Demand for DNA probe testing in three genetic centres in Britain (August 1986 to July 1987).

We report a preliminary analysis of the data collected during the first year of the evaluation of clinical genetics in the context of DNA probes in three genetic centres, to show the pattern of the demand for genetic services in the three centres and the services used in meeting that demand. The analysis includes information on 10,185 persons from 2852 families. The results are presented according to mode of inheritance and according to the most common disorders for which DNA probes have been used in the three centres. The results indicate that the use of DNA probes is now a major element of activity in genetic departments, and that as long as indirect DNA probe testing is the predominant manner of using recombinant technology, the clinical input will be an important element of the costs, probably more so than that of the DNA laboratories, as a large number of family members needs to be tested. In most cases centres have concentrated activity on DNA testing for common and severe genetic disorders. However, there are disorders, such as familial hypercholesterolaemia, which have not been part of the established pattern of services. Conversely, a relatively high number of families have been studied for some disorders of very low incidence. This suggests that the number of DNA laboratories should be limited. The precise arrangements will need to be established. With such services the distribution of DNA testing facilities for different disorders can be controlled to limit duplication. The model followed in Scotland based on collaboration between centres is worth considering. We have detected very large differences in take up rate of services within and between regions. Although many factors may contribute to these differences, ease of access and lay and professional awareness are probably the most important. This is supported by the fact that more patients from the same or neighbouring DHAs attend the genetic centre than from those further away. We also concluded that published guidelines for clinicians in general on the uses of DNA probes, the type of families that could benefit, and the centres to which referrals should be sent would be very useful in increasing coverage and maximising the effectiveness of the services. Since this may increase demand, this educative tool should be coordinated and agreed by the Departments of Health with all the genetic departments and centres in the country.     

Ten years of presymptomatic testing for Huntington's disease: the experience of the UK Huntington's Disease Prediction Consortium

Data on all presymptomatic genetic tests for Huntington's disease (HD) in the UK have been collected over the 10 year period since testing became available as a service. A total of 2937 completed tests have been performed up to the end of 1997, 2502 based on specific mutation testing, feasible since late 1993.
A total of 93.1% of these were at 50% prior risk, with a significant excess of females (58.3%); 41.4% of results were abnormal or high risk, including 29.4% in subjects aged 60 or over. The trend in test numbers has currently levelled out at around 500 per year.
Almost all presymptomatic tests are carried out in National Health Service genetics centres, with a defined genetic counselling protocol and with availability now in all regions of the UK. The introduction and establishment of HD presymptomatic testing shows that this form of predictive medicine for Mendelian disorders can be successfully incorporated into National Health Service structures. The comprehensive collection of simple data allows trends in demand and outcomes to be monitored and has also been the foundation for more detailed specific studies. A comparable approach to data collection in other genetic disorders will be important as presymptomatic testing becomes more generally feasible.


Keywords: Huntington's disease; presymptomatic testing     

A consortium approach to molecular genetic services. Scottish Molecular Genetics Consortium.

The four Scottish university medical genetics centres formed a consortium in 1985 to provide a DNA based service in prenatal diagnosis, carrier detection, and predictive testing for a range of Mendelian disorders. Each centre took sole responsibility for laboratory analyses of an assigned set of disorders, while families continued to be investigated and patients counselled within their own areas. DNA was extracted from relevant tissues in the centre most convenient to the family member and then dispatched to the appropriate laboratory for analysis. Results were interpreted and risks assessed by discussion between laboratory staff and the clinical geneticist in charge of the case. In the first three years of the consortium 92 prenatal diagnoses or exclusion tests were carried out, the majority being for cystic fibrosis (35), Duchenne muscular dystrophy (21), and Huntington's disease (11). Carrier testing was carried out in 271 X linked recessive disorders, the most common indications being Duchenne and Becker muscular dystrophies (198) and haemophilias A and B (48). Predictive testing was attempted in 41 consultants at risk for Huntington's disease, 37 at risk for myotonic dystrophy, and 32 at risk for developing adult polycystic kidney disease. The total of all carrier tests, including those for autosomal recessives, was 543. A consortium or supraregional approach to molecular genetics services has a number of advantages. Constituent laboratories need hold only those probes and enzymes relevant to their assigned disorders and can gain maximum experience with these systems. Scattered families may often be linked into single kinships, thus allowing rapid confirmation of diagnosis when an urgent request is made for a prenatal diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Presymptomatic testing for Huntington''s disease: a world wide survey. The World Federation of Neurology Research Group on Huntington''s Disease.

World wide data on presymptomatic testing for Huntington's disease using closely linked DNA markers show that 1479 persons at risk received completed test results up to the end of 1991. Testing has been carried out in 19 countries, with at least 88 centres involved, and numbers have levelled off after a peak in 1990. Only 5% of those at risk have been tested in six countries with the longest established programmes. Continued monitoring of international data will be of value in assessing the spread and impact of genetic testing, not only for Huntington's disease, but for other serious genetic disorders of later life.     

Genetic counselling and consent for tumour testing in HNPCC

Molecular pathological tests are performed on stored tumour material in order to identify individuals with hereditary non-polyposis colorectal cancer. We have previously identified that there is widespread use of this testing and now describe what counselling occurs prior to testing and the approaches in seeking consent. A respondent from every cancer genetic centre in UK offering microsatellite instability and/or immunohistochemistry testing (n= 20, response rate = 100%) was interviewed in order to ascertain pre-test counselling and consent protocols. Individuals providing consent are not always seen in person prior to providing consent but few services had supporting written information. Nine (of 19) consent forms documented consent to perform genetic testing, while the majority (14/19) sought consent to release pathology samples to the genetic service. Less than half of the services routinely seek consent to test samples from a deceased individual. Concerns were raised about spousal consent when the implications of results are for blood relatives. The differences identified between genetic counselling for testing of tumour tissue and for germ-line genetic testing suggest that counselling protocols specific for somatic testing should be developed. The results are discussed in the context of a changing legal environment and anticipated growing demand for testing.     

Genetic services in the context of DNA probes: what do they cost?

We describe results from the first year of a three year economic evaluation of genetic services in the context of DNA probes provided at three genetic centres in Great Britain. The analysis so far has concentrated on the costs of providing DNA diagnostic services. Estimates are given of the total costs of providing DNA probe services at each of the three centres, together with information for assessing the cost implications of future developments in these services. DNA probe services are likely to be funded as a Regional specialty. This paper concludes that relative to other developing medical technologies and as an investment by Regions, DNA probe services are inexpensive. An appraisal of the benefits to be derived from DNA probe services is still to be undertaken.     

A national perspective on prenatal testing for mitochondrial disease

Mitochondrial diseases affect >1 in 7500 live births and may be due to mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). Genetic counselling for families with mitochondrial diseases, especially those due to mtDNA mutations, provides unique and difficult challenges particularly in relation to disease transmission and prevention. We have experienced an increasing demand for prenatal diagnostic testing from families affected by mitochondrial disease since we first offered this service in 2007. We review the diagnostic records of the 62 prenatal samples (17 mtDNA and 45 nDNA) analysed since 2007, the reasons for testing, mutation investigated and the clinical outcome. Our findings indicate that prenatal testing for mitochondrial disease is reliable and informative for the nuclear and selected mtDNA mutations we have tested. Where available, the results of mtDNA heteroplasmy analyses from other family members are helpful in interpreting the prenatal mtDNA test result. This is particularly important when the mutation is rare or the mtDNA heteroplasmy is observed at intermediate levels. At least 11 cases of mitochondrial disease were prevented following prenatal testing, 3 of which were mtDNA disease. On the basis of our results, we believe that prenatal testing for mitochondrial disease is an important option for couples where appropriate genetic analyses and pre/post-test counselling can be provided.     

Ethical and social issues in presymptomatic testing for Huntington''s disease: a European Community collaborative study. European Community Huntington''s Disease Collaborative Study Group.

An analysis of social and ethical aspects of presymptomatic testing for Huntington's disease has been carried out, based on data on linked DNA markers, from four major testing centres in different European Community countries (Belgium, Italy, Netherlands, and United Kingdom). Information was available on 603 applicants, with 213 final results given, of which 32% gave an increased risk. A series of specific issues and problems were documented systematically for all applicants, results being given on frequency of occurrence and illustrated by individual case histories. The principal issues could be grouped as problems of inappropriate referral, problems involving relatives, and problems relating to disclosure of results. At least one important problem was encountered in 46% of applicants, emphasising the importance of expert counselling, preparation, and support of applicants, and of close liaison between clinical, counselling, and laboratory staff. The extensive and detailed information available for Huntington's disease from this and other studies will be of considerable value in relation to genetic testing for other late onset genetic disorders and will be even more relevant to Huntington's disease now that specific mutation analysis is possible for this disorder.     

Statement of the ESHG on direct-to-consumer genetic testing for health-related purposes

Many private companies offer direct-to-consumer (DTC) genetic testing services. Some tests may detect severe and highly penetrant monogenic disorders, while other tests are for genetic variants found associated with increased susceptibility for common and complex diseases in large-scale population studies. Through its Public and Professional Policy committee followed by member and expert consultation, the European Society of Human Genetics has developed the following policy on advertising and provision of predictive genetic tests by such DTC companies: (1) clinical utility of a genetic test shall be an essential criterion for deciding to offer this test to a person or a group of persons; (2) laboratories providing genetic tests should comply with accepted quality standards, including those regarding laboratory personnel qualifications; (3) information about the purpose and appropriateness of testing should be given before the test is done; (4) genetic counselling appropriate to the type of test and disease should be offered; and for some tests psychosocial evaluation and follow-up should be available; (5) privacy and confidentiality of sensitive genetic information should be secured and the data safely guarded; (6) special measures should be taken to avoid inappropriate testing of minors and other legally incapacitated persons; (7) all claims regarding genetic tests should be transparent; advertisement should be unbiased and marketing of genetic tests should be fair; (8) in biomedical research, health care and marketing, respect should be given to relevant ethical principles, as well as international treaties and recommendations regarding genetic testing; and (9) nationally approved guidelines considering all the above-mentioned aspects should be made and followed.Progress in biotechnology and genetic research has led to an increasing number of tests with potential predictive health information. In parallel with this development, private companies have established direct-to-consumer (DTC) genetic testing services, both for monogenic and severe genetic disorders and for genetic variants possibly associated with common complex diseases (susceptibility variants). Tests are also offered for conditions of minor or no health importance.The European Society of Human Genetics (ESHG) is concerned about the way in which commercial companies are currently introducing genetic tests into the market outside of the scope of the traditional healthcare system. With this Statement, we provide a formal policy with regard to DTC advertising and provision of genetic tests with predictive health information. Important issues, such as DTC paternity and ancestry testing, are thus outside the scope of this Statement.In line with the Council of Europe''s Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Genetic Testing for Health Purposes and the OECD Guidelines for Quality Assurance in Molecular Genetic Testing, this Statement highlights the importance of right to information, quality of the test performed, clinical usefulness of the tests provided, the need for individualized medical supervision, the provision of pre-test information and genetic counselling, follow-up and support in the interpretation of results and their psychosocial impact, the protection of persons not able to consent, respect for privacy and confidentiality, and the storing of the samples, their property and respect for ethical principles in research.     

Parents'' responses to predictive genetic testing in their children: report of a single case study.

There is a widely held view among health professionals that predictive genetic testing of children for late onset diseases is not desirable clinical practice. Yet, little is known about the views of parents, or their responses, to predictive genetic testing in their children. Since such testing is being carried out in some genetic centres, the opportunity was taken to conduct a single case study of the parents of 2 and 4 year old sisters who were tested for the gene for familial adenomatous polyposis. Interviews before testing, after, and 15 months later showed a stable attitude, that parental responsibility included making decisions about such testing, and that the role of health professionals should be one of information giving rather than decision making. These parents had no regrets about having their children tested and reported no changes in their behaviour towards either the child who tested positively or the child who tested negatively. Using standardised scales, mood was found to be within the normal range both before and after testing in the mother and father. This case study is a first step towards systematic empirical studies determining the consequences of acquiescing to parents' requests for genetic testing in their children.     

Les tests génétiques à l’heure de la deuxième révision des lois de bioéthique

This article focuses on six questions raised by genetic testing in human: (1) the use of genetic tests, (2) information given to relatives of patients affected with genetic disorders, (3) prenatal and preimplantatory diagnosis for late onset genetic diseases and the use of pangenomic tests in prenatal diagnosis, (4) direct-to-consumer genetic testing, (5) population screening in the age of genomic medicine and (6) incidental findings when genetic testing are used.     

An evaluation of clinical presentation and genetic testing approaches for patients with neuromuscular disorders

Inherited neuromuscular disorders (NMDs) are a large group of genetic conditions characterized by impaired peripheral nerve, motor neuron, neuromuscular junction, or skeletal muscle function. These conditions are also known to have clinical and genetic heterogeneity and variable ages of onset. Clinical evaluation for NMDs has increasingly incorporated molecular genetics. However, genetic testing is complicated by the variety of testing options and the ambiguity of NMD phenotypes. Examining test selection and yield may elucidate testing recommendations and improve the diagnostic journey for these patients. This retrospective chart review evaluated the clinical presentations, genetic testing approaches, and diagnostic outcomes of 155 patients with suspected NMDs at Cincinnati Children's Hospital Medical Center. A total of 262 individual tests were ordered, averaging 1.7 tests per patient. The clinic utilized 26 separate genetic tests, with test yields ranging from 0% to 66%. Overall, 21% of patients received a genetic diagnosis. Of all the clinical findings evaluated, elevated CPK levels with or without muscle weakness were the most informative symptoms correlated with a diagnostic result. This study highlights several genetic testing considerations for NMDs, including the variability of diagnostic outcomes. This knowledge is relevant to clinicians and patients, especially during the pretest counseling and consenting process.     

Cultural enhancement of a clinical service to meet the needs of indigenous people; genetic service development in response to issues for New Zealand Maori

The delivery of good health care services within clinical settings is predicated by an understanding of the needs of the stakeholders * . Most of the information generated to date on the transfer of mutational analysis to clinical service has been within a Eurocentric model favouring individual autonomy. It is predictable that this model does not easily translate for other cultures.
Current genetic technology has elucidated the molecular basis of many diseases. In familial cancer and other late-onset disorders, there is now the possibility of 'prediction' where a high risk conferred by family history can be confirmed or negated by genetic testing. In paediatric disorders, prediction is offered in the form of prenatal or pre-implantation genetic diagnosis. We report on the processes undertaken in an attempt to provide a culturally sensitive service for the Maori people of Aotearoa, New Zealand.     

Genetic testing in Italy, year 2004

A comprehensive and long-range monitoring of genetic testing is ongoing in Italy starting from 1987. The data collected by the last survey of year 2004, on behalf of the Italian Society of Human Genetics, included the activities of 88 clinical centres and 160 cytogenetic and 183 molecular genetic laboratories, hosted by 256 structures. Only 42% of them fulfilled the requirements of current Italian legislation. Genetic tests included 283,601 cytogenetic analyses. There have been 120,238 invasive prenatal samplings, 84% of which were amniocenteses. A significant north-to-south decreasing gradient was evident for all activities. This study has also surveyed 190,610 molecular genetic tests. CFTR gene analysis accounted for 23% of prenatal and 29% of postnatal molecular tests. In total, 420 different genes have been investigated, 10 of which comprised three-quarters of the whole activity. More than 10% of molecular tests were performed on fetal samples, the analysis of CFTR, DMD, FMR1, FMR2, and GJB2 genes accounting for 83% of all prenatal tests. In years 1997-2004, the demand of cytogenetic tests has increased two-fold and that of molecular tests has increased four-fold. Only 16% of cytogenetic and 12.5% of molecular tests have been followed by genetic counselling. This survey highlights the need for a major basic intervention in the general organisation of genetic structures in Italy, which should be rationalised in accordance with the national guidelines, and the necessity of constant training of general practitioners and education of consumers to the appropriate use of genetic testing.     

Role of the clinical immunology laboratory in disease monitoring

Immunological investigations provide useful information to guide diagnosis of several disorders. Many such tests are also commonly repeated at intervals, in an effort to facilitate disease monitoring. In general however, immunology test results are often slow to alter. Furthermore, audit activity has indicated that repeated testing accounts for a substantial workload in many immunology services, which may waste resources and compromise the efficient completion of necessary tests. Consequently, the need and appropriate minimum interval between repeated testing requires critical evaluation. In this review, the clinical utility of repeated performance of several common immunology investigations has been evaluated, based upon published evidence. In some cases (e.g., paraprotein quantification, or measurement of anti-glomerular basement membrane antibodies), repeated testing provides vital clinical information and can be justified on a frequent and individualized basis. However, many other investigations provided by immunology services provide less valuable information when used to aid disease monitoring rather than diagnosis. It is hoped that the data summarized here will facilitate a more evidence-based approach to repeated testing. Such information may also assist with the local implementation of demand management strategies based upon setting of minimum retesting intervals for these investigations.     

Attitudes toward presymptomatic testing in Huntington disease

One hundred thirty-one individuals at 50% risk of inheriting Huntington disease (HD) responded to a survey to study their attitudes toward taking a genetic test based on the identification of a genetically linked DNA polymorphism. Ninety-six percent of the respondents believe that presymptomatic testing should be available, and 66% say they will use it themselves. Fewer married individuals, in comparison to those single, separated, and divorced, intend to take the test. Many respondents (40%) said their primary reason for wanting to be tested is to end the uncertainty in their lives. Results suggest that there will be self-selection in test use, with many individuals who believe they will be depressed or possibly suicidal with a positive test result deciding not to be tested or unsure about testing. However, 15% of those who want to be tested acknowledge that they may be at risk for suicide if they are probable gene carriers. Only 12% of all respondents say they will be likely to use prenatal testing, suggesting that initial demand may be low in New England. Implementation of presymptomatic testing challenges health care providers to develop strategies to care for otherwise healthy persons who will be given a diagnosis years before the onset of illness.     

Treatment‐focused DNA testing for newly diagnosed breast cancer patients: some implications for clinical practice

Lobb EA, Barlow‐Stewart K, Suthers G, Hallowell N. Treatment‐focused DNA testing for newly diagnosed breast cancer patients: some implications for clinical practice There is accumulating evidence that women with breast cancer due to a familial BRCA1 or BRCA2 mutation benefit from specific surgical and chemotherapeutic treatment strategies. However, the rapid identification of such patients during the acute phase of treatment raises a number of issues. This study investigated Australian opinion leaders' views on the issues arising from such ‘treatment‐focused’ genetic testing. Semi‐structured interviews with 34 opinion leaders working in cancer genetics were undertaken. Interviewees acknowledged the introduction of treatment‐focused DNA testing has the potential to positively transform the management of breast cancer patients, but were concerned that certain ethical and logistical issues have yet to be addressed. These include decision‐making and consent, the familial nature of genetic information, and the management of genetics services within familial cancer clinics in the public hospital system in Australia. Service providers will need to have policies and strategies for managing the increased demand. It will also be necessary to include genetic counseling services within familial cancer clinics in the care pathway for newly diagnosed patients prior to any DNA testing to determine adjuvant treatment; such services may be more cost‐effective than expecting surgeons and medical oncologists to fulfill this role.     

Paediatric lymphoedema: An audit of patients seen by the paediatric and primary lymphoedema group of vascular European Reference Network (VASCERN)

Little is known about the overall prevalence of lymphoedema in children and the types of paediatric lymphoedema seen by specialist centres. Therefore, this study was aimed to provide a profile of children with primary or secondary lymphoedema seen by the expert centres of the paediatric and primary lymphoedema working group (PPL-WG) of VASCERN and to compare the profile between the different countries.A retrospective review of all children (aged up to 18 years) seen for the first time by the expert centres over one year (2019) was carried out. Lymphoedema-, patient- and genetics-related data was collected and described for the whole group and compared between the different European countries/UK.In 2019, a total of 181 new children were seen by eight expert centres. For primary lymphoedema, the phenotype was based on the St George's classification of lymphatic anomalies. The percentages diagnosed according to each category were: 7.2% for syndromic lymphoedema, 2.8% for systemic/visceral involvement, 30.4% for congenital, 35.9% for late-onset lymphoedema and 19.3% for vascular/lymphatic malformations. 4.4% had secondary lymphoedema. Nearly 10% of all children had had at least one episode of cellulitis. The median delay from onset of symptoms to being seen by an expert centre was 2.4 years. In 44.4% of the children with primary lymphoedema a genetic test was performed, of which 35.8% resulted in a molecular diagnosis. Across the different centres, there was a wide variety in distribution of the different categories of paediatric lymphoedema diagnosed and the frequency of genetic testing.In conclusion, this paper has demonstrated that there is a large delay between the onset of paediatric lymphoedema and the first visit in the expert centres and that an episode of cellulitis is a relatively common complication. Diagnostic variation across the centres may reflect different referral criteria. Access to genetic testing was limited in some centres. It is recommended that these issues are addressed in the future work of the PPL-WG to improve the referral to the expert centres and the consistency in service provision for paediatric lymphoedema in Europe.     

Identifying mental health services in clinical genetic settings

The purpose of this study was to examine the mental health needs of individuals at risk for adult onset hereditary disorder (AOHD) from the perspective of their genetic service providers, as it is unknown to what extent psychosocial services are required and being met. A mail-out survey was sent to 281 providers on the membership lists of the Canadian Association of Genetic Counsellors and the Canadian College of Medical Geneticists. The survey assessed psychosocial issues that were most commonly observed by geneticists, genetic counsellors (GCs), and nurses as well as availability and types of psychosocial services offered. Of the 129 respondents, half of genetic service providers reported observing signs of depression and anxiety, while 44% noted patients' concerns regarding relationships with family and friends. In terms of providing counselling to patients, as the level of psychological risk increased, confidence in dealing with these issues decreased. In addition, significantly more GCs reported that further training in psychosocial issues would be most beneficial to them if resources were available. As a feature of patient care, it is recommended that gene-based predictive testing include an integrative model of psychosocial services as well as training for genetic service providers in specific areas of AOHD mental health.     

Predictive testing for Huntington's disease: II. Qualitative findings from a study of uptake in South Wales

Semi-structured interviews were conducted with a cohort of 22 test applicants who requested Huntington's disease (HD) predictive testing in South Wales, and a random sample of 32 non-requesters, drawn from the South Wales HD register. Apart from identifying differences between the groups, the study afforded the opportunity to listen, at length, to at-risk individuals' accounts of living at risk and their thoughts about predictive testing and genetic services. Emergent themes included difficulties in family communication and the uncertainties inherent in being at risk and undergoing testing. Important factors in decision making about testing were: moral imperatives to clarify one's genetic status; views about the controllability of the future; family attitudes and norms; and the impact of a test result on family members. At-risk individuals' perceptions of the genetics service were that contact with the service would result in pressure to be tested and a need for test applicants to present a favourable view of coping capacities to secure testing. In addition, there was an expectation of ongoing contact with HD families at the initiative of the service providers. Implications of the findings for the way in which predictive testing services are structured and introduced to the at-risk population are discussed.