population-based carrier screening and in the context of existing screening criteria. It aims to contribute to the public and professional discussion and to arrive at better clinical and laboratory practice guidelines.

A model for offering carrier screening for fragile X syndrome to nonpregnant women: results from a pilot study.

Purpose: To develop a model of offering population carrier screening for fragile X syndrome to nonpregnant women in primary care, using a program evaluation framework.Methods: A three-phase approach included: (I) needs assessment exploring staff and client attitudes, and informing development of educational materials, questionnaires and protocols; (II) offering screening to women, with questionnaires at baseline (Q1) and another (Q2) 1-month later; (III) genetic counseling for test-positive women and interviews with a subgroup of participants.Results: Of 338 volunteering for Phase II, 94% completed Q1, 59% completed Q2, and 20% (N = 65) chose testing revealing one premutation carrier and three gray zone results; 31 women were interviewed. Tested women had more positive attitudes toward screening (Q1: P < 0.001; Q2: P < 0.001) compared with untested, although there was no significant difference in mean knowledge scores or anxiety. Women generally supported being offered prepregnancy screening; however, reasons against being tested included: not currently planning a family; perceiving benefits of screening as unimportant; and having to return for testing.Conclusion: This is the first prospective study exploring informed decision-making for fragile X syndrome carrier screening, using a thorough process of consultation, with no apparent harms identified. It provides a model for development of future genetic screening programs.

Serum levels of mullerian inhibiting substance in boys with cryptorchidism

Serum levels of Mullerian inhibiting substance (MIS) were measured in boys with cryptorchidism (n = 104) and paired, age-matched controls (n = 104) using an enzyme immunoassay. Control MIS levels were high during the first year of life with a peak level at 4 to 12 months, subsequently diminishing with age. MIS levels in patients with undescended testes also declined with age, although a surge was not found in the first year. Mean MIS concentration of cryptorchid boys was significantly lower than controls (P less than .001). There was a significant reduction of the mean MIS level in children with bilateral cryptorchidism compared with those with unilateral undescended testis (P less than .05). These differences might support the hypothesis that MIS initiates transabdominal testicular descent. However, because most undescended testes are probably the result of anatomical or functional abnormalities during transinguinal testicular descent, differences in MIS levels more likely result from secondary testicular degeneration. In the future, MIS immunoassay should play an important role in the investigation of gonadal function in boys with various genital disorders, including cryptorchidism.

Evaluation of a Tay‐Sachs Disease screening program

Tay‐Sachs Disease (TSD) is an autosomal recessive neurodegenerative disorder. TSD is prevalent in the Ashkenazi Jewish population, and carrier screening programs have been implemented worldwide in these communities. A screening program initiated in 1997 involving the Melbourne Jewish community (Australia) incorporated education, counselling and carrier testing of high‐school students aged 15 to 18 years. This study aimed to assess the participation rates, level of knowledge obtained and predicted feelings and attitudes of the students involved. Seven hundred and ten students participated, there was a 67% uptake for testing with a carrier rate of 1 in 28 determined. The level of knowledge of the students following education was high and of relative importance in regard to decision making, as were their feelings and attitudes about genetic testing for carrier status. A significant impediment to test uptake was the need for blood sampling, resulting in a recommendation for the introduction of DNA analysis on cheek brush samples. The evaluation of this program has given a wider scope for further development as well as providing valuable information for the implementation of community screening programs.

‘It is not in my world’: an exploration of attitudes and influences associated with cystic fibrosis carrier screening

Carrier screening for cystic fibrosis has been recommended for pregnant women and their partners, individuals and couples prior to conception, and for people with a family history. Many pilot programmes offering cystic fibrosis carrier screening, most commonly in the prenatal setting, have shown that uptake and acceptability are high. This article explores perspectives of the Victorian community regarding carrier screening for cystic fibrosis prior to offering screening. In particular whether or not such carrier screening should be offered, the best time for offering carrier screening, the information required for making a decision about carrier screening, and how this information can best be provided. A qualitative approach was taken to enable exploration of the views of stakeholders. Four focus groups and 32 interviews were conducted with a total of 68 participants. Participants were in agreement that cystic fibrosis carrier screening should be made available to everyone. However, potential consumers viewed cystic fibrosis carrier screening as ‘not in my world’ and were unlikely to request such screening unless it was offered by a health professional, or they had a family history. The best time for carrier screening was seen to be an individual preference and an information brochure was perceived to be useful when considering carrier screening. Lack of knowledge around the irrelevance of family history is a barrier to cystic fibrosis carrier screening. This study highlights the importance of community consultation, with stakeholders, prior to implementation of carrier screening programmes.

Implementation of HaemScreen, a workplace‐based genetic screening program for hemochromatosis

There is debate as to whether community genetic screening for the mutation(s) causing hereditary hemochromatosis (HH) should be implemented, due to issues including disease penetrance, health economic outcomes, and concerns about community acceptance. Hemochromatosis is a common preventable iron overload disease, due in over 90% of cases to C282Y homozygosity in the HFE gene. We are, therefore, piloting C282Y screening to assess understanding of genetic information and screening acceptability in the workplace setting. In this program, HaemScreen, education was by oral or video presentation in a group setting. C282Y status was assessed by polymerase chain reaction (PCR) and melt‐curve analysis on DNA obtained by cheek‐brush sampling. Of eligible participants, 5.8% (1.5–15.8%) attended information and screening sessions, of whom 97.7% (5571 individuals) chose to be tested. Twenty‐two C282Y (1 : 253) homozygotes were identified and offered clinical follow‐up. There were 638 heterozygotes (1 : 8.7). The determinants for participation have been analyzed in terms of the principles outlined in the Health Belief Model. Widespread screening for HH is readily accepted in a workplace setting, and a one‐to‐many education program is effective. The level of participation varies greatly and the advertizing and session logistics should be adapted to the specific features of each workplace.