ESHG Posters 8

WebLab is a problem-based on-line course in Medical Genetics, including original simulations of tests and relevant internet links. The course contains >100 problems, and tools to solve them. This is an abridged description. The course is free.
There are four chapters. In 'Cytogenetics' the student finds banded metaphases and FISH results from constitutional, acquired and prenatal cases. A photo-viewer allows to 'cut and paste' the chromosomes in a word document, making a karyotype. Clinical databases put the karyotype in context. The Human Genome is searched for clones suitable for making FISH probes for the regions of interest.
In 'Pedigrees', risk calculation is introduced through a series of pedigrees, including linked markers. A web page calculates risks using Bayes theorem.
The 'DNA Lab' includes a 'virtual freezer' with DNA sequence from families with mutations on the CFTR or FMRX genes. The sequences are not immediately readable but require the use of an original 'virtual electrophoresis lab' where four tests can be carried out on the samples in the freezer; heteroduplex analysis, denaturing gradient gel electrophoresis, sequencing and Southern blotting on double digests (EcoRI and EagI) with probe StB12.3.
Lastly, the 'Protein Lab' contains among other items links to metabolic pathway
charts, 3D viewers, and protein alignment programs. Access to all these tools is made for the purpose of solving specific clinical problems.

Psychosocial problems of genetic disorders in Bulgaria are severe and not good known.They were created on the base of their complexity by different diseases , the bad medical information of the Society and the medical doctors sometimes and the stress of the parents.The aim of our work is to investigate the psychosocial problems in families with children with lysosomal diseases.
With the methods of interview and testing there were investigated 58 families of children with mucopolyssharidosis,Gaucher disease,leucodystrophies.The interview showed that the diagnosis in more cases were late ,the parents worried the delayed physical development of their child,mental retardation ,behavior changes,haemorrhagic diathesis.The parents need multidisciplinary team of specialists for treatment their child.To help the doctors and themself the parents organisated Association for Gaucher disease ,which support the introdussing the Enzyme replacement therapy.The adult patients with Gaucher diseases had not possibility for ERT. The support of bulbar muscle function were the most important problems by children with leucodystrophies
The prenatal diagnosis in these families was very important and support the parents for a new life.The evaluated psychosocial problems of patients with lysosomal diseases will be used for recommendations against Ministry of health and Work and Social care.

Genetic Counselling for acute infective disease during pregnancy. Experience of a Italian Genetic Centre on 11 years of activity.

S. Belli¹, M. Brugnara¹, S. Fiorenza²;
¹Genetic Centre, Trento, ITALY, ²Dep. Morphological Sciences, University Modena, Modena, ITALY.

At the Genetic Centre of Trento, from 1990 to half 2001, 1124 Genetic Counselling have been performed about exposure to possible teratogenous factors, 87 cases of which regarding acute infective disease on pregnancy: 46 cases of herpetic infection , 18 of rubella, 11 cases of parotitis, 4 cases of hepatitis, 3 infections of parvovirus, 2 of salmonellosis and 1 case of measles, tuberculosis and borreliosis.
The average age of the woman arrived at the Genetic Centre for acute infective disease was 31 years and 2 months.
Chicken-pox: 41 genetic counselling: 8 virus exposures not followed by disease; 2 induced abortions; 1 spontaneous abortion; 2 new born with congenital malformations; 5 pregnancies still on going; 5 cases lost at follow-up; 20 healthy children.
Rubella virus: 18 genetic counselling; 8 virus exposures not followed by disease; 6 induced abortions; 4 infections not confirmed.
Parotitis virus: 11 genetic counselling; in 2 cases maternal infection has been excluded; 2 women were not pregnant at the time of infection; 5 healthy children ; 2 cases lost at follow-up.
The last 17 pregnancies are resolved in: 16 healthy children and 1 case lost at follow-up.
Conclusions: 1) the most represented average age is quite elevated, since the women were not primipare. Infact, infection disease is mostly transmitted by another child of the couple. 2) rubella virus vaccine reduces the number of epidemic by wild virus, so women not vaccinated have less probabilities to contract disease but more risk in pregnancy.

The questionnaire to parents of children with the Down syndrome: how to inform the parents and psychological responses to counseling

I. Dimofte¹, L. C. Enache², D. P. Balaban³, V. Broasca Madar⁴;
¹Medical Genetics Department, Faculty of Medicine, Constanta, ROMANIA, ²Cell and Molecular Biology Deparment, UMF "Gr.T.Popa", Iasi, ROMANIA, ³Biochemistry Department, Faculty of Medicine, Constanta, ROMANIA, ⁴Management and Public Health Department, Faculty of Medicine, Constanta, ROMANIA.

This study determined the experience of the 53 sets of parents when they were informed that their child had Down syndrome and how they would have preferred this matter to have been handled.
The survey revealed that the majority of parents would have preferred being told as soon as possible, with both of them present, and that they had suspected something wrong at the birth of the child.
This information prompted us to analyse critically the parental experiences and to formulate a positive approach with sensitive, supportive and progressive counseling.

Experiences, at the time of diagnosis, of parents who have a child with a bone dysplasia resulting in short stature.

V. L. Hill¹^,2, M. Sahhar²^,3, M. Aitken¹^,2, R. Savarirayan²^,3, S. Metcalfe¹^,2;
¹Murdoch Childrens Research Institute, Melbourne, Victoria, AUSTRALIA, ²Department of Paediatrics, University of Melbourne, Melbourne, Victoria, AUSTRALIA, ³Genetic Health Services Victoria, Melbourne, Victoria, AUSTRALIA.

There has been extensive literature pertaining to the time of diagnosis of a disability and the levels of satisfaction with disclosure of a disability. The information given and the attitudes of the disclosing health professionals during this critical period can have a significant effect on the family. This study explored parents‘ experience of being told that their child had a bone dysplasia resulting in short stature, and discussed ways of improving this experience for families.
Semi-structured interviews were conducted with 11 families. Families were recruited through the Bone Dysplasia Clinic at the Royal Children‘s Hospital, Victoria, Australia and via contact with the Short Statured People‘s Association of Victoria. They were asked about how they were told of their child‘s diagnosis and what effect that had on them and their families. Parents were asked about how they would have preferred to have been told and what would have made the experience less distressing. Of particular interest to the researchers was the role of information in making the experience less distressing for the families. Transcripts of the interviews were analysed, and major themes were identified relating to the parents‘ experiences.
We conclude that the manner in which the diagnosis is conveyed to parents plays an important role in their adjustment and acceptance of the diagnosis. The provision of appropriate written information relating to the condition, possible medical complications, positive outlook for their child‘s future, how to find social services and supports were some of the significant issues for the parents.

To tell or not to tell: a qualitative study exploring the passing on of genetic knowledge to family members.

S. A. Simpson, K. Forrest, N. Haites, E. van Teijlingen, B. Wilson, L. McKee, E. Matthews;
University of Aberdeen, Aberdeen, UNITED KINGDOM.

Background: Anecdotal evidence from genetic counsellors suggests that some people tell their relatives genetic risk information, whilst others do not. Similarly people tell some of their relatives, but not others. This issue is important because individuals might be disadvantaged emotionally, socially, financially or medically by having this information withheld or disclosed and conflicts may arise within families if some cannot accept a parent’s or sibling’s right to privacy.
Methods: In-depth interviews were undertaken with people who have received genetic counselling for risk of Huntington’s disease and hereditary breast/ovarian cancer, and their partners. The interviews explored whether relatives had or had not been told their risk by participants; the factors which influenced telling or not telling; who should tell; and views of genetic counselling.
Results: In total, 36 consultands and 19 partners were interviewed. The analysis confirms clinicians observations that people tell some relatives but not others. Data related to telling or not telling different relatives will be presented. Respondents’ views about whose responsibility it is to pass on this type of information will be particularly explored.
Conclusions: The level of disclosure to relatives can at times be limited but also depends on the psychosocial, familial and disease context. Disclosure, moreover, should be viewed as a process of telling as opposed to a dichotomy of ‘telling’ versus ‘not telling’. Ultimately, we hope this study will contribute towards a wider understanding into the dynamics within families after someone in that family attends for genetic counselling.

A study of information needs of primary care physicians (GPs) for management of a rare genetic disorder: Osteogenesis Imperfecta (OI). - Preliminary data

Does lack of knowledge form an important barrier to primary care management of a genetic disorder, and if so, how can we overcoming it? These questions were addressed using qualitative and quantitative methods.
Parents of all children with OI in Greater London were contacted and their consent requested. From a total of 59, consent was gained from 37 (63%). Details of over 1000 clinical encounters (including telephone) were extracted from hospital and GP notes for a 5-year period. Mean GP contacts were 3.8/yr, compared with 3.2/yr at the specialist hospital clinic. Many (31%) GP contacts were related to the condition, including a wide range of non-fracture problems.
In semi-structured interviews, 65 % of GPs felt that lack of knowledge was a problem in managing these patients. 78% believed that they changed their practice, mainly by referring patients more often or attempting to learn more about the condition. A variety of sources of knowledge were used, the most common being clinic letters, textbooks and the WWW.
When asked to identify features of information resources that made them useful, aspects related to credibility (perception that information is true) were not seen as more important than accessibility or clinical significance. Credibility was assessed by most GPs using authority (from a trusted source) rather than transparency (use of references etc).
These results will be used in a follow up study to construct and validate clinical genetics knowledge resources.

FOXL2-Mutations in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) - Challenges for genetic counselling of sporadic female patients

S. Fokstuen, S. E. Antonarakis, J. Blouin;
Division of Medical Genetics, University Hospital, Geneva, SWITZERLAND.

Mutations in the forkhead transcription factor gene (FOXL2) were recently reported to cause blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) types I and II. Evidence was provided that type I BPES (eyelid abnormalities and female infertility) is caused by mutations resulting in a truncated FOXL2 protein. In contrast, extension of the FOXL2 protein is found in type II BPES, in which fertility is generally normal. This genotype/phenotype correlation provides challenges for genetic counselling, as molecular testing may be predictive of female fertility.
We report a 32-year-old female patient with sporadic BPES and a history of menstrual irregularities and periods of secondary amenorrhoea. Mutation analysis revealed a protein extending mutation (c959-960insG) in the FOXL2 gene with a modified sequence for the last 57 amino acids, suggesting a type II BPES despite the menstrual irregularities. The clinical presentation of our patient and of three female patients with type II BPES described by De Baere et al. (Hum Mol Genet, 10, 1591-600; 2001) indicate phenotypic overlap between type I and type II BPES. These observations question clear-cut prediction of female fertility based on molecular results, particularly in sporadic female patients with irregular menstruation and in young women referred for evaluation of facial dysmorphism.
As a consequence, FOXL2 mutation testing in female patients of child-bearing age with BPES should be handled with caution and a two-step genetic counselling approach including a first pre-test information session is proposed.

Nondirectiveness has long been the ethically preferred approach in reproductive genetic counseling. Patients are expected to make their own decisions, using unbiased information. To ascertain the attitudes of genetics professionals worldwide toward directiveness in counseling after prenatal diagnosis, we used anonymous mail questionnaire surveys with case vignettes in 12 languages, distributed by colleagues in 36 nations with ten or more practicing medical geneticists (n=4629). Questionnaires presented 21 conditions identified after prenatal diagnosis and asked how the respondent would counsel. 2906 geneticists (63%), including 1084 in US (70%) and 499 US nongeneticist physicians (59%) responded. Except in North America, the UK, and Australia, many geneticists reported that they would be both directive and pessimistic for many conditions, especially in Eastern Europe and Asia. In the UK, 10% would counsel in favor of abortion for Trisomy 21; in Northern Europe, 34%; in Southern Europe, 47%; in Eastern Europe, 63%. For cystic fibrosis, percents were 10%, 33%, 43%, and 63% respectively, and for Huntington disease 10%, 21%, 34%, and 48%. Most regarded educational success of a session as more important than empathy or support; many thought their goal was to prevent the birth of children with genetic conditions, by prenatal diagnosis and selective abortion if necessary. Although internationally recognized ethical standards support counseling that is as unbiased as possible, it appears that many geneticists would use other approaches. There is a need for global discussion of optimum counseling approaches.

Evaluating Internet Information on Down Syndrome: Descriptive criteria are not enough

A. Zahn¹, J. Kunze², J. Pelz¹;
¹Reformstudiengang Medizin, Charité Campus Mitte, Berlin, GERMANY, ²Institut für Humangenetik, Charité Campus Virchow, Berlin, GERMANY.

Because of the huge number of websites, it is difficult to find relevant information on the internet which supports coping with genetic conditions. There are also concerns about the quality of the medical information available in the internet. Therefore, many authors published criteria mainly descriptive ones for rating medical websites. But many problems persist:
Data can change quickly; there is no way to search the internet entirely; it is not clear who should set criteria and control websites; indirect markers of quality like the numbers of links to a site or the number of visitors a day are easy to manipulate. Moreover, it is unknown if such criteria reflect the quality of medical information.
After having conducted a search for "Down syndrome" with two search engines and in two languages (Altavista and Yahoo in German and in English), we investigated 324 hits using a catalogue of medical, psychosocial and formal criteria drawn from pediatric textbooks and litterature.
Formal criteria were more often met than medical or psychosocial criteria. Neither the medical content nor the psychosocial content of websites correlated with the formal content. Beyond that, there were no important correlation between the search engine ranking and the catalogue ranking. However, authorship, language and search engine influenced the information score.
Descriptive parameters are useful but cannot replace an analysis by an expert since they don´t correlate automatically with a website´s medical content. Combining formal description with expert review is necessary.

The theoretical and normative foundations of genetic counselling - completing a jigsaw puzzle without a picture.

The speciality of genetic counselling is paradigmatic in many aspects. As a fairly recent member on the medical frontier its practitioners are pioneers of an evolving ethos.
Upon examination of the theoretical foundations of genetic counselling there appears to be an absence of a formal ethical framework. This is further highlighted by the lack of presence of a formal implementation of the four main bioethical principles that are commonly perceived to govern good clinical practice. The normative foundations of genetic counselling rely heavily on the formality that lies within the code of ethics by which a genetic counsellor practises. There is a commendable objective for the counsellor to be adequately trained in order to deliver the best service they can, however, it is not sufficient to have good intentions.
This paper will explore the implications and importance of having a formal ethical framework and whether it can be universally attainable. It will question if regulating the ethics of conduct is a sufficient activity or whether the professionals (genetic counsellors and geneticists) have a parallel duty to define boundaries (and thereby dispelling possible ambiguities and inconsistencies in clinical practice), and debate the desirability (and feasibility) for these boundaries to be independent of the laws of society and public opinion.

N. Tremblay¹, C. Prevost¹^,2, A. Vigneault¹, D. Gaudet¹^,3;
¹Corporation for Research and Action on Hereditary Diseases and ECOGENE 21 Project, Chicoutimi, PQ, CANADA, ²Genetic Counselling, Complexe hospitalier de la Sagamie, Chicoutimi, PQ, CANADA, ³University of Montreal Preventive and Community Genomic Medicine Center, Chicoutimi, PQ, CANADA.

Historical and demographic phenomena explain that certain hereditary diseases are specific to the Saguenay-Lac-St-Jean region (Quebec, Canada) while others, although not peculiar to a region, are proportionally more prevalent there than elsewhere. Myotonic dystrophy and familial hypercholesterolemia figure among the most frequent dominant diseases; cytochrome oxidase deficiency, spastic ataxia of Charlevoix-Saguenay, type 1 tyrosinemia, sensorimotor neuropathy with agenesis of the corpus callosum as well as cystic fibrosis are the recessive diseases which have been observed.
With a view to better understand this problematic and seek solutions to it, parents, researchers and health professionals have regrouped, twenty years ago, to create the Corporation for Research and Action on Hereditary Diseases (CORAMH). This organization’s mission is to promote awareness, information and prevention of these health problems in the population.
To achieve this goal, one of CORAMH’s activity encloses the dissemination of a genetics information program, which consists in presentations on basic notions related to heredity and monogenic diseases present in the region. Every year, through the program, CORAMH provides information to over 2500 youngsters in academic environments. Since the beginning of the program in 1983, almost 30 000 people have received information via the latter.
CORAMH is also the community partner of an important research program called ECOGENE-21: From DNA to the community. In this regard, the corporation plays an essential role in the transfer of knowledge between the universe of scientists and that of the community.

M. R. V. C. Pinto Leite¹, M. Martins¹, M. Souto², E. Ribeiro²;
¹Hospital S. Pedro, Vila Real, PORTUGAL, ²Hospital S: Pedro, Vila Real, PORTUGAL.

Male with 46, XX chromosome constitution is a rare disorder, occurring only 1 in 20.000 newborn males. Affected individuals have a male phenotype, small testes and small phallus. This disorder resembles Klinefelter Syndrome. Approximately 80% of phenotipycally XX males, one of the X chromosomes carries the SRY gene.
The authors present a case of a prenatal diagnosis, which cytogenetic result was 46, XX. The amniocentese was performed at 14 weeks of gestation with the indication of advanced maternal age. The diagnosis was made with the routine GTG banding.
A morphological ultrassonography made at 21 weeks of gestation showed a fetus with a visible phallus and testis, with normal development. Maternal contamination was excluded.
After birth, the confirmation of the cytogenetic diagnosis was done in cord blood, and with FISH studies using the SRY probe- the SRY gene was localized at the Xp chromosome.
How and when should the information be given to the parents?
The authors present their perspective in the social and ethics issues and genetic counselling in this particularly case.

The study of the prevalence of different types of disorders with different proportions of pathogenetic role of genetic factors in families with severe reproductive disorders

S. Vilimova, P. Potuznikova, M. Macek, sr.;
Institute of Biology and Medical Genetics of 2nd Medical School and of University Hospital Motol of Charles University, Prague, CZECH REPUBLIC.

The aim of this pilot study is the ascertainment of different types of genetic load in 307 families with 2482 members of partners with severe reproductive disorders. The three generation genealogy including only first degree relatives did not find any disorders with Mendelian or multifactorial inheritance or solid tumors in 51/307 families (16.6%). In 142/307 families (46.3%) only one disorder was found. In 114/307 families (37.1%) two or three disorders were revealed.
Monogenic diseases were found in 56/2482 (2.26%) of family members with most frequent prevalence of cystic fibrosis and carriers of CFTR mutations (10/2482), (5/2482), different thromboembolic diseases (17/2482). Myotonic dystrophy, polycystic kidney disease, hearing deffects, M. Scheuermann and idiopathic thrombocytopenic purpura were found in 4-7/2482. Multifactorial disorders were revealed in 94/2482 with rather equal proportion of congenital anomalies (48/2482) an other diseases (46/2482). Congenital anomalies of cardiovascular and uropoetic system were disclosed in 11 - 16/2482 respectively and congenital hip luxation in 10/2482. In multifactorial diseases prevailed immunity disorders (90/2482), cardiovascular diseases (76/2482) and type 2 diabetes mellitus (58/2482). In different types of tumors (89/2482) prevailed tumors of gastrointestinal system (23/2482), breast carcinoma with gynaecologic tumors (31/2482) and tumors of urogenital system (10/2482). The hematopoetic malignancies represented only 7/89 patients with malignancies.
Further study of different types of genetic loads might contribute to the elucidation of their family impact on reproductive disorders and vice versa to the improved genetic counselling and genetic care for families with these problems.
Study was supported by grants: 00000064203, 111300003, LN-00A079, IGA6462-3, IGA6411-3

P. Blanchet¹, M. Mondain², N. Pallares-Ruiz³, P. Sarda¹, M. Claustres³, A. F. Roux³;
¹Genetics Department - Arnaud de Villeneuve Hospital, Montpellier, FRANCE, ²Pediatric ORL Department - Gui de Chauliac Hospital, Montpellier, FRANCE, ³Molecular Genetics Department - IURC, Montpellier, FRANCE.

We have studied two cases referred for multiple congenital anomalies associated with profound deafness. Case 1 : the child was born in 1990 and presented a ventricular septal defect, camptodactyly of the toes, right embryotoxon, bifid uvula with submucous cleft palate and facial dysmorphism. At one year, she presented an acute polyarthritis affecting both large and small joints. At the age of 7 years, she was evaluated in the genetics department. Karyotyping with probe D22S75 showed a 22q11 deletion and the sensorineural deafness, diagnosed at the age of 9 months, was thought to be related to this 22q11 deletion. Case 2 : the patient was born in august 2001, 7th child of first cousins parents. The child was diagnosed with Down syndrome (47,XY,+21) with atrial septal defect. Additional tests were performed for known familial history of vesico-renal reflux (VRR), myopia and deafness. The child was shown to have also VRR, optic nerve hypoplasia and deafness. Despite the context of syndromic associated anomalies, we tested the GJB2 gene (CX26) to evaluate the origin of the profound deafness. Both cases were found to be homozygote for the 35delG mutation.

B. Press, J. Pelz;
Reformstudiengang Medizin, Charité Campus Mitte, Berlin, GERMANY.

Within the specialities of medicine human genetics is one of the youngest. The introduction of its concepts and its molecular methods has an influence on medical thinking and the use of basic medical concepts. Genetic research is highly interdisciplinary and collaborative which makes necessary the communication between geneticists, various academic disciplines and the public. The informational content of technical terms, which have a (nearly) clear meaning in the realm of medicine in general, is liable to be garbled when transferred to and uncritically used within human genetics. One of the technical terms we focussed on is 'prevention', which e.g. as primary prevention means keeping a disease from occurring at all by removing risk factors but in human genetics especially in prenatal diagnosis is mainly understood as prevention of the ill.
Fourteen scenarios were developed from genetic counselling before conception to abortion of a child with trisomy 21. Three groups of students of medicine differing in their level of clinical and theoretical experience (1st, 3rd and 6th years of medical education) were interviewed using these scenarios in a structured questionnaire. Confounders, concepts of disease and assessment of human genetics in the realm of medicine were recorded.
About 50% of the study group made a distinction between prevention of a disease and 'prevention' of a (genetically)diseased human being, while on the other hand rating human genetics highly responsible for the prevention of genetically caused diseases. The judgement of the different scenarios by the participants was done without a clear concept of 'prevention'.

Understanding of risk by patients and physicians - how to raise the haze of Bayes?

Genetic tests become increasingly accessible. Possible benefits of testing for susceptibility to chronic disease may be substantially outweighed by confusion raised by test results. The concept of sensitivity, specificity and positive predictive value of a test are all complex and therefore not necessarily understandable to an uninitiated patient. On the other Hand in order to make informed decisions on participation in genetic screening programs and in prenatal diagnosis patients should be told about these concepts. Moreover several studies have shown that even physicians have a poor understanding of probabilities and the predictive value of test results. Gigerenzer and coworkers hypothesised that due to human evolutionary development mental algorithms were not designed for probabilities and a Bayesian reasoning but for the understanding of natural frequencies.
In order to test their hypothesis for genetic counselling four problems were presented to more than 200 of our fellow students (representatives of an upper-middle class lay population) either as probabilities or as natural frequencies: (1) positive triple test and the risk of trisomy 21, (2) insulin dependent diabetes mellitus and DR3/DR4, (3) breast cancer and BRCA1/BRCA2, (4) inheritance of familial polyposis and symptom free ageing. Participants received in a randomised order all four problems, two presented as probabilities and two as natural frequencies. They generally ranked the natural frequency questions as less difficult and yielded a significant better understanding of the risk. The representation of complex concepts in natural frequencies rather than in probabilities can improve the understanding of patients and of physicians.