European School of Genetic Medicinegrc.sbmu.ac.ir/uploads/5-genetic_counselling_in_practice.pdf · 2014-10-14 · Harper P S (2004) Practical Genetic Counselling 6Th Edition. London,

European Genetics Foundation

European School of Genetic Medicine

7th Course in

Genetic Counselling in Practice

Bertinoro di Romagna, ITALY, November 9th-14th, 2006

Course Directors:

H. Skirton (Plymouth, UNITED KINGDOM), D. Coviello (Milano, ITALY), V. Anastasiadou

(Nicosia, CYPRUS)

European Genetics Foundation c/o U.O. Genetica Medica – Mail Box 2254

40137 Bologna (Bo) – Italy Phone: +39 051 306171 Fax +39 051 6364004

www.eurogene.org

Bertinoro University Residential Centre

Via Frangipane 6 Bertinoro (Fc) - Italy

Tel +39 0543 446500, +39 0543 446553 Fax +39 0543 446599 www.centrocongressibertinoro.it


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7th Course in


CONTENTS • INDEX • PROGRAM • ABSTRACT OF LECTURES • ABSTRACT OF WORKSHOPS • ABSTRACT OF POSTER • STUDENT’S WHO’S WHO • FACULTY ADDRESS BOOK


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7th Course in


INDEX


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• PROGRAM 5

• ABSTRACTS OF LECTURES 9 • ABSTRACTS OF WORKSHOPS 41 • ABSTRACTS OF POSTERS 44 • STUDENT’S WHO’S WHO 56 • FACULTY ADDRESS BOOK 58


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7th Course in


PROGRAM


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EUROPEAN SCHOOL OF GENETIC MEDICINE

7th Course in

GENETIC COUNSELLING IN PRACTICE

Bertinoro di Romagna, Italy November 9th – 14nd, 2006 DIRECTORS: H. Skirton (Plymouth, UNITED KINGDOM), D. Coviello (Milano, ITALY), V. Anastasiadou (Nicosia, CYPRUS) FACULTY S. Stenhouse (Glasgow, UINTED KINGDOM), C. Patch (London, UNITED KINGDOM), A. Tibben (Leiden, The NETHERLANDS), D. Turchetti (Milan, ITALY), F. Forzano (Genoa, ITALY), M. Soller (Lund, SWEDEN), J. CROLLA (SALISBURY, UNITED KINGDOM), PROGRAM Wednesday 8 November - Arrival at the Residential Centre of Bologna Thursday 9 November, 2006 Morning: plenary lectures 09.30 Course Directors Practical session- Introduction to the course and goal setting 10.30 H. Skirton Setting the scene- aims, process and outcomes of genetic

counselling. 11.15 Coffee break 11.45 H. Skirton/ D. Coviello and Faculty Ice-breaking session 12.30 C. Patch Mendelian inheritance 13.15 Lunch 14.15 S. Stenhouse Diagnostic tools – molecular analysis 15.00 S. Stenhouse/C.Patch Dice games as an educational tool 16.00 Coffee break 16.30 17.15 All faculty Discussion and questions Friday 10 November, 2006 Morning: plenary lectures 08.30 H. Skirton Development of genetic counselling in Europe 09.15 Questions/discussion 09.30 J. Crolla Diagnostic tools - Cytogenetics 11.00 Coffee break 11.30 D.Turchetti Introduction to cancer genetics 12.15 Question/Discussion 12.30 Lunch 14.00 Workshop 1 : H.Skirton - Pedigree taking and risk analysis J. Crolla/ C.Patch - Prenatal diagnosis counselling scenarios D. Coviello/S. Stenhouse - Interpretation of laboratory results V. Anastasiadou/D: Turchetti - Familial cancer counselling scenarios 15.30 Coffee break 16.00 Workshop 2


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H.Skirton - Pedigree taking and risk analysis J. Crolla/C. Patch - Prenatal diagnosis counselling scenarios D. Coviello/S. Stenhouse - Interpretation of laboratory results D. Turchetti/V. Anastasiadou - Familial cancer counselling scenarios Saturday 11 November, 2006 Morning: plenary lectures 8.30 V. Anastasiadou Cross-cultural perspectives in genetic counselling and testing

examples from the hemoglobinopathies 9.15 Questions/Discussion 9.30 M. Soller Prenatal diagnosis 11.00 Coffee break 11.30 D. Coviello Genetic heterogeneity: the example of hereditary deafness 12.15 Questions/discussion 12.30 Lunch 14.00 Workshop 3

H.Skirton - Pedigree taking and risk analysis M. Soller/ C.Patch - Prenatal diagnosis counselling scenarios D. Coviello/ S. Stenhouse - Interpretation of laboratory results D. Turchetti/ V. Anastasiadou - Familial cancer counselling scenarios 15.30 Coffee break 16.00 Workshop 4

H.Skirton - Pedigree taking and risk analysis M: Soller/ C.Patch - Prenatal diagnosis counselling scenarios D. Coviello/ S. Stenhouse - Interpretation of laboratory results D. Turchetti/ V. Anastasiadou - Familial cancer counselling scenarios Sunday 12 November, 2006 Morning: plenary lectures 08.30 C. Patch Practical issues of consent, confidentiality and disclosure 09.15 Questions/Discussion 09.30 A.Tibben/ H.Skirton Genetic screening and testing in children 10.45 Coffee break 11.15 M. Soller Non-traditional inheritance 12.15 Questions/Discussion 12.30 F. Forzano Basic concepts in dysmorphology 13.30 Lunch Free afternoon with optional walk arranged Monday 13 November, 2006 Morning: plenary lectures 08.30 F. Forzano Genetics of mental retardation 09.30 Questions/Discussion 09.45 4-5 small groups with 2 faculty each group Discussion of challenging cases brought by students 11.00 Coffee break 11.30 V. Anastasiadou Medical genetics and public health: Community genetics 12.30 Lunch 14.00 A.Tibben/H.Skirton Counselling skills workshop (Including coffee break)


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Evening Farewell Party Tuesday 14 November, 2006 Morning: plenary lectures 08.30 A.Tibben Counselling for predictive testing 09.45 Coffee break 10.15 Students attend two workshops of choice, to probably include:

- Practical use of databases in dysmorphology - More practical risk calculation - Difficult ethical situations - Difficult psychological counseling situations - Setting up and organizing genetic services - Counselling in disorders with non traditional inheritance - Practical counseling in dysmorphology

13.00 Lunch 14.00 Farewell and depart for home


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7th Course in


ABSTRACTS OF LECTURES


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7th Course in


Thursday, November, 9th


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Mendelian inheritance

C. Patch In this lecture we will go over Mendelian patterns of inheritance in order to provide a platform of basic knowledge for the rest of the week. This may be revision for some course participants. We will work through family trees identifying patterns of inheritance and working out risks. This topic is covered in many genetics text books and references are given below. In summary Mendelian inheritance refers to phenotype characteristics that are under the control of single genes. Thus the patterns of inheritance observed in the family structure refer to observable characteristics or diseases that are assumed to be caused by single genes. There are five basic Mendelian inheritance patterns. In medical genetics, the term affected is used to describe an individual who has signs and symptoms of the condition. A carrier has no signs and symptoms, but has one mutated copy of the relevant gene. Characteristics of inheritance patterns 1 Autosomal Dominant • one copy of the genetic mutation is sufficient to cause the condition • either sex may be affected • the characteristic may be transmitted by a parent of either sex. • an affected person has a 50% or a 1in 2 chance of passing the condition to each of their offspring. • unless the condition is caused by a new mutation, an affected child will have an affected parent. 2. Autosomal recessive • two copies of the genetic mutation are required to cause the condition • either sex may be affected • affected children are normally born to unaffected parents • each parent of an affected child will have one copy of the mutated gene and one normal copy and will

therefore be asymptomatic carriers. • if a couple are both carriers they have a 25 % or 1 in 4 chance of having an affected child in each

pregnancy. an affected person will only have an affected child if their partner is a carrier of the same recessive mutation. 3. X-linked recessive • the genetic mutation is within a gene on the X chromosome • affects mainly males (occasionally females will be affected due to non random X inactivation) • the mother of an affected male will usually be an asymptomatic carrier (show no or minimal signs of the

condition) but may have affected male relatives • no male to male transmission is seen on the family tree • all the daughters of affected males will be carriers. • all sons of an affected male will be unaffected. 4. X-linked dominant • the genetic mutation is on the X chromosome • females are more mildly affected than males • most X-linked dominant conditions are lethal in males so in family trees there is an excess of females • any child of an affected female will have a 50% or 1in 2 chance of inheriting the genetic mutation. 5. Y linked inheritance


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• the genetic mutation is on the Y chromosome • only males are affected • all sons of affected males will also be affected. References: Harper P S (2004) Practical Genetic Counselling 6Th Edition. London, Hodder Arnold. Skirton H, Patch C and Williams J (2005) Applied Genetics in Health Care. Taylor Francis. Abingdon 2005 Skirton H and Patch C (2002) Genetics for Health Care Professionals. Bios Oxford 2002 Turnpenny P, Ellard S (2005) Emery’s Elements of Medical Genetics 12th ed Churchill Livingstone Oxford.


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Diagnostic Tools – Molecular Analysis

S. Stenhouse

Molecular genetic testing is now available for more than 400 single gene disorders and the information from such a test can be crucial in the genetic counselling process. Is a molecular test the most appropriate option? Before ordering such a test the counsellor must decide whether the test will benefit the patient and their family in terms of a firm diagnosis, refinement of risks, or possible treatment options; in other words does the test have good clinical utility. In some cases other alternatives to molecular testing will be more appropriate. If a molecular test is required where can it be done? There are now many websites and directories of testing which can help with this and many will provide information on the accreditation status of the laboratory and target reporting times. What does the laboratory need from the referring counsellor? They will need all of the patient information with a clear clinical question and some indication of whether there is a family history. Information is needed about whether the test is for a diagnosis or carrier testing or pre-symptomatic testing. Interpretation of the molecular results will differ according to the question being asked. For some tests, samples will be required from more than one family member. Information on what is required for a particular test should be clear from the information provided by the laboratory. What is involved in molecular genetic testing and what do the results look like? Molecular genetic tests take many different forms. They may test for a panel of the commonest mutations (e.g. CF), look for a triplet repeat expansion (e.g. Fragile X syndrome) or involve sequencing a whole gene to look for an unknown mutation (breast or bowel cancer). They may use the polymerase chain reaction (PCR), multiplex ligation dependent probe amplification (MLPA) or Southern blotting all of which produce very different looking results. What can the counsellor expect from the laboratory? A timely, accurate report which answers the clinical question which was asked in a clear, concise and straightforward manner. There should also be an indication of the sensitivity and specificity of the test and where appropriate a statement of the residual risk to the patient. If a diagnosis has been made or excluded this should be clearly stated. It is a general principle of reporting that the result should be understood by the patient themselves should they have the opportunity to read it. What if the laboratory fails to deliver the service you expect? Laboratories are keen to hear from their users when things haven’t been satisfactory so that steps can be taken to prevent it happening again. This is how services are constantly improved. And of course they also like to hear from you when their service has been good!


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7th Course in


Friday, November, 10th


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Human cytogenetics and molecular cytogenetics: past present and future.

J. A Crolla

In 2006, the science of human cytogenetics celebrates 50 years since the discovery of the correct chromosome number in man by Tijo and Levan . This lecture will explore the early days of chromosome technology, recognition and classification and also the first links between phenotype and karyotype. It will then briefly cover the history of evolving technologies (chromosome banding, in situ hybridization, FISH, multicolour FISH, CGH and more recently Array-CGH), and look at how each step in this technical and scientific evolution has allowed more detailed characterisation and understanding of chromosome abnormalities. However, as in all areas of science, progress brings with it difficulties in interpretation and so the lecture will include examples of how modern cytogenetic methodologies can at once provide more detailed diagnoses of chromosome abnormalities but can subsequently give rise to difficult genetic counselling issues.


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Introduction to cancer genetics

D. Turchetti Cancer is always a genetic disease, as it results from genetic defects in cells. In the majority of cases, the accumulation of genetic changes in a tissue is random, and the tumour is termed sporadic. In a fraction of cases, however, all the cells of the body carry an inborn genetic defect, which increases the chance that certain tissues would become cancerous. This type of cancer susceptibility can be passed down to the offspring, and cancer occurring in such susceptible individuals is therefore regarded as “hereditary”. Observation of large populations of individuals revealed that as much as 5-10% of cancer cases show marked familial clustering suggesting hereditary cancer predisposition. This is a small fraction of the total cancer burden, if compared to those attributed to dietary risk factors (35%) and to smoking (30%). Nevertheless, if one estimates that 5-10% of the most common cancers, like breast, colorectal and prostate cancer, are associated with a genetic predisposition, it becomes clear that the absolute number of hereditary cancer cases is significant. Moreover, the identification of cancer genetic syndromes allows for the identification of individuals at increased risk, who can benefit from specific prevention strategies Genes conferring an increased susceptibility to cancer belong to three main classes: 1. Oncogenes 2. Tumor suppressor genes 3. DNA-damage response genes

1. Oncogenes are genes that are normally involved in cell growth and proliferation and cause cancer when they are over-expressed, amplified, or mutated (gain of function).

2. Tumour suppressor genes, on the other hand, normally regulated cell growth, and only result in malignant progression when their negative control is impaired (loss of function).

3. Similarly to tumour suppressor genes, also DNA-damage response genes cause cancer predisposition through a loss of function, which allows for multiple genetic defects to accumulate in the cell genome, leading to the malignant phenotype.

Oncogenes Syndrome Inheritance RET Multiple Endocrine Neoplasia 2, Familial Medullary Thyroid Cancer Autosomal Dominant MET Familial Papillary Renal Carcinoma syndrome Autosomal Dominant

Tumor suppressor genes Syndrome Inheritance APC Familial Adenomatous Polyposis Autosomal Dominant VHL Von Hippel-Lindau Syndrome Autosomal Dominant WT1 Wilms tumor syndromes Autosomal Dominant RB1 Hereditary Retinoblastoma Autosomal Dominant NF1 Neurofibromatosis 1 Autosomal Dominant NF2 Neurofibromatosis 2 Autosomal Dominant P53 Li Fraumeni syndrome Autosomal Dominant P16/CDK4 Hereditary Melanoma syndromes Autosomal Dominant PTCH Nevoid Basal Cell carcinoma syndrome Autosomal Dominant MEN1 Multiple Endocrine Neoplasia 1 Autosomal Dominant BRCA1 Breast Ovarian Cancer Syndrome Autosomal Dominant BRCA2 Breast Ovarian Cancer Syndrome Autosomal Dominant

DNA damage response genes Syndrome Inheritance hMSH2 Hereditary Nonpolyposis Colon Cancer Autosomal Dominant hMLH1 Hereditary Nonpolyposis Colon Cancer Autosomal Dominant hPMS1 Hereditary Nonpolyposis Colon Cancer Autosomal Dominant hPMS2 Hereditary Nonpolyposis Colon Cancer Autosomal Dominant MYH Adenomatous Colorectal Polyposis Autosomal Recessive ATM Ataxia Telangiectasia Autosomal Recessive XPA,C,D,F Xeroderma Pigmentosum Autosomal Recessive BLM Bloom Syndrome Autosomal Recessive


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Cancer Genetic Counselling

Cancer genetic counselling often involves a multidisciplinary team, which may include a genetic counselor, genetic advanced practice nurse, or medical geneticist; mental health professional and medical expert such as an oncologist, surgeon, or internist. Professionals involved in cancer genetic counselling must display the necessary understanding and ability to explain concepts regarding molecular biology, epidemiological and genetic risk of cancer, options for prevention and early diagnosis. Even when cancer risk counseling is initiated by an individual, inherited cancer risk has implications for the entire family. Because genetic risk affects biological relatives, contact with these relatives is often essential to collect an accurate family and medical history. Cancer genetic counseling may involve several family members, some of whom may have had cancer.

The cancer genetic counselling process includes the following components: 1- Contracting 2- Baseline risk perception 3- Pedigree construction and documentation 4- Medical history 5- Exposure history 6- Physical examination 7- Empirical/genetic risk assessment and explanation of mode of inheritance and risk for relatives 8- Options for early detection and prevention 9- Options, risks, limitations and benefits for genetic testing 10- Response to questions, support, and plans for follow-up.

When genetic testing is available, step 9 becomes of great relevance: it is recommended that individuals eligible for genetic testing undergo one (or more, if needed) pre-test educational session and that their awareness of test result interpretation and implications is ascertained before a consent form is signed. Moreover, a test result disclosure session will be included as part of the genetic counselling process. In this session, provided by the same counsellor, the evaluations and the options discussed in the first session will be re-examined on the basis of the specific test result, and the implications to the other family members analyzed. The educational and counselling process will be facilitated by graphic aids and precompiled forms. A written report which includes an interpretation of the results and options for early detection and prevention will be given to the patient. Whenever the efficacy of risk-reduction strategy is not definitely demonstrated, a


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non-directive approach should be adopted in counselling patients at increased risk for cancer. The purpose of counseling may include helping the individual explore feelings about his or her personal risk status and make a healthy adjustment to that risk status. Either alone or in consultation with a mental health provider, professionals offering cancer genetic counseling attempt to assess whether the individual’s expectations of counseling are realistic and whether there are factors suggesting unusual risk of adverse psychological outcomes after disclosure of risk and/or genetic status. To limit the chances of adverse consequences of risk assessment and communication, in addition to a continued follow-up by the counsellor, the availability of psychological support, preferably provided by mental health professionals with experience in cancer genetics, is recommended. References • Offit K.: Clinical Cancer Genetics. Risk Counselling and Management, Wiley-Liss 1998 • Genetic Cancer Risk Assessment and Counseling: Recommendations of the National Society of

Genetic Counselors Journal of Genetic Counseling, Vol. 13, No. 2, April 2004 • http://www.nci.nih.gov/cancerinfo/pdq/genetics/overview • http://www.nci.nih.gov/cancerinfo/pdq/genetics/risk-assessment-and-counseling

Daniela Turchetti Cattedra di Genetica Medica – Università di Bologna, Italy


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7th Course in


Saturday, November, 11th


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Cross–cultural perspectives in genetic counseling and testing. Examples from the Hemoglobinopathies and beyond

V. Christophidou-Anastasiadou

Introduction

Culture is a set of beliefs, values and assumptions that groups of people share. As it represents a complex synthesis of qualities (beliefs, rules of behavior, language, rituals, art, technology, styles of dress, ways of producing and cooking food, religion, and political and economic systems), it characterizes and distinguishes groups, social, ethnic and other.

Culture has its own virtues; it is symbolic, learned, shared and adaptive. Each ones cultural background is openly and sub-consciously involved in many important personal decisions and plans. Subsequently it affects our actions but also the reactions of societies as a whole, towards historical facts and political changes as well as towards progress in general. Having these in mind it is evident that culture is much more than a synonym of folklore and it shapes our lives and behaviour.

The power within culture has a good and a bad dimension. Ethnocentrism can sometimes lead to the worst, while cultural relativism, under terms, can bridge the differences that could lead to tensions.

Obviously the changes and progress achieved in medicine and genetics in the recent years have a great impact on our culture and societal rules. Furthermore our response to this progress is a reciprocal one, strongly influenced by our cultural beliefs.

Genetic counselling and testing involve modern technology in practice and a communication process in dealing with health and disease. These services are offered in various set-ups, to people of different ethnic and cultural backgrounds. When offered, one should leave aside the paternalistic model of the traditional medical practice.

Several studies in the recent years have indicated how cultural differences between the patients and the health professionals can affect the course of genetic counselling. Literacy and educational level, socioeconomic differences, faith and religion, trust or mistrust to the medical system and many other factors can become barriers in the offer and uptake of genetic services as well as in the perception of genetic counselling.

In this aspect, western medicine leads the way in a rather ethnocentric manner. We often forget that perceptions about health and disease can vary between individuals and ethnic or other groups. Also relevant education, appreciation for, necessitation for genetic services and even accessibility to medical services are not homogeneously found everywhere in our world.

Lessons from interaction with ethnic-cultural diverse groups can help us realize that ethnocentrism and rigidity in rules and tactics is unnecessary and even dangerous.

Haemoglobinopathies and beyond


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Examples taken from the history of managing a public health problem like “the haemoglobinopathies”, will help us illustrate how cultural perspectives and consequently differences affect the way people offer and receive the service of testing and genetic counselling.

Haemoglobin is the protein responsible for the essential to life transportation of oxygen from the lungs to the tissues. Disorders in the synthesis of haemoglobin can cause different types of anaemia. They result from inherited abnormalities of the globin production and can be classified broadly in two types. Structural alterations in one of the globin chains result in diseases such as sickle cell anaemia while defects in the rate of synthesis of one or more globin chains cause the spectrum of thalassemia.

A large number of mutations in either of the genes for the globin chains have been identified the last years.

The sickle cell disease presents with a variable in severity clinical picture of anaemia, complicated by haemolytic and other crises, some of which are painful, splenomegaly and vulnerability to infections.

In the case of the thalassemia syndromes, splenomegaly, bone changes, growth impairment, cardiac failure and other sequelae can lead to death if systemic management (i.e. transfusions, chelation etc) is not available.

The Haemoglobinopathies are considered the most common single gene disorders or human genetic diseases in the world. At least six percent of the world’s population is carriers of one of these disorders. These disorders were originally found around the Mediterranean Sea and borders, Middle East, Africa, Southeast Asia, and the Indian Subcontinent, areas endemic from malaria. As population waves have moved and spread, carrying along their genes (and their culture), these disorders became known to the western countries.

For many in this world, these disorders are still lethal, as modern management consists of frequent blood transfusions, chelation, folic acid, immunization etc demanding extremely costly care and support.

A variety of national or local programs offering testing, prenatal diagnosis, screening of population at risk and relevant genetic counselling for the hemoglobinopathies has been applied in many countries since the early 1980’s.

The diversities in the uptake of these services, the decision making profile and the emotional response in culturally different groups as shown in several studies will be discussed in this lecture.

More recently other national and local programs for prenatal diagnosis of chromosomal aberrations and also disorders like cystic fibrosis and familial cancers are offered in many countries. Studies on the perception, uptake and decision-making of these services by different population groups reveal the cultural diversities existing.

Discussion-Conclusions

Cultural diversities affect the perception of the patients and their families concerning genetic and heritable disorders and also their mode of response towards genetic counselling and decision-making.

Factors playing important role in this behaviour and reaction include among others the general educational level and the relevant awareness in genetics, socio-economic class, religion, ethnicity and the closeness of the community. Other issues are perception of illness and health, bodily integrity; control of health and future, body parts, their meanings and symbolization.

Consequently health systems and national legislation affect and are affected by the local cultural characteristics when dealing with genetic and heritable disorders. In multiethnic societies these factors need to be addressed with excessive care in order to offer services effectively and in equity and eventually culturally sensitive.


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Cultural diversities affect and shape not only the behaviour of the patients but also of the health professionals (geneticists, genetic counsellors, physicians) involved in the process of offering relevant services. We must therefore not only acknowledge the factors and the barriers included in the course of genetic counselling but even more, react in such a knowledgeable and understanding way that we can minimise any negative effect on our behaviour that can jeopardise our service and professionalism due to our own cultural stereotypes.

Therefore issues of appreciation of cross-cultural diversities and techniques in providing genuinely appropriate genetic counselling to our patients will be discussed in this lecture.

In conclusion, once we have realized that cultural differences exist and affect the reaction of our patients to the specific problem they face, we then need to become aware of our own cultural dispositions. This is one of the most difficult parts in understanding our role in offering genetic counselling. The effort needed for this kind of self-awareness is not at all small, and often leads people involved in genetic counselling, to a more self/psycho-analytical approach.

Arriving to this point of self-awareness we can then acknowledge, appreciate and respect individual diversities and autonomy.

Violetta Christophidou-Anastasiadou, MD


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Prenatal diagnostics

M. Soller

Topics • What’s “classic” • What’s recent • What’s new or coming • Genetic counseling in a complex prenatal world • Indications for prenatal diagnostics

Today most women at least in the western world are included in some kind of prenatal screening. The program offered differs in different countries concerning times and what is offered in both methods and amount of investigations The methods used in non-invasive testing is serum screening and ultrasound, and for diagnostic testing (invasive testing) the methods used today are amniocentesis, CVS, cordocentesis & fetal biopsy.

What’s “classic”

Non-invasive methods

Ultrasound This is in many countries routinely offered during the 18th week of pregnancy to date the pregnancy, to detect twin pregnancies and to screen for major abnormalities. Here abnormalities like anencephaly, omphalocele, dwarfism, hydrops or absence of the kidneys can be detected. Approximately in 1 out of 200 pregnancies some abnormalities are discovered. Routines vary how many investigations are offered during a pregnancy. Nuchal translucency measurements are offered at some units at the 10-12th week of pregnancy. An increased nuchal translucency is a risk factor for trisomy 21. Nuchal translucency can also be so large that it is considered a hygroma, which is a risk factor for Turner´s disease.

Screening methods Age of the mother (see table 1) is a known risk factor for trisomies like trisomy 21. During the recent years screening methods using a blood sample from the mother, to detect trisomy 21 has been developed. The most used is so called trippel test, in which the value of three biochemical markers is measured (AFP, β-HCG, and estriol). These values are then correlated to the actual age of the mother and a risk estimate is given. It has been calculated that with these tests approximately 60-70 % of the pregnancies with trisomy 21 can be identified. Trippel-test combined with nuchal translucency can raise this figure to 90%.

Invasive methods Invasive methods are used to clarify if the foetus is affected of a specific disease or not. Two of the methods used routinely are amniocentesis and chorionvilli biopsy. In some very specific case a muscle biopsy, fetoscopy or chordocentesis is done. Here follows a description of the two methods mostly used. Amniocentesis: Is routinely taken during around 15th week of pregnancy. The amnion contains cells from the skin, airways and the bladder and can be cultured in order to get cells to divide for a chromosomal analysis. The amount needed is approximately 10 ml. The analysis takes 2-3weels. Sometimes a FISH-analysis is made on interphase cells. Chorion villi biopsy: Is taken in the 10-12th week of the pregnancy. If a DNA analysis is requested this is the procedure of choice. A chromosomal analysis or FISH-analysis can also be made, but placental mosaicism can be present.


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What’s recent • first trimester serum screen • the “genetic sonogram” • interphase F.I.S.H & QF-PCR methods have been introduced for faster aneuploidy screening instead

of traditional cytogenetic investigations of amniocytic fluid or chorion villi biopsy • Foetal cells are found in the blood stream of the mother and can be so several years after the

pregnancy.

What’s new or coming • fetal DNA / RNA in maternal blood • fetal cells from cervical mucus? From coelocentesis?

Indications for prenatal diagnostics • Maternal age 35 or over, paternal age over 40 • Two or more unexplained pregnancy losses • Directly-inherited condition in parent or sibling • Isolated birth defect in 1st (or 2nd) degree relative (of fetus) • Genetic/dysmorphic syndrome in 1st (2nd) degree • Heritable chromosome anomaly in 1st (2nd) degree • (watch your information sources--get the records)

Table 1. Risk for chromosomal abnormalities according to the age of the mother Age of the mother Risk for +21 v 16 All birth 25 - - 1/1400 30 - - 1/900 33 1/420 1/200 1/550 35 1/260 1/120 1/360 40 1/70 1/40 1/95 45 1/20 1/14 1/20

Genetic counselling in a complex prenatal world Couples with an inherited disorder in the family or where a pregnancy is not developing as expected needs genetic counselling in order to be able to make autonomic decisions. The risk for the foetus to be affected is depending on many factors of which some are listed below. The counselling is complicated by the fact that many diseases have a variable expression, i.e. the severity of the diseases is unpredictable.

• Chromosomal anomalies: • all chromosomes studied? high-risk populations tested – screening or diagnostic tests • Monogenic disorders • : Direct DNA analysis (amnio, CVS) • Indirect, by phenotype (imaging, histology) • Multifactorial • diagnosis by indirect means • Mitochondrial? UPD / Imprinting?

References: Principals and Practices of Medical Genetics, 4th addition, Churchill Livingstone, 2002 Essential Medical Genetics. G M Connor, M A Ferguson, Smith 4th addition, Blackwell Scientific publication, 1993 Maria Soller, Department of Clinical Genetics, Lund University Hospital SE-221 85 Lund, Sweden,


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[email protected]


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Sunday, November, 12th


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Practical issues of consent, confidentiality and disclosure

C. Patch Principles regarding consent for procedures and protecting the confidentiality of medical information are enshrined in codes governing ethical practice. They are also subject to statutory oversight which may vary according to the area of administration. It can be argued that medical genetics is no different from other medical specialties. However the practice of clinical genetics may give rise to situations where issues of consent and confidentiality do require special consideration. In relation to consent for procedures the key aspects are that i) the person understands the nature and risks of the procedure to which they are consenting and ii) that the person gives consent without coercion. In this session we will consider cases where there may be special issues relating to consent and confidentiality. The text below is adapted from ‘Applied genetics in health care’. In genetic healthcare settings, consent most often relates to: 1.Taking a family history Consent can generally be assumed if the proband provides the information requested, providing that the process and reason for taking the pedigree have been explained. However, when using the pedigree to counsel other family members, the confidentiality of the original proband must be respected. For this reason, it may be appropriate to take a new pedigree when seeing a different branch of the family. 2. Obtaining specific medical history from the proband and/or other relatives It is frequently necessary to request medical notes on the proband in order to advise him or her properly, consent must be sought to view or request medical records. The purpose of viewing records of other family members must be explained to them and written consent obtained. 3. Obtaining blood or tissue samples Permission to take a sample must be explicitly given by the client. This is sometimes written consent, but if the procedure has been explained the co-operation of the client in giving the sample is usually deemed to be evidence of consent. For example, if a client lifts his sleeve and presents his arm after being asked to consent to a blood sample, this would be evidence that the client has given consent. 4. Performing genetic tests The exact nature of the tests and the implications of the result must be explained to the client . It is good practice to give the client written information as well as a verbal explanation, and written evidence of consent must be recorded. Risks associated with genetic testing might include the discovery of false paternity, this should be mentioned if a possibility. Other aspects of consent for genetic tests include whether consent is given for the sample to be stored and the possible outcomes of the test. Separate consent should be obtained for use of the sample in research and to share the results with relatives in the process of their own testing. Confidentiality Confidentiality of personal information is a basic tenet of healthcare and is considered so important to the rights of the client that it is enshrined by law in many countries. However, there may be provision under some statutes for the healthcare professional to disclose the client’s confidential medical information, if not disclosing would result in serious but avoidable harm to others. This is the case in UK law. A good example covered in law would be where a person had a serious infectious disease that was putting others in the community at risk.


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In a genetic healthcare setting, the situation may be complex, as the information about the genetic structure of one individual may (and often does) have implications for other family members. Where this occurs, the proband is usually encouraged to share the information with relatives who may be affected, especially if screening or treatment is available that would reduce the health risk. It is usual to offer support in the form of written information that can be given to relatives and contact details so that they can seek more information and guidance from the genetics team if they wish. When an individual refuses to share information with relatives, there is always an underlying reason that might not be obvious to the practitioner. The situation is rarely urgent, and effort spent in gaining the proband’s confidence and allowing time for psychological adjustment to their status can often be helpful in enabling the proband to share the information. However, this is not always the case and then the decision about whether to break confidentiality may arise. References: American Medical Association statement on informed consent http://www.ama-assn.org/ama/pub/category/4608.html General Medical Council Seeking patient consent the ethical dimension http://www.gmc-uk.org/standards/default.htm General Medical Council Confidentiality protecting and providing information http://www.gmc-uk.org/standards/default.htm Human Genetics Commission Inside information 2002 Department of Health UK Chapter 4 of this report concentrates on consent and confidentiality as they relate to medical genetics. http://www.hgc.gov.uk/Client/document.asp?DocId=19 Kent A Consent and confidentiality in genetics: whose information is it anyway? 2003 J Med Ethics 29 16-18 Skirton H, Patch C and Williams J (2005) Applied Genetics in Health Care. Taylor Francis. Abingdon 2005 United States Department of Health and Human Services. Office for Civil Rights- HIPPA. Medical Privacy – National standards to protect the privacy of personal health information [Internet] [cited August 22 2005] http://www.hhs.gov/ocr/hipaa/finalreg.html


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Genetic screening and testing in children

A Tibben/ H Skirton The necessity of screening and testing children at risk brings along its own sensitivities. The natural wish of parents is to ensure the safe and normal development of their offspring. However, in families at risk of genetic diseases, the future of a child can be shadowed by the chance that life may be shortened or adversely affected by the condition. Families who seek genetic counselling frequently wish to discuss the issue of telling their child about the condition in the family, and informing the child that they are at personal risk. This issue arises whether or not testing is available. The decision to tell may not be clear-cit, as the desire to inform the individual may be juxtaposed with reluctance to cause anxiety in the child (1). The general opinion among professionals is that testing for adult-onset disorders holds more potential for harm than for benefit (2). Testing is only justified if onset is expected in childhood or adolescence, and if treatment options are available. Testing removes the individual’s future right to make own decisions as an autonomous adult, it removes the confidentiality, expected for any adult undergoing the same test, and it may alter the upbringing and the pattern of relationships within the family ands with peers, with the inclusion of stigmatisation and discrimination. Hence, DNA tests for adult-onset diseases on asymptomatic children - at parental request - is generally not performed in most genetic centres. A family life overshadowed by the risk of a hereditary disease will obviously influence the way parents perform their parental tasks (3). An important task regarding their children is the establishment of a stable and safe environment for the family, which may become difficult if the parents fear the disease. They also have a task in explaining facts and circumstances of the grandparent’s disease and their personal risks, which requires openness and courage to discuss these issues with their children. Parents must be able to understand their children’s’ developmental capacities for coping with their risk and a disease and they must be able to express this understanding. They must assist in tolerating and expressing uncertainty and anxiety, and facilitate the change to new relationships and responsibilities. Having considered the tasks of parents and children, the tasks of the counsellor can be made more explicit. The counsellor can increase the awareness of how a hereditary disease has specifically affected every member of the family. He or she can help to further discuss the traditions, the myths, and the coping strategies in the family regarding the disease. The counsellor can help to explore the underlying motives of the test request and consider this in the light of the developmental and parental tasks. The counsellor can give clarity about the developmental issues and tasks of each member, and facilitate openness and nonreactivity (that is being able to listen, hear the emotions and considerations of the other without counteracting immediately). Such work might increase the cohesion in the family and lead to new, constructive, and creative ways to deal with the disease. It takes time, specific training and knowledge and much experience to be able to recognise and explore the specific themes in the family regarding their development. The themes and issues to be addressed include the individual beliefs, attitudes, and feelings about the disease and its impact in the family. Further, the impact on the current interactional framework of the family needs to be viewed. Subsequently, the way this framework is carried over into social contexts such as work, school, social life, and finally, what is the common theme that links to family legacies, loyalties, and traditions? Counsellors may benefit from the attainments of family system theory; education in the use of family dynamics could enrich their work (4). Test requests should be considered against the background of the specific age and role-related tasks that each member in a family with a hereditary disease has. The achievement of these tasks may have been extremely burdened by the occurrence of a specific disorder in the family. The test applicant’s motives should be explored to enable him or her to make an informed decision. The decision should be hold against the personal and family history and future. The decision must be understood as part of or reflection of the entire family and individual coping mechanisms regarding the risks and the disease.


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References: 1) Skirton H. Telling the children. In: Clarke A, editor. The genetic testing of children. Oxford: Bios

Scientific Publishers, 1998: 103-111. 2) Clarke A, Flinter F. The genetic testing of children: a clinical perspective. In: Marteau T, Richards M,

editors. The troubled helix: social and psychological implications of the new human genetics. Cambridge: Cambridge University Press, 1996: 164-176.

3) Fanos JH. Developmental tasks of childhood and adolescence: implications for genetic testing. American Journal of Medical Genetics 1997; 71(1):22-8.

4) Carter EA, McGoldrick M. The Expanded family life cycle: individual, family, and social perspectives. 3 ed. Allyn & Bacon, 1998.


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Non-traditional inheritance

M. Soller Topics: multifactorial inheritance dynamic mutations mitochondrial inheritance imprinting multifactorial inheritance environmental factors and genes interact sometimes additive or interactive effects of different gene loci diseases do not follow Mendelian inheritance patterns - still they can be enriched in families or in populations many ”common disorders”and congenital malformations continuous traits: normal distribution (height, intelligence) Threshold effect: a threshold of liability exceeded before the disease is expressed Characteristic for multifactorial inheritance: disease occurs in families – does not follow Mendelian rules recurrence risk influenced by: –the degree of relationship –the number of the affected relatives –the disease severity Dynamic (unstable) mutations a trinucleotide repeat becomes pathogenic when the number of repeats exceeds a certain limit in previous generations there may have been mildly affected individuals and, as the number of repeats increases, severe phenotype appears anticipation: the symptoms become more severe or start earlier in later generations


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Diseases with unstable mutations are for example Huntington-, Dystrophia myotonica-, and Fragile X- syndromes Mitochondrial inheritance about 1% of the DNA in the cell is mitochondrial also several nuclear genes guide the important function of the mitochondrias in the cell The phenotype is very variable all mitochondria in a human being may be identical= homoplasmy some mitochondria may be normal, some mutated = heteroplasmy a female may be symptomless but have heteroplasmic mitochondrial mutation and have affected children Imprinting Normally a child inherits half of the (nuclear) genes from the mother and half from the father in case of most genes, it appears to make no difference from which parent an allele has come in case of some (a minority) genes the parental origin matters What is imprinting? Some genes become imprinted in either maternal or paternal meiosis (or later in the course of formation of the germ cells). T the phenomenon is also called epigenetic modification It leads to inactivation of the gene (by methylation). Can disappear or happen again in next meiosis. It is not exactly known when imprinting happens, but most probably in an early phase of the germ cell formation. However, it might also happen after fertilisation. t is not exactly known when imprinting occursIt How do we know that imprinting has important consequences? uniparental disomy (UPD) for some genes lead to diseases a deletion may lead to different phenotypes depending on its parental origin Two examples are Prader-Willi and Angelman syndromes were a deletion or UPD of a part of chromosome 15 lead to completely different diseases the genes of Prader-Willi (PWS) and Angelman (AS) syndromes are next to each other in chromosome 15 q to be healthy, a child has to get a normal PWS-gene from the father and a normal AS-gene from the mother Nontraditional inheritance in genetic counselling? multifactorial: common, recurrence risks low dynamic mutations: not extremely rare, create counselling problems and thus form a big part of the work load of genetic units mitochondrial inheritance: rare diseases, risk estimation difficult (heteroplasmy) imprinting: rare diseases, recurrence risk low, difficult to understand Maria Soller, Department of Clinical Genetics, Lund University Hospital SE-221 85 Lund, Sweden, [email protected]


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Basic concepts in dysmorphology

F.Forzano “Dysmorphology” literally means "the study of abnormal form", and, as a term, has been coined by Dr. David W. Smith in the 1960's to define the study of human congenital malformations, particularly those affecting the “morphology” (anatomy) of the individual. Dr. Jon Aase stated a few years later that "As a scientific discipline, dysmorphology combines concepts, knowledge, and techniques from the fields of embryology, clinical genetics and pediatrics. As a medical subspecialty, dysmorphology deals with people who have congenital abnormalities and with their families." Clinical delineation of dysmorphisms and dysmorphic syndromes is crucial for patient management and family counselling, and is also important for basic research. A structural defect is in fact an inborn error in morphogenesis, and the study of these anomalies will ultimately lead to an extended knowledge on mechanisms which regulate normal embryonal development too. A dysmorphological assessment should be offered in any person with congenital abnormalities, growth abnormalities and dysmorphic features and rests on familial and personal history, physical examination and investigations that may lead to a specific diagnosis. The physical examination shall be thorough and shall pay particular attention on growth, simmetry, ectodermal features, skeleton, joints, hands and feet, genitalia. But what mainly distinguish a dysmorphological examination is probably the face examination. Prof. Robin Winter wrote that “distinctive facial features are frequently associated with specific defects of other organ systems, and the genes responsible must all play a significant part in normal development”. The overall impression of a facial appearance (“gestalt”) can sometime be the key clue in getting a diagnosis (e.g. Down syndrome). If no diagnosis is made at a glance, it is then important to focus on each single facial trait and to compare them with other family members’ ones (siblings and parents), in order to determine whether the features noted are familial or syndromic. Recently, new computer-based 3D techniques are being developed to analyse facial features in an objective, operator-independent way and to assist clinical training in pattern recognition. Databases like OMIM, London Medical Databases, Possum are useful tools commonly used by dysmorphologists to achieve a diagnosis in difficult cases. When a syndrome is suspected, investigations like eye examinations, renal ultrasound, echocardiogram, skeletal radiographs and cranial ultrasound may be indicated. As for laboratory tests, blood chromosomes are very often indicated when there are multiple congenital abnormalities, dysmorphic features and abnormalities of growth, most commonly growth retardation and microcephaly. A normal chromosome analysis, however, does not exclude a single gene mutation or a micro deletion syndrome, so that single gene analysis, FISH tests and biochemical tests can also be indicated. Communicating with parents of a dysmorphic child is a very delicate matter. Terms like “dysmorphic” or “abnormal” can be perceived as offensive as well as the feeling that the child wears a recognizable diagnosis on his face. It’s very important to accurately select terms (e.g. “peculiar” or "distinctive” feature instead of “dysmorphic”) and to explain that the reason for examining the child's aspect, as well as other family members’, is to look for clues to unravel the cause of his problems. References Aase JM. “Diagnostic dysmorphology”, Plenum Medical Book Company, New York, (1990) Hammond P et al “3D analysis of facial morphology”, American Journal Medical Genetics part A, May 1 ; 126(4) : 339-48 (2004) Winter R.M. “What’s in a face”, Nature Genetics 12, 124 - 129 (1996)


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7th Course in


Monday, November, 13th


35

Genetics of mental retardation

F.Forzano Mental retardation (MR) is a common condition which affects 2-3% of people worldwide. Notwithstanding, its etiopathogenesis is still poorly understood, although it’s well known that both genetic and environmental factors can play a role. Mental retardation is currently defined as “a significant impairment of cognitive and adaptive functions, with onset before age 18 years” and is subgrouped in four degrees of severity according to the Intelligence Quotient level (IQ): mild MR (IQ 50-70), moderate MR (IQ 35-50), severe MR (IQ 20-35), profound MR (IQ below 20). The diagnosis is often suspected in the first years of life, as many children show developmental delay (DD), but it is usually clearly defined during the school years. To search the causes of mental retardation is important for many reasons. First, it might allow to define a prognosis, especially in the youngest children, and to identify which tests are appropriate and which one are not. That would also avoid to perform invasive and expensive examinations which might be unhelpful in the specific case. Second, it’s important in order to start a proper care plan. Finally, it’s crucial to the family in that it enables to provide a specific recurrence risk and to get a proper support. A genetic cause can be found roughly in a half of the cases, beeing much more likely as the IQ progressively decrease. Chromosome abnormalities and Fragile-X syndrome are the most frequent disorders. Guidelines on the evaluation of mental retardation have been established through the Consensus Conference of the American College of Medical Genetics in 1997. As for the clinical evaluation, they underlie the importance to obtain both personal and familial history, a thorough physical examination and appropriate psychometric examination. As for the laboratory tests, 550 bands karyotype and Fragile-X test are recommended basically in all the patients, while further examination should rely on more specific clinical suspicion. Neuroimaging can also be useful. As the research advances, new genes get identified and new techniques available, thus improving both knowledge and tools that can drive clinicians in the diagnostic process. It’s now emerging that mental retardation can be the end result of a number of different abnormal pathways, noone of them overriding the others, which underlie the huge complexity of our intellectual processing. So unraveling the causes of mental retardation phenotypes will ultimately be important to understand how the brain develops and works and eventually to find out possible specific treatments. References: Battaglia A, Carey JC, Diagnostic Evaluation of Developmental Delay/Mental Retardation: An Overview, Am J Med Genet C Semin Med Genet., 2006, Feb 15;142(1):3-7 Curry CJ, Stevenson RE, Aughton D, Byrne J, Carey JC, Cassidy S, Cunniff C, Graham JM Jr, Jones MC, Kaback MM, Moeschler J, Schaefer GB, Schwartz S, Tarleton J, Opitz J The Consensus Conference of the American College of Medical Genetics, Am J Med Genet, 1997, Nov 12;72(4):468-77 Raymond FL, Tarpey P The genetics of mental retardation . Hum Mol Genet. , 2006, Oct 15;15 Suppl 2:R110-6


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Medical Genetics and Public Health: Community

Genetics

V. Christophidou Anastasiadou

Introduction Some fifty years ago genetics was still unknown not only to the general public but even to physicians. Most medical schools taught little or no genetics. Then, gradually clinical genetics appeared in clinical practice, mostly referring to rare autosomal dominant disorders, in order to teach young physicians that some conditions needed some special expertise. At the time nobody expected to see todays’expansion of genetics. It is now evident that the advances in medical genetics have changed the route of traditional medicine. Almost all conditions have a genetic basis involving one or more genes, often interacting with environmental factors. Genetics means no more “rare” or “weird” or merely dysmorphism and therefore cannot be the exotic knowledge of a lonely medical elite of geneticists anymore. The explosion of genetic knowledge is reformatting the perception of health and disease. Genetics in medical practice Physicians in all specialties are called to answer the challenge of understanding and addressing the issues of genetic predisposition, susceptibility and risk. Health professionals in general, need to readjust to this development that affects all levels of health services. This new knowledge due to the expansion and application of molecular genetics has to be implemented in medical practice. A necessary step is to incorporate genetics into the education of health professionals and this has to be done on a continuous basis. In addition we have to educate the public in such a way, that scientific and technological progress will improve but not stigmatize health status and reproduction choices. Genetics and Public Health This geneticization of medicine, the flow of knowledge and the explosion of molecular diagnostics have, and will even more in the future influence the implementation of public health policies. Public health officials will increasingly need to deal with the management and prevention of genetic and/or inherited disorders that will prove to be much more common, as infectious and other disorders are better manageable. A new field is therefore emerging, that of public health genetics and new disciplines need to be addressed in educational curricula for officials and policy makers. Such disciplines include among others genetic epidemiology, statistical genetics, bioinformatics, genomics and ecogenetics. Ethical, legal and social considerations are critical issues and together with societal partnership play an important role in decision making when genetics and biotechnology are implemented in public health programs. One must not forget though that financial considerations and restrictions are usually involved and play a critical role in the process of the final designing of public health programs. Community Genetics Community genetics can be described as bringing the genetic services to the community as a whole. Community in this case can be a village or a country, ethnically homogeneous or diverse, advantaged or disadvantaged. An important difference between clinical genetic services and community genetics is that in the first case we offer the services to the individual or the family in need at the time. This happens usually after a referral by another physician or after a diagnosis is given. In addition a growing number of people have a privilege by education, social or other status so as to have access to relevant knowledge and to the service if they wish to.


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Therefore the clinical geneticist offers service and information to the specific patient/patients while the majority of the population, often those who are in greater need, have no access. At the community level, unless appropriately organized, there is a lack of services mainly due to lack of education of the public. It appears then that community genetics means the implementation of genetic services to the community level aiming to: the detection of people at risk for a genetic disorder, who would like to be informed about their risk and to have the opportunity of informed free choice. This application is beneficial as more people who would like to be informed and have access to the service, get this opportunity. Necessary strategies in community genetics include: epidemiological studies and development of registries for genetic and congenital disorders introducing genetic screening programs and appropriate offer of genetic counseling preconception and prenatal consultation on a routine basis, and public and professional education on genetics and related psychosocial and ethical issues A pioneer form of community genetics has been applied in the past in many countries and communities, often without realizing that this would be a new and different form of incorporating genetics into public health policies. Examples of pioneer programs are blood grouping, prevention of rhesus hemolytic disease, neonatal screening programs, screening for hemoglobinopathies etc. In other cases, epidemiological studies indicated preventable congenital anomalies and relevant management was implemented on a population level as in the case of folate deficiency and related neural tube defects. Establishment and organization of community genetic services has certain prerequisites, the most important being the health professionals with the knowledge, the emotion and the “ethos” necessary for this kind of broad genetic application. Professionals of this mentality are expected and able not only to educate public health authorities but also to influence politicians and the general public towards financial and structural changes in public health planning, aiming to equity of access to services and information. Indispensable professionals for the successful introducement of community genetics approach include trained primary care physicians, nurses and geneticists of various specialties (clinical, epidemiologists, molecular etc) in a balanced group with psychologists, social workers, ethicists and public health professionals. Discussion Nevertheless the implementation of community genetics needs careful monitoring as overenthusiasm in introducing screening programs together with ambivalent public education could endanger the important essence of non-directive counseling and the right for individual choice. Pressure arising from social, family and medical assumptions referring to “prevention” of preventable births can be controlled if proper education and ethical guidelines are preserved. In conclusion the field of community genetics is yet young and ambitious. It is to our duty to see that the readjustment of public health into public health genetics will guarantee equal access to relevant services for all people. It is therefore important to organize and offer genetic services to the community level. It remains on us to appreciate and nourish the ideas of sharing the benefits of new genetics while avoiding the pitfalls of immense geneticization. References: • Berg K. The ethics of benefit sharing. Clin Genet 2001: 59; 240-243 • Community Control of Genetic and Congenital Disorders, World Health Organization, Regional Office

for the Eastern Mediterranean, EMRO Technical Publication Series, 1997. • Harris R, Harris H: Genetics in primary care; Report on workshop of EC Concerted Action on Genetic

Services in Europe (CAGSE) in association with the Royal College of GP Spring Meeting, Blackpool, UK, 28 April1995. J Med Genet 1996; 33:346-348.

• Holtzman NA: Primary care physicians as providers of frontline genetic services. Fetal Diagn Ther 1993; 8(supple 1): 213-219.

• HUGO Ethics Committee statement on benefit sharing. April 9,200. Clin Genet 2000;58: 364-366.


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• Genetic Services Provision: An International Perspective. Birth Defects: Original Article Series, Vol 28,No 3,1992. March of Dimes Birth Defects Foundation, White Plains, New York.

• Modell B, Kuliev AM: The History of Community Genetics: The Contribution of the Hemoglobin Disorders. Community Genet.1998: 1:3-11.

• Morton NE: Genetic aspects of population policy. Clin Genet 1999; 56: 105-109. • Ten Kate LP: Editorial, Community Genet.1998: 1:1-2. • The Implications of Genetics for Health Professional Education. Proceedings of a Conference chaired by

Leon Eisenberg, MD. Edited by Mary Hager. Josiab Macy, Jr. Foundation, 1999.


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7th Course in


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40

Counselling and predictive testing

A Tibben Genetic counselling has been perhaps the most important way of assisting families with a hereditary disease in managing the consequences of the disease, and in helping individuals at-risk to find creative solutions for their problems. The increased awareness of the genetic aspects of a disease, and genetics in general, together with the more widespread availability of genetic centres have contributed to a more appropriate approach for those who ask for assistance in making important life decisions. Clinicians involved with families with a hereditary disease may prefer to refer their patients to a clinical genetics centre to address the genetic questions. The way such questions are dealt with can have a profound impact on the attitude of individuals at risk, their partners and children, and on further relatives. Before the availability of predictive or susceptibility testing, general counselling of the genetics of a hereditary disease was the most important issue that led individuals at risk to visit the genetic counsellor. Currently, people often apply for general genetic counselling when they have only recently first learned of a hereditary disease in their family, although many of them come with the intention to discuss predictive or prenatal testing. Most people seen for genetic counselling regarding a hereditary disease are the asymptomatic children of an affected patient, seeking reassurance for themselves and their (future) children. Sometimes people apply for predictive testing because they have the opinion that a test result might solve their psychological or family problems. Those professionals who have much experience with general counselling and predictive testing know that alternative ways of coping with personal risks and, subsequently, life decisions might be preferable in some cases. Genetic counselling involves a process of consultation by which information is imparted to individuals or families affected by or at risk for a genetic disorder. It includes information on the nature of the disorder; the size and extent of genetic risks; the options, including genetic testing, that may help clarify the risks; the available preventive and therapeutic measures, and the provision of psychological, social and practical support. In the context of genetic testing it may include responding to the concerns of individuals referred and their families, discussing the consequences of a test, and enabling them to choose the optimal decision for themselves, but not determining a particular course of action (American Society of Human Genetics 1975). The definition emphasises the two-way nature of the interaction between the test candidate and the counsellor. Moreover, counselling is considered as a process, taking place over a period of time. This process allows the assimilation of the potentially distressing information regarding diagnosis, prognosis, risk, emotional reactions, family dynamics etc. The counselling process allows attention for the autonomous decisions taken by the test candidate. The appropriateness of the decisions can be discussed and weighed extensively. This all requires ‘appropriately trained persons’ which implies special knowledge and skills distinct from those needed in other medical and counselling interactions (Platt-Walker 1998). Individuals at risk for HD often come for genetic counselling to discuss aspects of the disorder they find difficult to deal with. Exploring with them their experiences, emotional responses, goals, cultural and religious beliefs, financial and social resources, family and interpersonal dynamics, and coping styles has become an integral part of the counselling process. Many individuals at risk with life long experience with a specific hereditary disease have no full awareness of how the disorder has influenced their psychological make up. An experienced counsellor must be able to recognise and bring forth these responses. He or she can identify normal and maladjusted responses, reassure candidates that their reactions are normal, prepare them for the near future, new issues and emotions that may come up, and help them to mobilise the resources needed to encourage coping and adjustment. A central assumption of genetic counselling has been the non-directive approach. This assumption is often misunderstood in a way that non-directiveness does not mean that the counsellor should by no means express their personal views, opinions or feelings (Kessler, Kessler et al. 1984; Djurdjinovic 1998). An individual at-risk can expect that the counsellor is willing to provide some guidance when needed to enable him or her to proceed in his own process of consideration. Yet, it requires from the counsellor a level of introspection and


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awareness of his or her personal feelings and interests in order not to be coercive. The lack of treatment options and future perspectives may facilitate the psychological defences of professional persons such as denial and displacement of responsibility. Families can be threatening to those professionals who have difficulties in working with conditions that cannot be cured. Although the defences protect professionals from the difficult and unsettling task of providing genetic counselling to healthy relatives at risk, they may prevent caregivers from establishing a relationship that is characterised by confidentiality, respect for autonomy and empathy (Martindale 1987). Permanent education and increase in awareness of the psychodynamics involved may lead to creative and constructive thinking about the current deficiencies in care and counselling services provided for families with a hereditary condition. American Society of Human Genetics, A. H. C. o. G. C. (1975). “Genetic counseling.” American Journal of Human Genetics 27: 240-242. Baker, D. L., J. L. Schuette, et al., Eds. (1998). A guide to genetic counseling. New York, Wiley-Liss, Inc Djurdjinovic, L. (1998). Psychosocial counseling. A guide to genetic counseling. D. L. Baker, J. L. Schuette and W. R. Uhlmann. New York, Wiley-Liss: 127-170. Kessler, S., H. Kessler, et al. (1984). “Psychological aspects of genetic counseling. III. Management of guilt and shame.” Am J Med Genet 17(3): 673-97. Martindale, B. (1987). “Huntington's chorea: some psychodynamics seen in those at risk and in the responses of the helping professions.” Br J Psychiatry 150: 319-23. Platt-Walker, A. (1998). The practice of genetic counseling. A guide to genetic counseling. D. L. Baker, J. L. Schuette and W. R. Uhlmann. New York, Wiley-Liss: 1-26.


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7th Course in


ABSTRACTS OF WORKSHOPS


43

Counselling skills practical session

A. Tibben and H. Skirton During this session you will be encouraged to develop your skills in communicating with families who are concerned about a genetic condition. The objectives of the session are to help you: a) Understand the core skills used in counselling in a genetic context b) Have practised the core skills used in counselling in a practical scenario c) Have observed and given feedback on counselling skills in other students d) Had the opportunity to role-play a client. General guidelines for counselling in a genetics context 1. Be focussed on the client’s needs • check at start of session what the client thinks they have come for • acknowledge the client’s issues, even if not strictly related to the genetic condition. It is more helpful to

say that you understand what they want and give reason why you can’t help than to ignore the issue • before end of session, ask client if they have any questions (and allow time!) 2. Non-verbal communication • sit with an ‘open posture’, avoid crossed legs and arms • sit slightly forward and slightly sideways • give client your attention, but don’t stare • avoid distractions e.g. watch, phone • don’t have a desk between you and client 3. Questions • avoid factual questions while client telling their story • use open questions when asking about feelings • e.g. ‘how did you feel when the doctor said that?’ rather than ‘ were you sad when the doctor said that?’ 4. Let the client know you are listening by: • using non-verbal cues……umm • mirroring the words of the client • paraphrasing • making brief summaries of what has been said so far • summarising at the end of the session 5. Convey information effectively by: • using the client’s vocabulary • using aids such as pictures, models, visual images (but not too many!) • phrasing risk figures in both percentages and ratios • checking if client has understood (go over again if not clear). 6. Other important issues • the client may have a strong need for certainty – discuss, particularly if no certain answer available


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• the client will already have a lay explanation for what has happened - find out what client thinks about the condition

• use the client’s family tree to explain inheritance 7. At the end of the session • ‘Is there anything else you think we should discuss?’ • leave door open for client to re-contact • send summary letter and invitation to re-contact. Skills practice - Rules for feedback Definition of feedback: comments and information from others about behaviour and way of communication, with the purpose of increasing awareness and – if needed – to make improvements Giving feedback • Always give positive feedback first - tell the counsellor what they did well! • Be descriptive and concrete – identify comments or actions that worked well or didn’t work so well such

as, “You asked a good open question then” or “You could have left more time for the person to answer at that point”.

• Do not make judgements about the person, only comment on what they DID. • Take personal responsibility for what you are saying e.g I felt that … • Finish with a positive comment. Receiving feedback • Try not to become defensive – the feedback is given to help you develop further • Take time to think about what has been said – you do not need to respond, or explain, just take what is

offered and think about it. Remember, no-one ever does counselling work perfectly, and no-one has ever been helped by being told they were perfect!


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7th Course in


ABSTRACTS OF POSTER


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Identification of MYH mutation carriers in newly diagnosed colorectal cancer: a prospective,

multicenter, case-control, population-based study

F. Balaguer, S. Castellví-Bel, A. Castells, M. Andreu, J. Muñoz, J. P. Gisbert, X. Llor, R. Jover, R. de Cid, V. Gonzalo, X. Bessa, R. M. Xicola,

E. Pons, C. Alenda, A. Payá, J. M. Piqué Background & Aims: Whereas it has conclusively demonstrated that biallelic MYH mutations confer a significant risk for colorectal cancer (CRC), the influence of monoallelic mutations remains controversial. Characterization of patients with MYH-associated CRC is critical to identify individuals who may benefit from genetic testing and, consequently, from specific screening and surveillance strategies. However, clinical criteria to identify MYH mutation carriers in this setting are not well established. This prospective, multicenter, case-control, population-based study, performed within the Epicolon project in which all CRC diagnosed in 25 centers between 2000 and 2001 were included, was aimed at: 1. establishing the CRC risk associated with specific germline MYH mutations, and 2. devising a set of clinical criteria to identify MYH mutation carriers among newly diagnosed CRC. Methods: Genotyping for Y165C and G382D was performed by TaqMan technology. SSCP analysis was performed in heterozygous patients to screen for mutations in the entire gene. All individuals were re-screened for any additional pathogenic variant. Results: Biallelic and monoallelic MYH mutations were found in 8 (0.7%) and 19 (1.7%) out of 1,116 CRC patients, respectively. None of the 934 control subjects carried biallelic mutations, whereas 22 (2.3%) of them were monoallelic carriers. In a meta-analysis including all previous case-control studies, monoallelic MYH carriers were not at increased risk for CRC (OR, 1.11; 95%CI, 0.90-1.37), although a significant asscociation was found with the Y165C mutation in either homozygosis or heterozygosis (OR, 1.67; 95%CI, 1.17-2.40). Furthermore, presence of more than 15 synchronous colorectal adenomas or CRC diagnosed under the age of 50 was the most effective set of criteria for the identification of biallelic MYH mutation carriers. Conclusions: This study proposes the first set of clinical criteria designed to identify CRC patients with biallelic MYH mutations, and it argues against an increased risk for monoallelic carriers. Francesc Balaguer, Sergi Castellví-Bel, Antoni Castells, Montserrat Andreu, Jenifer Muñoz, Javier P. Gisbert, Xavier Llor, Rodrigo Jover, Rafael de Cid, Victòria Gonzalo, Xavier Bessa, Rosa M. Xicola, Elisenda Pons, Cristina Alenda, Artemio Payá, Josep M. Piqué, for the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association.


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Recurrent trisomy 21: when the genetic counseling is not taken into account

I. C. Jaouad, S. C. Elalaoui, N. Aboussair, Y. Benbouchta, F. Elkerch,

S. C. Dequaqi, A. Sefiani Trisomy 21 or Down’s syndrome is the most common autosomal chromosome abnormality with an incidence of 1/700 live births. Down’s syndrome associates a psychomotor delay, characteristic facial features, and sometimes cardiac, digestive and ocular malformations. Several risk factors have been incriminated. But, advanced maternal age remains the only well- documented risk factor of trisomy 21. The middle maternal age of Moroccan mothers of children with trisomy 21 is 34,4 years old. Couples with a previous trisomy 21 pregnancy have a significantly increased recurrence risk above that expected for the maternal age (about 1%). We present an unusual observation of a 40 years old woman, who had a first child with free trisomy 21. The genetic counseling provided to the couple was that the risk of recurrence is raised and a prenatal diagnosis for the next pregnancy is highly recommended. This couple wanted absolutely a second child. Unfortunately, prenatal diagnosis was not performed because of the low socioeconomic level of the family, and the mother had a second child with free trisomy 21, at the age of 44 years. In this observation, we present how it’s difficult to manage the genetic risk in well informed but fatalistic families with low socioeconomic level. This work shows also the great necessity to set up health programs to inform about risk of advanced maternal age. I. Cherkaoui Jaouad, S. Chafai Elalaoui, N. Aboussair, Y. Benbouchta, F. Elkerch, S. Cherkaoui Dequaqi, A. Sefiani Department of Medical Genetics – National Institute of Health- Rabat- Morocco


48

Free fetal DNA in maternal circulation: a potential prognostic marker for chromosomal

abnormalities?

A. Gerovassili, C. Garner, K. H. Nicolaides, S. L. Thein, D. C. Rees Objectives: Previous studies on the association of fetal cell-free (cf)DNA levels in maternal circulation have produced conflicting results but the sample sizes were small and based on archived material. We aimed to quantify the levels of fetal and total cfDNA on prospectively collected samples, to understand its correlation with other variables and to clarify its diagnostic value. Methods: DNA from pre-CVS maternal plasma was extracted from 264 controls, 72 Trisomy 21, 24 Trisomy 18, 12 Trisomy 13, 16 Turner’s syndrome and 8 Triploidy first-trimester pregnancies and quantified using real-time PCR. β-globin was used to determine total cfDNA levels and DYS14 and SRY assays to determine fetal cfDNA levels. Results: Fetal cfDNA levels (DYS14) showed correlation with crown rump length (CRL)(p=0.004), BMI (p=0.01) and storage time (p=0.007) while there was an inverse correlation of total cfDNA levels with nuchal translucency (NT)(p=0.001). No significant difference was observed between the levels of fetal cfDNA in controls and aneuploidy cases. Conclusion: Quantification of fetal and total cfDNA in maternal circulation showed inverse correlation between NT and total cfDNA levels. Our results also suggest that fetal cfDNA is not an ideal prognostic marker for chromosomal abnormalities in first-trimester pregnancies. Key words: circulating nucleic acids, cell-free DNA, non-invasive prenatal diagnosis, aneuploidy Ageliki Gerovassili1*, Chad Garner2, Kypros H. Nicolaides3, Swee Lay Thein1, 4, David C. Rees1, 4 Addresses: 1 Division of Gene and Cell Based Therapy, King’s College London School of Medicine, London, SE5 9PJ, UK 2 Epidemiology Division, University of California, Irvine, California, 92697-7550, USA 3 Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London SE5 9RS, UK 4 Department of Haematological Medicine, King’s College Hospital, London SE5 9RS, UK * Corresponding author, [email protected] Emails: [email protected] [email protected] [email protected] [email protected] [email protected]


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Partial trisomy 8 due to maternal translocation

L. Kraoua, I. Ouertani, M. Chaabouni I. Chelly, L. Ben Jemaa, H. Chaabouni

Trisomy 8 is a viable aneuploidy. The occurrence is about 1 per 300000 live births. It’s characterized by clinical and cytogenetic heterogeneity. Trisomy 8 may be complete with one added chromosome 8, in all cells or in mosaic, either the trisomy is partial due in most cases to parental balanced translocation. Clinical expression is made of variable dysmorphy , inconstant visceral malformations and mental retardation. We report the case of familial translocation diagnosed after prenatal diagnosis. Fetus karyotyping was indicated because of high nuchal translucency (3.5mm) and showed a derivative of chromosome 15 with added material. Parental karyotypes revealed an abnormal karyotype of the mother with balanced translocation (8,15): 46, XX t(8,15)(q22-p11). The father’s karyotype was normal. Ultrasound Fetal echography showed cardiac anomaly and facial dysmorphy. Parents decided for pregnancy termination. Fetal examination revealed a severe mandibular hypoplasia and other facial dysmorphic features. Using molecular probes we have to determine the point breakages. L. Kraoua, I. Ouertani, M. Chaabouni I. Chelly, L. Ben Jemaa, H. Chaabouni. Department of Genetics Charles Nicolle hospital. Tunis. Tunisia


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A novel PSEN2 mutation in early-onset dementia with profound semantic loss

SG Lindquist, JM Czarna, A Nørremølle, M Schwartz, L Hasholt, G

Waldemar, JE Nielsen Introduction The early-onset autosomal dominant inherited variant of Alzheimer’s Disease (AD) can be caused by mutations in the genes for the amyloid precursor protein (APP), presenilin-1 (PSEN1) or presenilin-2 (PSEN2). Mutations in PSEN1 account for the majority of these cases, whereas mutations in APP and especially PSEN2 are rare [1]. Previously, only 10 presumed pathogenic mutations in PSEN2, in a total of 18 families, have been reported [1]. Clinically, AD can be difficult to distinguish from Frontotemporal dementia (FTD). 30-50% of families with autosomal dominant inherited FTD have mutations in the microtubule-associated protein tau (MAPT) gene located on chromosome 17 [3]. Objective To present clinical data and molecular results from studies of a Danish family with a novel mutation in exon 11 of the PSEN2 gene. Results The proband had early onset and a family history of dementia. The phenotype was characterized by impairment of memory and early profound semantic loss. Neuroimaging results were compatible with a diagnosis of Alzheimers disease. Automated DNA sequencing of PSEN1 (exon 3-12), PSEN2 (exon 3-12), APP (exon 16-17) and MAPT (exon 9-13) was performed. The proband had a novel PSEN2 missense mutation in exon 11 indicating an amino acid change from Valine to Methionine in a conserved region of the protein. Apart from previously reported polymorphisms, we found no other mutations in PSEN1, PSEN2, APP or MAPT. The mutation was found in none of 10 unaffected family members and 384 control individuals tested. Ongoing studies include introduction of the mutation in cDNA for expression studies in order to determine the effect of the mutation on Amyloid β production. Conclusion We present a novel missense mutation in exon 11 of PSEN2 in a Danish family with clinical and molecular data. The conserved nature of the region and the fact that the mutation was not detected on examination of 384 control individuals could indicate that this is a pathogenic mutation. Further studies are ongoing in order to determine the effect of the mutation on APP degradation. SG Lindquist1,2,3, JM Czarna4, A Nørremølle3, M Schwartz2, L Hasholt3, G Waldemar1 , JE Nielsen1,3 1Memory Disorders Research Group, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Denmark 2Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Denmark 3Department of Medical Biochemistry and Genetics, Section of Neurogenetics, The Panum Institute, University of Copenhagen, Denmark Department of autoimmunology, Statens Serum Institut, Copenhagen, Denmark


51

Diagnosis of aneuploidy with fluorescence in situ hybridization (FISH): First Tunisian experience

I.Ouertani, M.Chaabouni, M.Belhiba, H.Chaabouni

This is a retrospective study on the results of the first Tunisian experience in prenatal diagnosis using interphase fluorescence in situ hybridization (FISH), performed for chromosomes 13, 18, 21, X and Y. It is a series of 74 amniotic fluid samples tested in a 6 months period in the human genetic department of Charles Nicolle Hospital of Tunis. Interphase FISH for chromosome 21 was performed in 19 amniotic fluid samples for age, positive maternal serum screening and Down syndrome specific ultrasonographic indications. It was performed for the five chromosomes (13, 18, 21, X and Y) in 55 amniotic fluid samples following the indications: age, ultrasonographic indications, and one case of exposition to radiation. Karyotypes from standard cytogenetic analysis were compared to the FISH results. Using conventional cytogenetics no chromosome structural rearrangements, i.e. balanced autosomal reciprocal or Robertsonian translocations or inversions were detected in this series and 5 numerical chromosomal anomalies were diagnosed 6.75% (5/74) all detectable by FISH (2 cases of trisomy 21, 2 cases of Turner syndrome and complex anomaly due exposition to radiation). With interphase FISH we detected 5/5 of these numerical chromosomal anomalies. Maternal cell contamination of amniotic fluid samples occurred in 1.35% (1/74) of samples and it was uninformative by FISH. Through this new experience of FISH in Tunisia, we found that it is a reliable and effective technique for the rapid prenatal diagnosis of the most frequent aneupolidies. However, we can offer interphase FISH only in very high-risk pregnancies or/and at late gestational age because of the high cost of the test.


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Genetic counselling and prenatal diagnosis in a couple with paternal balanced translocation

t(6;7)(p22,q32)

Rifai L., Cherkaoui Jaouad I., Aboussair N., Sbiti A., El Kerch F., Benbouchta Y., Natiq A., Sefiani A.

In this report, we present the case of a couple referred by a pediatrician for genetic counselling about their 9 month-old girl who who showed developmental delay and several anomalies. R-banding chromosome analysis of the peripheral blood lymphocytes of the daughter and the parents showed an unfavourable segregation of a paternal chromosome rearrangement 46,XY,t(7;?)(q32;?). Chromosome fluorescence in situ hybridization (FISH) was used to clarify the paternal karyotype and showed that the karyotype of the girl was actually 46,XX,der(7)t(6;7)(p22,q32)pat. Having this precise diagnosis allowed us to explain to the parents the implications for the care of their daughter, the potential risks for further pregnancies and to propose a prenatal diagnosis. When the mother became pregnant for the second time, performing the prenatal diagnosis allowed the discovery of a masculine fœtus, with normal karyotype. This case further demonstrates the advantage of FISH in the identification of anomalous chromosome regions and breakpoints. It also reiterates the importance of the genetic counselling, when the family can afford the expenses of prenatal diagnosis for preventing chromosomal diseases, while the Moroccan public health system is still not efficient in this field. Rifai L., Cherkaoui Jaouad I., Aboussair N., Sbiti A., El Kerch F., Benbouchta Y., Natiq A., Sefiani A. Department of Medical Genetics – National Institute of Health


53

Genetic counseling in microdeletions syndromes

C. Skrypnyk, M. Bembea, V. Belengeanu, E. Tomescu, P. Grigorescu Sido, M. Covic

Introduction: Microdeletions syndromes are a collection of genetic syndromes that are associated with small chromosomes deletions spanning several genes that are too small to be detected under the microscope using conventional cytogenetic methods. Depending on the size of the deletion, FISH or other methods of DNA analysis can identify the deletion. The birth of an infant with a microdeletion syndrome creates a stressful and devastating experience for families, considering the severe consequences encompassing major malformations and mental retardation. Material and methods: We presented a number of 27 cases of different microdeletion syndromes: 6 patients with Williams syndrome, 9 patients with Prader Willy syndrome, 5 patients with Angelman syndrome, 3 patients with Rubinstein Taybi syndrome and 5 patients with DiGeorge1 syndrome. We evaluated the family history and medical records, appreciate the genetics test needing for patients and their parents, evaluated the results and established the recurrence risk, helping parents understand the disease of their child and providing support to reach decisions about what to do next. Results: All these patients had essentially the classical clinical phenotype for the respective syndromes and a positive score for the consensus diagnostic criteria. All cases were the first case in their family and became from healthy parents without clinical signs of the syndromes. The typical deletions correlated with the syndromes were detected in 4 patients of Williams syndrome, 3 patients with Prader Willi, 1 patient of Angelmann syndrome, and 3 patients of DiGeorge1 syndrome. The molecular analysis confirmed one case of Rubinstein Taybi syndrome. For all of this patients we appreciated a recurrence risk for sibs less than 1% and 50% for the probands offsprings, if they will reproduce. For the other cases the clinical diagnosis could not be sustained by molecular tests and the differential diagnosis had to be reconsidered. Discussion: Considering the possibility of the high recurrence risk of 50%, to provide an accurate information on the diagnosis and chance of recurrence within the family, the clinical diagnosis has to be fallowed by the molecular cytogenetis and molecular tests. Once the etiology established we can understand the particular aspect of the phenotype for each patient, implement the correct management for the patient and can offer the correct counseling. C. Skrypnyk1, M. Bembea1, V. Belengeanu2, E. Tomescu3, P. Grigorescu Sido4, M. Covic5 1 University of Oradea, Faculty of Medicine, Genetics Department, Oradea, Romania 2. University of Medicine and Pharmacy, Genetics Unit, Timisoara, Romania. 3. Institute for Mother and Child Care, Genetics Unit, Bucharest, Romania 4. University of Medicine and Pharmacy, Pediatric Unit I, Cluj Napoca, Romania. 5. University of Medicine and Pharmacy, Genetics Unit, Iasi, Romania.


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Hereditary spastic paraplegia (HSP): a new variation in SPG13

K. Svenstrup, J. Hansen, M. Nyholm Nielsen, P. Bross, L. Hasholt, J.

Nielsen Background: HSP is a clinical and genetic heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and weakness of the lower limbs. At present 28 genes have been localized but only 10 genes are identified. Mutations in the SPG4 gene account for approximately 40% of autosomal dominant HSP cases, and variable penetrance has been shown. Only few families are described for the remaining known genes. The gene encoding SPG13 known as heat shock protein 60 (HSP60) was characterised in 2003. Only one HSP family with a disease-associated variation in this gene has been described. Here we report a second family. Methods: DNA samples from 23 Danish probands diagnosed clinically with HSP were sequenced for the entire HSP60 coding region. Relevant family members were investigated clinically. Results: In one female patient a missense mutation in HSP60 was found. The patient showed slowly progressive spastic paraplegia with onset at age 52. She was investigated clinically, neurophysiologically and with MRI. 62 years old she died from pulmonal cancer. Her mother had shown an identical gait disorder. None of 5 siblings had any symptoms or signs of HSP but two brothers at 56 and 65 years, respectively, carried the mutation. The mutation was not found in 800 control chromosomes. Conclusion: We report a variation in SPG13 in a HSP patient. The variation could not be shown to segregate with the disease due to the small kindred. The findings suggest reduced penetrance in this family as seen in other families with autosomal dominant HSP. Kirsten Svenstrup(1), Jakob Hansen(2), Marit Nyholm Nielsen(2), Peter Bross(2), Lis Hasholt(1), Jørgen Nielsen(1). Institute of Medical Biochemistry & Genetics, Department of Medical Genetics, Section of Neurogenetics, The Panum Institute, University of Copenhagen. (2) Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences.

Formatted: Bulletsand Numbering


55

A study of 319 Egyptian cases with limb & skeletal anomalies

Temtamy SA, Aglan MS, Aboul-Ezz EHA, Ashour AM, El-badry TH

Genetic diseases and congenital anomalies constitute a heavy burden to the society since many are chronic diseases that cause permanent disability. Limb and skeletal anomalies can be considered as one of the most important causes of disabilities in Egypt since they are among the most common at the population level. They comprise two main categories: limb anomalies as isolated defects and limb anomalies as part of syndromes with involvement of other organs or systems. From our previous studies, we classified limb anomalies into 10 main categories. For each category, numerous syndromes exist which are inherited as autosomal dominant, recessive, X-linked or are due to chromosomal aberrations or environmental causes. Therefore, genetic counseling varies according to diagnosis. In 2002, Professor Temtamy initiated a specialized clinic for limb and skeletal anomalies at the Medical Services Unit, National Research Centre, Egypt. During the first 3 years the clinic received 319 cases with different types of limb and /or skeletal anomalies, which were included in this study. We aimed by this work at the accurate diagnosis, classification and proper genetic counseling of cases with limb and skeletal anomalies. All cases were subjected to detailed physical examination, pedigree analysis, orodental examination and anthropometric measurements. Cytogenetic, biochemical, radiological and neurophysiologic studies were used as indicated to aid in the diagnosis. This study allowed us to define and analyze the most common causes of limb and skeletal malformations in Egyptians and their types of inheritance. New orodental findings were found in some syndromes. Orodental changes offered valuable diagnostic tools in syndrome identification. Rare cases were diagnosed and new syndromes were reported. Genetic counseling was offered to the cases and families with the ultimate goal of prevention and gene therapy in the future. With the recent advances in molecular medicine and the unraveling of molecular basis of many limb and skeletal anomalies, it is becoming mandatory to apply such techniques to our study. Samples were collected from selected cases and families for further florescent in-situ hybridization (FISH) and molecular studies. Temtamy SA*, Aglan MS*, Aboul-Ezz EHA**, Ashour AM*, El-badry TH** Departments of Clinical Genetics* and Orodental Genetics**, Division of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt


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Genetic counselling and BRCA1/2 testing in breast cancer patients: referral, knowledge and opinion of

primary care physicians

E. van Riel, C. C. Wárlám-Rodenhuis, M. G.E.M. Ausems

This study is conducted among primary care physicians (surgeons, internists, radiotherapy-oncologists, radiologists), who take part in the treatment of patients with breast cancer. By means of a questionnaire, primary care physicians in all hospitals in the region from the Comprehensive Cancer Centre Middle Netherlands were asked which criteria they use in daily practice to select breast cancer patients for referral for genetic counselling and BRCA testing. Also, knowledge about hereditary breast cancer and opinion on genetic counselling and DNA testing were studied. The participation rate was high (67%). The results of our study show that a substantial (25-50%) part of breast cancer patients who meet criteria for referral are not referred for genetic counselling and genetic testing. Primary care physicians did score well on the knowledge questions, although questions about the heritability of breast cancer are less well answered. Primary care physicians have in general a positive attitude towards genetic counselling and DNA testing. The major point of concern is the distress genetic counselling and DNA testing may cause in family members. The majority of the primary care physicians state that the best time for referral is just after adjuvant therapy or during follow-up of the patient. Another important determinant of the most convenient time-point is the wish or the need of the patient. Further studies are needed to determine the role of physician and patient in taking the initiative for referral. Also, the questionnaire will be send to primary care physicians in another region of The Netherlands to increase numbers.

Els van Riel1, Carla C. Wárlám-Rodenhuis2, Margreet G.E.M. Ausems1

1Department of Medical Genetics, 2Department of Radiation Oncology, University Medical Center Utrecht, The Netherlands


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7th Course in


STUDENT’S WHO’S WHO


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Aboul-Ezz Eman

Hassen Anwar Egypt

Aglan Mona Sabry Egypt Al-Ashtar Ali Ahmed Malta

Alonso Maria Jesus Spain

Balaguer Francesco Spain Borg Isabella Malta Cherkaoui Imane Jaouad Morocco Dakkak Wafa Samara Jordan Dubras Charlotte Mary Uk Ferraud Lilianne Sweden Fischer Jeanette Denmark Gaki Eleni Cyprus Gerovassili Ageliki Greece Ghaffari Saeed Reza Iran Hosseini Parviz Iran Jansson Madelene Sweden Koch Inge Lise Denmark Kraoua Lilia Tunisia Kuiper Karin Netherlands Levy-Shohat Vered Israel Lewis Celine UK Lindquist Suzanne Granhøj Denmark M'rad Ridha Tunisia Ouertani Ines Tunisia Ouldim Karim Morocco Regev Miriam Israel Rifai Laila Morocco Sánchez Eva María Spain Skrypnyk Cristina M. Romania

Spiteri Rose Mary Malta

Stam Paulien Netherlands Stenman Elisabeth Margareta Sweden Svenstrup Kirsten Denmark Telleria Juan Jose Spain Temtamy Samia Egypt Tomaszewska Agnieszka Poland Van de Beld Mirjam Netherlands van Gilst Johan Netherlands van Riel Els Netherlands van Wijngaarden Jens Netherlands


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7th Course in


FACULTY ADDRESS BOOK


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ANASTASIADOU, Violetta

The Cyprus Institute of Neurology and Genetics Clinical Genetics P.O. Box 23462 1683 Nicosia, CYPRUS Tel. +357-22405117 Fax +357-22315739 <[email protected]>

[email protected]

COVIELLO, Domenico

Domenico Coviello, MD, PhD Head of Laboratory of Medical Genetics Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena Via Commenda 12, 20122 Milano, Italy Tel. +39.02.55032173 Fax +39.02.55032019 Mobile +39.3355793885 e-mail [email protected]

[email protected]

CROLLA, John Dr John A Crolla PhD., FRCPath, Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wilts. SP2 9LN U.K. Tel: +44 (0)1722 429069 Fax: +44 (0)1722 338095 Email: [email protected]

[email protected]

FORZANO Francesca

Francesca Forzano S.C.Laboratorio di Genetica, E.O.Ospedali Galliera, via Volta 8, 16128 Genova - Italy Tel: 0039-010-563-4372 Fax: 0039-010-563-4381 Mobile 0039-338-2812049 E-mail: [email protected]

[email protected]


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PATCH, Christine Senior Research Fellow Health Care Research Unit Level B South Academic Block, MP 805 Southampton General Hospital Southampton SO16 6YD, UK Tel 023 8079 6742

[email protected]

SKIRTON, Heather

Dr Heather Skirton Reader in Health Genetics Faculty of Health and Social Work University of Plymouth Wellington Road Taunton TA1 5YD 44 (0) 1823 366911 Fax 44 (0) 1 823 366901 <[email protected]>

[email protected]

SOLLER , Maria Maria Soller MD, PhD Department of Clinical Genetics Lund University Hospital SE-221 85 Lund SWEDEN +46-46-173583 [email protected]

[email protected]

STENHOUSE, Susan A.R.

Susan A.R. Stenhouse Consultant Clinical Scientist Head of Molecular Genetics Duncan Guthrie Institute of Medical Genetics Yorkhill Hospital Glasgow G3 8SJ Tel: 0141 201 0360 Fax: 0141 201 0713 [email protected]

[email protected]


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TIBBEN, Aad Dept of Neurology Centre for Human and Clinical Genetics Dept of Clinical Genetics, Section Genetic Counselling LUMC P.O.Box 9600 2300 RC Leiden tel +31 (0) 71 526 8033

[email protected]

TURCHETTI, Daniela

Cattedra e U.O. Genetica Medica Padiglione 11 Policlinico Sant'Orsola-Malpighi via Massarenti, 9 40138 Bologna, Italy --39 051 6363694

[email protected]

European School of Genetic Medicinegrc.sbmu.ac.ir/uploads/5-genetic_counselling_in_practice.pdf · 2014-10-14 · Harper P S (2004) Practical Genetic Counselling 6Th Edition. London,

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