Journal of Genetic Counseling Vol. 4, No. 4, 1995

Abstracts of Papers Presented at the Fourteenth Annual Education Conference Conditions That Affect Adults 1

Psychological Impact of Predictive Genetic Testing for Cancer K. Australie, R. Weksberg, C. Shuman, M. Barrera, and D. Malkin The Hospital for Sick Children, Toronto, Canada Genetic screening tests are currently available for some adult-onset disorders. The potential benefits of such tests to decrease morbidity and mortality must be balanced against adverse effects including the psychological distress associated with knowledge of disease risk. Parents of children with cancer are known to suffer psychological distress at various stages of the illness in their child. We set out to determine whether parents of children with cancer suffer increased psychological distress as a result of the availability of predictive genetic testing for cancer. Virtually all types of cancer have been reported to occur in a familial form. The parents of two different groups have been included in the study cohort, because they face significantly different "predictive" genetic testing approaches. One model of familial cancer aggregation, known as the Li-Fraumeni syndrome (LFS) is recognized in kindreds affected with multiple early adult-onset and childhood malignancies. Recent identification of the inherited germline mutations of the p53 tumor suppressor gene in several LFS families and in some other patients with nonfamilial forms of cancer has confirmed the genetic nature of this cancer predisposition. Beckwith-Wiedemann syndrome (BWS) is characterized by somatic overgrowth, macroglossia, omphalocele, in addition to other developmental abnormalities and has an increased risk for embryonal tumors. For the first group, a gene test predictive of cancer development is available but clinical screening methods are relatively inadequate; for the BWS group an increased risk for tumor development exists and pre-clinical screening is available with abdominal ultrasound and serum AFP, but genetic predictive tests have yet to be developed. All parents of a child with cancer are eligible for inclusion in the study with or without a family history of cancer. Using semi-structured interviews in a prospective manner, parents of children with cancer or children with BWS at The Hospital for Sick Children are asked questions addressing their understanding of the implications of genetic testing, genetic risk of cancer, methods of acquiring genetic information, and of transmitting this information to their children and other family members. Demographic data are also obtained and standardized assessments of the parents' psychological characteristics such as anxiety and de1Correspondence should be directed to Barbara Pettersen, Genetics Department, Kaiser-Permanente Medical Center, 260 International Circle, San Jose, California 95119-1197. 315 1059-7700]95/1200~315507,50/1 © 1995 National Society of Genetic Counselors, Inc.



pression are performed. To date, 18 parent sets have been enrolled and have completed the initial study phase. Preliminary data suggest that most parents do wish to know about predictive genetic testing for cancer. However, a small number feel that testing should not be offered to the general population but to only those who are known to be at increased risk. Parental attitudes to genetic testing for cancer will be an essential component to the development of appropriate and acceptable predictive testing programs. Therefore, the data and recommendations arising from this study should find widespread application in predictive genetic testing programs in the international medical and scientific community.

Clinical Genetics Best Practices: Establishment of Guidelines for Counselors Providing Patient Counseling Services for a Commercial Genetic Testing Laboratory B. Balkite and S. Puck Integrated Genetics, 2000 Vivigen Way, Santa Fe, New Mexico 87505 Although considerable effort has been expended to assure quality in the genetics laboratory, formal standardization of other aspects of clinical genetics is still a relatively new concept. Much of what genetic counselors do in clinical genetics is guided by a commitment to excellence in providing patient care. The California Department of Health Services has written guidelines for provision of genetic services for its Maternal Serum Screening Program and follow-up testing. The Great Lake Regional Genetics Group published Minimum Guidelines for the Delivery of Clinical Genetic Services in 1992. Guidelines, QA/QC, and standardization have also been addressed in presentations at the Annual NSGC Education Meeting in the last 3 years. In January 1995, the Medical Director and Program Manager for Genetic Counseling of Integrated Genetics recognized the need to establish clinical practice guidelines for genetic counselors and consultants providing patient counseling services for the company. The objectives were to establish guidelines in four categories: (1) Genetic counselor/consultant standards: qualifications, recruitment and hiring practices; orientation of new counselors; supervision/evaluation of counselor clinical practice. (2) Clinical policies with legal implications: telephone communications with patients; genetic consultations based on test results from a laboratory other than Integrated Genetics; referral of patients to an MD geneticist. (3) Standardization of genetic consultations: medical intake data; pedigrees; report format, turn around time, and content; record keeping practices; referral for tests not performed by Integrated Genetics. (4) Future clinical practices: group information sessions; consultation services for clients involved in the delivery of health care services. An identified major challenge was how to accomplish the objectives in an established time frame given the different regional clinical practices in place, the diverse levels of experience of the counselors, and the four time zones in which people worked! The methods used to establish Clinical Genetics Best Practices and the Guidelines that have been established to date will be presented.

Epilepsy and Pregnancy: What Women Know About Their Risks T. Bartell and E. Pergament Northwestern University, Chicago, Illinois 60611 Women with epilepsy have unique concerns regarding pregnancy. Their pregnancies are considered at high risk for complications including increased seizure frequency, teratogenicity,



status epilepticus, congenital anomalies, and bleeding disorders in the newborn. Since limited research has addressed the level of knowledge of women with epilepsy about pregnancy, a questionnaire consisting of 22 true-false items was developed. Eighteen women with epilepsy were recruited from the Illinois Teratogen Information Service (ITIS) and the Epilepsy Foundation of Greater Chicago (EF). Questions covered issues of fertility, inheritance, risks of anticonvulsant medications to their offspring, risks of seizures to the mother and fetus during pregnancy, seizure frequency during pregnancy, timing of receiving risk information (before or after pregnancy), and changes in dose and type of anticonvulsant medication prescribed during pregnancy. The mean correct response rate was 64% and included individual misperceptions and uncertainties. All women (160%) responded that they would continue to take their anticonvulsant medications if they were to become pregnant, although, 89% correctly believed that anticonvulsant medications could cause birth defects. Additionally, 89% of the women incorrectly believed that their physician might change their anticonvulsant medication during pregnancy. Thirty-nine percent of the women incorrectly believed that seizures during pregnancy could cause birth defects. Twenty-eight percent did not know that their anticonvulsant medications could render the pill less effective. Over half (53%) of the women did not know their specific seizure type. The women from the ITIS and the EF had comparable levels of knowledge, however, there was a significant relationship between younger women and higher levels of knowledge. This relationship possibly reflects an increased awareness of, and response to, the medical and psychosocial issues for women with epilepsy and possibly a diminished ability of older women to accurately recall risk information due to the time that has passed since they completed their families. Level of knowledge was not associated with age at seizure onset, seizure frequency, education level, pregnancy history, or having other family members with epilepsy. We conclude that women with epilepsy of childbearing age would benefit from the services offered at a preconception clinic. Preconception clinics would provide risk information to women with epilepsy before pregnancy and the opportunity for optimal medical management of their seizures and anticonvulsant medications according to the guidelines developed by the Commission on Genetics, Pregnancy, and the Child (International League Against Epilepsy, 1993).

Assessing the Acceptability of Preimplantation Genetic Diagnosis Among Sickle Cell Carriers J. Bartelt, V. Headings, L. Failon, F. Ampy, and C. Uzoma Howard University, Washington, D.C. 200 Embryo biopsy and preimplantation genetic diagnosis is a new technique which may allow parents to have a child free of genetic disease. Only embryos diagnosed as unaffected are introduced to the uterus for implantation. This procedure does not involve prenatal diagnosis and selective pregnancy termination. This study was designed to assess attitudes of sickle cell carriers toward preimplantation diagnosis. Objectives included: (I) determine if sickle cell carriers are more receptive to preimplantation diagnosis for sickle cell disease over diagnosis in utero, and (2) learn if these individuals find preimplantation diagnosis more morally acceptable than pregnancy termination. Participants were recruited from a sickle cell treatment center and an IVF facility. Each was read a description of the procedures and a questionnaire was administered verbally. Statistical relationships were demonstrated between carders and views on pregnancy termination. Those less accepting of termination attended church regularly, had an affected child, were currently pregnant, or were a partner in a couple at risk for sickle cell disease. Preferences were not demonstrated between prenatal diagnosis and preimplantation diagnosis. It was concluded that sickle cell carriers find preimplantation and prenatal diagnosis equal alternatives, with neither more nor less morally acceptable. A larger sample



size is required to support the findings of this pilot study. Specific statistical relationships and opinions will be discussed in more detail.

BRCA1 Counseling and Presymptomatic Testing: Protocols and Lessons from the First Year B. Baty, J. Botkin, R. Croyle, K. Smith, J. Nash, J. McDonald, C. Halls, and B. Flick

University of Utah, Salt Lake City, Utah 84112 Genetic counseling for presymptomatic genetic testing will become an increasingly important issue in adult health care delivery. The BRCA1 Counseling and Information Project at the University of Utah is offering genetic counseling and presymptomatic testing to approximately 400 adult men and woman in a large research kindred with a BRCA1 gene segregating (C--~T at codon 1313 resulting in Gln~Stop). Gene positive and gene negative men and women are interviewed by telephone before testing and at 2 weeks, 4 months, 1 year, and 2 years after receiving results to assess the psychosocial impact of the information on individuals and families, and their health related behaviors. Spouses of married subjects are interviewed over this same time period. Kindred members make two in-person visits with project counselors. At the first visit, subjects are seen by a genetic counselor and assessed by a family counselor. If DNA testing is requested, blood is drawn for direct gene testing. Results are given in a second session with both counselors present. Counseling protocols will be presented and discussed. Thus far, the response rate to the study has surpassed our expectations. In the first 6 months of the study, genetic counseling was offered to 95 individuals, with a 98% acceptance rate. All 19 men and 29 women who completed counseling have requested genetic testing, although two women have had testing deferred by our psychiatrist and family counselor due to psychological concerns. Twelve gene positive individuals and 13 gene negative individuals have received genetic testing results to date. The genetic counselors have learned many lessons from qualitative observations of subject responses to genetic counseling. Common misperceptions among subjects include lack of knowledge of the increased risk of gene positive males for cancer and lack of increased risk for male breast cancer. Subjects were often in "pockets" of the family with only breast cancer or only ovarian cancer and did not know BRCA1 confers a risk for both cancers. Many subjects were surprised that prophylactic mastectomy is an option, and that we are recommending prophylactic oophorectomy (NIH Consensus Conference, 1994). This kindred is large enough to have its own statistics of risk for breast and ovarian cancer, and has a risk for ovarian cancer that is higher than the Breast Cancer Consortium data. Many subjects had not thought about the psychological risks of testing and appreciated being made aware of possible psychological responses to both positive and negative BRCA1 status. Both men and women who had close relatives affected with cancer sometimes appeared to have deep emotional scars. There was an overwhelming concern about risks to the children of subjects. Although our protocol did not originally include a discussion of communication with minor children about risks in the family, we found that this was often an important part of the results session. Problems were created when participation was offered to adults whose parents had not been tested. Our approach to dealing with these problems will be discussed. We strongly recommended that each subject bring a support person. Married subjects who came to the initial counseling session without a support person were sometimes disappointed that they did not bring their spouse. Spouses usually had just as many concerns as the subjects. We chose a genetic counseling model to provide education and counseling. Although some of the material presented could have been handled using an education model, counseling was intertwined with the process of education. We feel that it is important to distinguish the need for genetic education from the need for counseling, and to provide for both needs. These are examples of preliminary impressions from the first 6



months of the study. At the time of our presentation, we will discuss insights learned from almost 12 months of genetic counseling in this large kindred.

Attitudes About Genetic Testing for Breast Cancer Susceptibility Among Individuals with a Family History of Breast Cancer J. Beeman, H. Saal, and E. Lower* Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio.* It has often been said in genetics that technological advances are racing beyond our knowledge of the impact on the individuals and families who will be served by these advances. It is of particular interest to determine attitudes toward genetic testing among both women and men who may be candidates for genetic screening for breast cancer susceptibility. The purpose of this descriptive study is to provide insight into the following: (1) women's and men's attitudes and motivations for susceptibility testing, (2) their concerns about receiving results, (3) their anxiety and risk perception about getting breast cancer, and (4) their sources of support and information about breast cancer. In order to reach individuals with a first degree relative with breast cancer, 123 breast cancer patients were contacted through their oncologist, Dr. Elyse Lower. Patients were eligible who experienced the onset of breast cancer before 46 years of age. These women provided four generation pedigrees and were asked for permission to contact a first degree relative. Preliminary results: 21 women have been interviewed in person during breast cancer clinic visits. The remaining 102 patients have been contacted through the mail, and will be interviewed by phone. Telephone interviews will be also conducted with the first degree relatives, using a questionnaire developed by the researcher. Data will be presented from the surveys of the patients and their relatives.

An Assessment of the Perspectives that Parents of Deaf Children in a Residential School for the Deaf Have About Genetics and Genetic Counseling J. Coppinger, S. R. Young, V. Vincent, and J. Israel University of South Carolina, Columbia, South Carolina 29023 Over 28 million Americans have some degree of hearing loss, and the incidence of profound prelingual deafness is approximately 1/1000 births. Because an estimated 50% of all cases of deafness are due to genetic causes, genetic counseling is an appropriate option that should be made available to the deaf community. Previous studies have shown that genetics services are underutilized by the deaf population. Reasons for underufitization include lack of awareness by the deaf community about genetics services, lack of referrals from physicians, financial and geographic barriers, and cultural or language barriers. Studies from the Genetics Service Center at Gallaudet University have shown that deaf individuals are receptive to genetics and genetic counseling if it is presented in a culturally sensitive manner. This study investigated the perceptions that parents of deaf children at the South Carolina School for *University of Cincinnati Medical Center, Cincinnati, Ohio



the Deaf and Blind have about genetics and genetic counseling. It was determined that 60% of the parents of deaf children did not use genetics services because they were not aware of them, or did not know where to find them. All parents expressed neutral or positive views of genetics and genetic counseling, and 68.7% expressed willingness to obtain more information. Results of this study provide jusfification for the planning and provision of educational materials to parents of deaf children, and possibly to physicians in South Carolina.

A Study of the Knowledge and Attitudes of Oncologists and Oncology Nurses in South Carolina About Genetics in Cancer Allison M. Davis, Angela Tutera, and S. Robert Young

University of South Carolina, Columbia, South Carolina Recent advances in the genetics of neoplasia have led to the possibility of DNA testing for the identification of individuals with a predisposition to develop cancer. While widespread testing may not be standard care for some time, the identification and counseling of at-risk individuals and families for hereditary cancers may facilitate patients' informed decision-making about future participation in prevention and therapeutic strategies as well as assist in case management and prognosis. A questionnaire was devised to investigate the opinions and knowledge of oncologists and oncology nurses practicing in the state of South Carolina about the dissemination of genetic principles and genetic counseling/testing in the field of Oncology. The study population included 31 of 105 (29.5%) physicians and 33 of 302 (10.9%) registered nurses in oncology practices. Several important conclusions can be drawn from the results of this study. The majority of oncology professionals (82.8%; 53/64) believe it is very important for their patients to understand the genetics of their disease. Given this need for the provision of genetic services, only 25% (16/64) feel comfortable providing these services. Finally, 93.8% of oncology professionals recognize the need for continuing education in cancer genetics. Although caution should be taken interpreting these results because of the small study population, we feel this data supports the need for the development of comprehensive cancer risk counseling and continuing education programs in South Carolina and throughout the United States.

The Stability of Unconjugated Estriol in Serum and Whole Blood Over Time C. Dickerson, M. Berry, R. Grubs, C. Ruiz, G. Campbell, K. Curtis, F. Lamm, J. Meyer, and S. Hart

Bowman Gray School of Medicine of Wake Forest University, Winston Salem, North Carolina Many laboratories currently include unconjugated estriol (uE3) in their maternal serum screen for Down syndrome. Our laboratory receives approximately 75% of its samples by way of first class mail. Although studies have been published on the stability of maternal serum alpha feto-protein (MSAFP) and human chorionic gonadotropin (hCG) at various temperatures over time, no studies to our knowledge have been published on the stability of uE3. The purpose of our repeated measure study design was to simulate various handling conditions



which samples undergo after they have been obtained and mailed for delivery to our laboratory. The stability of uE3 was evaluated in 30 maternal blood samples submitted for MSAFP/hCG/uE3 screening between 15.0 and 20.9 weeks gestation. Each sample was divided into two aliquots, whole blood and spun serum, and maintained at room temperature over a 14~ay period. The level of uE3 present in each aliquot was assayed on day 1 after sample receipt and again on days 2, 5, 7, 9, 12, and 14. Based on paired t-tests, we found that the raw value of uE3 in each of the 30 samples was significantly higher (p = 0.0001) in spun serum as compared to whole blood. The mean difference in uE3 raw values between spun serum and whole blood on day 2 was 0.065 ng/ml whereas the mean difference was 0.19 ng/ml on day 14. The mean difference in uE3 raw values across all spun serum aliquots on day 1 vs. day 14 was 0.379 ng/ml which was significantly higher (p = 0.0001) than 0.189 ng/ml, the mean difference in raw values across all whole blood aliquots on day 1 vs. day 14. Regression analysis revealed a significant (p = 0.0001) linear trend of increasing uE3 raw values across the 14-day study period in both spun serum and whole blood with the number of days elapsing prior to sample assay explaining 17% of the variation in spun serum raw values and 7% of the variation in whole blood raw values. Although there may not be a significant effect on the overall detection rate for Down syndrome, individual samples received as spun serum several days after blood draw may be inappropriately taken out of the at-risk pool because of inflated uE3 values. These findings may be meaningful to other laboratories that routinely receive samples through the mail. Further studies are being conducted to determine the effects of temperature on uE3 stability.

Enhancement of Genetic Counseling by Utilization of Fluorescence in Situ Hybridization (FISH) to Elucidate Small Chromosomal Rearrangements and Recombination Products S. Eubanks, R. Best, J. Brock, V. Vincent, and S. Trapp University of South Carolina, Columbia, South Carolina Genetic counselors deal with small structural chromosome rearrangements repeatedly over the course of their careers. Often the content of such rearrangements can not be characterized using conventional cytogenetic techniques. Fluorescence in situ hybridization (FISH) is a technique that can further elucidate the structural content of small chromosomal rearrangements. Knowing the content of the rearrangements allows more informative genetic counseling. This thesis describes the use of FISH in identifying subtle chromosomal rearrangements and subsequent use in assistance with genetic counseling. Case One presented here is an example of the utility of FISH to confirm the identity of a de novo chromosomal rearrangement. An additional chromosomal segment occurring on the short arm of chromosome 3 was found in an infant born with multiple congenital anomalies. Without further analysis, this segment was open to multiple interpretations. The exact identity of the rearrangement was determined by FISH and permitted a more accurate prognosis by comparison with similar genotypes reported in the medical literature. Case Two presented here illustrates how FISH can be used to help determine recurrence risks by defining a parental rearrangement and comparing the recombinant offspring. A structural rearrangement of the long ann of chromosome 3 was observed in an infant born with multiple congenital anomalies. Parental chromosome studies revealed a maternal intrachromosomal insertion on chromosome segment 3q. FISH clarified the content of the rearrangements in the mother and infant, which allowed clarification of the mechanism believed to account for the rearrangement in the child. Recurrence risks were therefore more certain for the mother. Case Three presented here illustrates how FISH can be used in specific instances to confirm estimated or questionable recurrence risks. The patient was



a man who presented with his wife because of multiple pregnancy losses following artificial insemination with his sperm. Chromosome studies revealed a small paracentric inversion of chromosome 2q. Recombination of the small segment was not thought to explain the consecutive losses. FISH on sperm cells confirmed that the number of recombinant sperm was not elevated. This allowed more specific information to the couple, who were concerned that the paracentric insertion would cause further pregnancy losses. The significance of this research is a riffler characterization of the utility of FISH for enhancing genetic counseling. The ability to identify the composition of small chromosome rearrangements will allow more accurate genetic counseling, more information by which couples can make reproductive decisions, and therefore, clients who are more satisfied with their experience with a genetic counselor.

Involving Consumers in the Development of a Model Informed Consent Process for BRCA1 Testing: What Do They Want to Know? G. Geller, B. A. Bernhardt, and N. A. Holtzman

Johns Hopkins School of Medicine, Baltimore, Maryland 21205 Alterations in the BRCA1 gene are associated with 5% of breast cancer. Now that this gene has been identified, a genetic test is being incorporated into clinical practice under research protocols. Little is known about what information consumers find relevant and what role they want to play in making testing decisions. As the first phase of a study designed to develop a model informed consent process for BRCA1 testing, we conducted ten consumer focus groups of 8-10 participants each, recruited primarily in response to a newspaper ad. Participants included women and men with a positive family history of breast cancer, as well as women in the general population, stratified into separate groups by gender, risk status, race, and socioeconomic status (SES). Using a semi-structured discussion guide, we explored participants' beliefs about the causes of cancer, what they would want to know about a genetic test for breast cancer, their attitudes about the advantages and disadvantages of having such a test, what they would do with test results, and their expectations of their role in decisionmaking. This paper summarizes the qualitative analysis of the transcripts. We found that although there were many misperceptions about the cause of breast cancer, most participants were aware that genetics cotfld play a role. Women in high risk groups were more aware of risk factors than were women in the general population. In general, participants believed that breast cancer usually occurs in women before the age of menopause. In terms of the content of disclosure, women in high SES groups wanted information on the validity and accuracy of the test, cost of testing, follow-up recommendations, and implications of test results for other family members. Women in low SES groups were more concerned about practical aspects of testing, such as what testing involved (blood sample, etc), who will do the test, when are results available, and does the test detect other cancers. Regardless of SES, participants were initially very interested in genetic testing until the limitations and uncertainties associated with the test were understood. In particular, when they learned that most breast cancer is not associated with a mutation in the BRCA1 gene, and that no treatments of proven effectiveness are available to prevent breast cancer in those in whom mutations are found, they were less likely to favor being tested. Even after providing information about testing, many participants had difficulty understanding the meaning of test results. Many participants believed that a positive test result is synonymous with a diagnosis of cancer, and that a false negative could be clarified by repeating the test. They were often unaware of the risks of disclosing test results to employers and insurers, but expressed concern about such risks once they were described. Participants were not generally in favor of testing children or of prenatal testing.



Views of the process of informed consent varied by gender and SES. Men and poor women preferred individual discussions with their own doctor (i.e., not a genetic counselor, a nurse or an unknown expert), and would trust their provider's recommendation. Women of higher SES preferred group discussions with an expert, regardless of whether they knew the provider, and expected greater autonomy in decision-making. Most participants believed printed materials to supplement face-to-face education would be helpful, and that they should be given time to discuss testing with others before making a decision. This paper wilt conclude with a discussion of how these data will be used. Although qualitative data are not intended to be generalizable, they are useful in guiding and enriching subsequent quantitative research. We will use these data to aid in development of a questionnaire that will be distributed widely to both consumers and providers. Such large-scale consumer input will be invaluable in developing an educational and decision-making process that reflects the priorities of those most likely to be offered testing.

Counseling Families with Velo-Cardio-Facial Syndrome (VCFS) for Deletion Related Psychiatric Disease R. Goldberg,* D. F. Papolos, B. Morrow, H. Sirotkin, R. Kucherlapati, and R. J. Shprintzen Albert Einstein College o f Medicine, Bronx, N e w York In 1978, Shprintzen et al. (Cleft Palate J 15:56-62) reported a series of 12 patients with a previously undelineated syndrome of characteristic facies, cleft palate, and congenital heart disease designated velo-cardio-facial syndrome (VCFS). In the last 17 years, the phenotypic spectrum of the disorder has widened and as a result over 40 clinical features are associated with this syndrome. VCFS patients are being identified from craniofacial clinics, pediatric cardiology clinics, learning/developmental centers, and most recently from institutions housing mentally retarded and mentally ill patients. VCFS is associated with hemizygous deletions in chromosome 22q11. Fluorescence in situ hybridization (FISH) with the N25 probe obtained from Oncor is routinely used to identify these deletions. We have now developed a simple PCR assay to detect deletions in the most commonly deleted region (Morrow et al. (June 1995) AJHG (in press)). Seemingly, a strikingly high proportion of deleted patients have complex behavioral phenotypes in addition to learning disabilities prompting the following systematic study. Psychological and/or psychiatric assessments on 40 patients including six of the original 12 index cases were conducted by clinicians using two different methodologies. In the first study, 20 patients with the clinical diagnosis of VCFS over the age of 15 were evaluated by a psychologist using semi-structured clinical assessments and consensus diagnoses (DSM 111R). In the second study, parents and patients were administered separate computerized versions of the Diagnostic Interview for Children and Adolescents-Parent and Child Versions (Revised). Patients were diagnosed with attentional deficit hyperactivity disorder, schizoaffective disease, schizophrenia, obsessive-compulsive disorder, unspecified functional psychosis and major depression. This report reviews psychiatric patient data and reactions in parents and patients upon learning of the genetic susceptibility to certain behavioral phenotypes. Genetic counseling, when the diagnosis of VCFS/DGS or congenital heart disease with 22qll deletion is made, must include discussion of the psychiatric prognosis regardless of the preliminary prognostic nature of this information. The relevance of hemizygosity of potential candidate genes in the region requires alerting families to possible dangers of certain therapies. *Center for Craniofacial Disorders/Plastic Surgery, Montefiore Medical Center, Bronx, New York.



Genetic Counseling and the Mentally Impaired Client: Issues to Address J. Habecker-Green, M. Murray, and G. Cohn Baystate Medical Center, Springfield, Massachussets 01199 When working with the adult mentally impaired, many questions, both practical and ethical, must be considered. Genetic counseling is by definition a nondirective communication process to which special challenges are presented by the mentally impaired patient. The presentation to our service of three mentally impaired women over the past year has highlighted for us the special concerns faced by these patients with respect to informed consent, response to directive and nondirective counseling, their rights to reproduce, their rights to parent, and the right vs. the fear to pursue medical information. Three patients with mental impairment were seen by our service. In two cases, patients presented for prenatal genetic counseling for unrelated issues. Both patients reported having had difficulty in school and attending "special" classes, but were considered legally competent. On the basis of clinical evaluation and family history, additional testing to rule out a genetic basis of suspected mental retardation in one and recurrent spontaneous abortions in the other was offered and performed. Symptomatic fragile X carrier status and mosaicism for trisomy 8 were respectively diagnosed based on clinical and laboratory results. The patient with fragile X agreed to prenatal diagnosis, and the fragile X mutation in the male fetus was subsequently detected. The patient with trisomy 8 mosaicism declined any additional genetic testing. Both patients delivered and went home with their babies. In a third case, an infant presented for genetic evaluation to rule out de Lange syndrome based on failure to thrive, developmental delay, and suspected parental phenotype. The infant's parents were both labeled as borderline mentally retarded according to the social service worker assigned to their case. The three members of this family were all evaluated by our service, and a genetic diagnosis could not be made, although we did state that the child's failure to thrive and delays likely had a genetic basis. The child's condition did not improve with 6 months of foster care, however, on the basis of the parents' mental retardation and the child's condition, this couple lost custody of their child and declined additional evaluation of their medical conditions. We believe the responsibilities of a genetics service are increased when dealing with the mentally impaired patient who is his or her own legal guardian. These responsibilities include: • • •

establishing the patient's competence to understand information and to provide informed consent, to maintain nondirectiveness; nondirective counseling, though challenging, is still possible through the use of very concrete models, to be cognizant of the local and state regulations which may protect the reproductive rights of the mentally impaired, but fail to protect their custodial rights, and to educate patients with respect to these rights, to be aware that patients may be reluctant to obtain medical testing which may be medically indicated but socially detrimental, and to support the patient's decisions.

The Benefits and Limitations of a Fragile X Syndrome Neonatal Screening Program: Genetic Center's Perspectives T. Horejsi, R. Best, E. Pearson, and J. Tarleton University of South Carolina, Columbia, South Carolina 29212 Thirty randomly selected genetic centers completed a questionnaire soliciting opinions regarding various aspects of a population based neonatal screening protocol for fragile X syn-



drome as well as issues which should be addressed prior to implementation of any pilot study research. Data from the questionnaire were analyzed to determine potential benefits and/or limitations of a fragile X newborn screen as indicated by genetic health care professionals. These specific benefits and limitations were compared to the overall opinion of these professionals regarding possible future newborn screening protocol. Most respondents listed potential benefits as well as limitations, although several solely indicated one or the other. Family reproductive planning was the sole benefit which displayed statistical significance. One limitation, that early intervention is not a cure for fragile X syndrome, showed significance. The results of the overall opinion of fragile X newborn screening revealed that 33.3% of the respondents indicated they were in favor of such a protocol, 46.7% against it, and 20% were undecided. The predominant discrepancy among these opinions was the perceived benefit of early intervention. Because early intervention is the only form of treatment for fragile X syndrome, the potential benefit of this therapy must be assessed. Further study must be done to determine cost effectiveness, benefit of early diagnosis, and overall validity of a populationbased newborn screening program for fragile X syndrome.

Teaching Genetic Counselors and Nurses to Provide BRCA1 Counseling: A Training Program Model S. A. Kieffer, K. A. Schneider, J. E. Stopfer, K. A. Calzone, M. Adler, A. Patenaude, and J. Garber Division of CEC, Dana-Father Cancer Institute, Boston, Massachusetts 02115 Genetic counselors are well trained and practiced in assisting patients in decision making about genetic testing; however, many report very little training and experience in counseling patients with family histories of cancer. Nurses may have expertise in taking care of cancer patients, but their exposure to genetic counseling may vary. With the discovery of cancer susceptibility genes such as BRCA1 there is a growing need not only for genetic counselors, but for those trained in providing cancer risk counseling. One out of every nine women will develop breast cancer at some point in her life. It is estimated that 5-10% of these women will have a cancer susceptibility gene underlying the onset of their cancer, and it is likely that 2/3 of these will be due to germline mutations in the BRCA1 or BRCA2 genes. As researchers continue to identify mutation positive families, the dilemma exists as to the best way to provide genetic counseling for family members. The Dana-Farber Cancer Institute and the University of Pennsylvania have an ongoing research project which is part of the Human Genome Consortium for Studies of Genetic Testing and Counseling for Heritable Breast, Ovarian and Colon Cancer Risks. One of the aims of this project is to develop, implement, and evaluate a training program for genetic counselor and nurse pairs to provide counseling for BRCA1 predisposition testing. Genetic counselors and nurses were chosen based on their geographic location to members of BRCA1 mutation positive families. The BRCA1 mutation positive families were participants in a previous research study to isolate breast cancer susceptibility genes. The training program involves several educational components including; two training workshops, conference call role playing sessions preceding each counseling session, and educational articles and handouts. The training workshops were conducted by telecommunications satellite allowing 50 sites around the U.S. to be linked together., The first workshop covered the genetics of BRCA1, the surveillance and management of breast and ovarian cancer, the psychological aspects of testing, nursing, and genetic counseling issues, and ethnocultural issues in counseling. The second workshop was conducted concurrently at four sites and focused on counseling issues and program flow. The four sites were linked together for discussion using Picturetel, which is a telecommunications system. The final components of the training program are conference calls during which a genetic counselor and nurse counsel a mock patient. The majority of nurses and genetic counselors (70/82) felt that prior to participating in this



training program they did not have sufficient training and experience to provide counseling for BRCA1 predisposition testing. Following the second training workshop, most nurses and genetic counselors (53/82) felt they were ready to provide cancer predisposition counseling either independently or within the context of the program. Some (28/82) did feel that they required further training. Further assessments of readiness together with initial follow-up from patient encounters will be reported.

Evaluation of Genetic Testing Services by Potential Carriers of Hemophilia in Region I E. Kraus, D. Brettler, and The New England Regional Hemophilia Centers Carrier Study Group New England Center, The Medical Center of Central Massachusetts-Memoria~ Worcester, Massachussets At present we are able to perform genetic testing for detecting hemophilia with a high level of accuracy. Utilization of testing services for determination of carrier status and prenatal diagnosis however, has historically been low. This underutilization of services could be attributed to inadequate education of potential carriers, concern about cost of testing, lack of perception of need for genetic testing, or lack of direct access to educational information and services. In order to examine these issues, and evaluate genetic services as provided through the federally funded comprehensive hemophilia centers in the New England region, we are surveying women who are potential carriers of hemophilia who have never had genetic, testing. Potential carriers are identified through databases at the hemophilia centers in the region. To date, 40 women (median age: 37 years) have been enrolled in the project. Each participant receives educational materials, and completes a questionnaire regarding perceptions of genetic risk, genetic testing, and genetic services. 18 women have a first degree relative with hemophilia, with 27 having family members with clinically severe disease. 20 think hemophilia is a very serious disease. 67% think their risk of being a carrier is moderate, high or very high, while 74% believe they have a similar risk of having a son with hemophilia. 28 women would like to have a carrier test. 23 would have prenatal testing, however, only three women would consider terminating a pregnancy because of a diagnosis of hemophilia. Before receiving educational materials for the study, 90% of the women were aware of carrier testing for hemophilia, but only 63% were aware of prenatal testing. Nineteen women preferred to discuss genetic testing with a genetic counselor, and 16 with a physician. When asked when the best time would be to have carrier testing for hemophilia, the majority of women responded when considering having children. Since the majority of women would prefer to have genetic counseling in a hemophilia center, it is imperative that this be offered to all at risk family members through the hemophilia centers. Although many women have been exposed to persons with severe hemophilia and believe they have a significant chance of having an affected son, they have insufficient knowledge regarding available genetic testing. Carrier testing is important to this population, however the majority of test results are utilized for decision making in pregnancy management and preparation. Considering the magnitude of women who first consider carrier testing after they are pregnant, this further demonstrates the need for appropriate education of this at-risk population. Hemophilia centers have access to extended families of individuals with hemophilia, and should be utilized for implementing educational programs for this population.



Exploring the Impact on the Genetic Counseling Process When the Counselor Has a Significant Genetic or Reproductive History M. S. Martin and M. E. Walker University of Cincinnati, Cincinnati, Ohio 45229 Genetic counselors who have a personal or family history of a genetic disorder and also those who have experienced reproductive difficulties such as pregnancy loss or infertility, are potentially faced with providing services to clients who are experiencing health or psychosocial issues similar to their own. For example, a counselor who has a sibling with Down syndrome may be working with a client whose prenatal test results revealed trisomy 21. In such situations, genetic counselors may displace feelings about their past or present experiences onto the client with the potential to either help or hinder the counseling process. Literature from the fields of psychology and counseling has used the terms "countertransference" and "theme interference" in reference to this phenomenon. Countertransference, in its broadest sense is defined as "the counselor's emotional reaction to the client." The purpose of this investigation is to identify what genetic counselors believe is the impact on the counseling process when the counselor has a significant genetic or reproductive history. A survey was sent to all full members of the NSGC in January, 1995. The survey response rate was 522/884 (59%). Nearly 36% (186/522) of responders identified themselves as personally affected in some way by genetic disorder or reproductive difficulties. Of this group of responders, 164/186 (88%) identified ways in which their genetic or reproductive history had helped in their effectiveness as genetic counselors; 43/186 (23%) could identify ways in which their background has presented challenges for them as genetic counselors. Given a list of counseling behaviors, responders most frequently identified the ability to verbalize empathy and discussing and exploring feelings as "easier." Controlling biases and controlling emotions were the behaviors most fi'equently identified as "more difficult." Interestingly, 91/186 (49%) of the genetic counselors who reported a significant genetic or reproductive history, also reported disclosing their situation to a client at least one time. Reasons for disclosure, the perceived impact on the client and on the counselor, a summary of responders' learning experiences, and recommendations for genetic counseling practitioners and graduate students will be presented. The results of this investigation provide insight for genetic counselors who have a significant genetic or reproductive history as well as implications for the training of genetic counselors.

Late-Onset Tay-Sachs Disease: A Brief Overview Including the Implications for Genetic Counseling E. Merrill Brandeis University, Waltham, Massachusetts 02154 Late-Onset Tay-Sachs disease (LOTS) is a newly recognized, adult-onset variant of GM2 gangliosidosis. It is a progressive, neurodegenerative disorder with onset of symptoms occurring between adolescence and the third decade of life. It is an allelic variant of classical TaySachs disease, and like infantile Tay-Sachs is also more prevalent among Ashkenazi Jews. Age of onset is roughly correlated with the amount of residual 13-hexosaminidase A activity in cellular lysosomes. Presenting symptoms can include proximal muscle weakness, fasciculations, dysarthria, ataxia, and psychosis. Psychiatric symptoms are a feature in 40% of cases. There is considerable inter- and intra-familial variability. LOTS is often misdiagnosed as other neurodegenerative disorders such as A/_~, Kugelberg-Welander, and atypical Friedreich ataxia.



Although it is rare, LOTS is also underrecognized in the medical community, perpetuating misdiagnosis. This can have serious consequences given that certain drugs have been shown to inhibit hex A activity in vitro, and can potentially worsen the clinical course. Genetic counselors should have some familiarity with this disease, because there are several important issues for genetic counseling and testing brought about by LOTS: presymptomatic testing of at-risk individuals, genetic counseling and prenatal testing for LOTS, and molecular testing for enzymatically defined carrier couples and at-risk pregnancies to distinguish between infantile, late-onset, and pseudodeficiency alleles. As a master's project, I conducted in-depth interviews with individuals affected with LOTS, reviewed the literature, and designed a comprehensive fact sheet about LOTS for distribution by NTSAD (National Tay-Sachs & Allied Disease Association) and LOTSF (Late-Onset Tay-Sachs Foundation). The results of this project will be presented.

An Assessment of Primary Care Physicians' Attitudes Toward Genetic Testing and Genetic Counseling S. Miller

University of Cincinnati, Cincinnati, Ohio 45229 As advances in The Human Genome Project become known, physicians are learning more about genetic tests and their use in predicting carriers of disease-causing genes. The occurrence of late-onset diseases and the ascertainment of family histories with genetic disorders have brought genetics to the front lines of adult medical practice. Today, many genetic tests for hereditary disorders have become available and it is believed that DNA tests will soon be used to predict other disorders such as diabetes, Alzheimer disease, and various hereditary cancers. Due to an insufficient number of trained genetics professionals, determining which patients are at risk and helping them to understand the implications of genetic tests will inevitably fall to primary care physicians. The objective of this study was to examine current attitudes regarding genetic testing and genetic counseling among primary care physicians (internists and family practitioners) currently in practice or in training. Questionnaires were distributed over a 3 month period. While some were mailed, others were received during grand rounds presentations at several major hospitals in the Greater Cincinnati Area. Closed-ended survey questions centered on demographic and practice characteristics, degree and type of exposure to genetics, reasons (if any) for genetics referral, attitudes concerning presymptomatic testing, and methods of providing education in the field of human genetics. Data from more than 250 questionnaires indicate that although most primary care physicians feel comfortable with their current level of understanding of genetics, they feel that their knowledge will be somewhat insufficient 5 years from now. Attitudinal differences between family practitioners and internists (and the subspecialists within each field) will be presented, as well as insight into how genetics professionals can better educate and involve primary care physicians in the field of genetics.

Community Empowerment and Genetic Education I. Mittman and S. Shapiro

Department of Women and Children Services, Sinai Hospital of Baltimore, Baltimore, Maryland A new grant was awarded to Sinai Hospital of Baltimore by the Maternal and Child Health Bureau of the Department of Health and Human Services, to increase access to genetic services among underserved African-American and Russian Jewish communities in Baltimore. The



new project named "Genetic LINC-Liaisons INto Cultures," is employing community empowerment techniques in disseminating genetic education. A Community Advisory Board was put together to assist the project's staff on community needs. A large community outreach health fair focusing on genetic education targeted an underserved, African-American community in Northwest Baltimore. The Advisory Board worked together with the project's staff to organize a spring health fair named "Spring Into Good Health." Approximately 1000 middle school students and their families participated in the health fair. Funds for the event, food, and entertainment were all donated by community groups, merchants, and community health clinics. Community residents and groups volunteered to help the project's staff during the event and several set up their own exhibits. The health fair focused on genetics but also offered blood pressure evaluation; HIV education; diabetes screening; information on mammography, obstetric, pediatric care and nutrition; height and weight checks; scoliosis screening and education on holistic medicine and acupuncture. Light snacks, helium balloons, and a marching band turned this educational event into a celebration. Health fair attendants enjoyed matching up chromosomes, learning about "detective DNA" (DNA fingerprinting), checking out career options in human genetics and getting their family tree taken. Health fair participants visited all exhibits enthusiastically, participated in available screening and collected brochures and flyers about health care issues and services available. The project's staff received invitations to repeat the health fair activities at a local church and two other schools immediately following the event. Outreach related to health care to culturally diverse groups presents many challenges to health care providers. Relaying genetic information is particularly difficult considering the complexity of information and the general lack of public awareness to genetic risk and testing. Getting to know the community on its own turf and involving it's members in the process of education is a must for an effective end meaningful genetic education.

A Movement Towards Managed Health Care and the Role of the Genetic Provider: A Survey of Medical Directors of Managed Care Programs in New York State A. M u s i a l

Sarah Lawrence College, Bronxville, New York In recent years, biologic and technologic advances have resulted in an increased understanding of inherited disorders and human genetics resulting in a greater demand for these services by providers and consumers alike. This fact, coupled with the health care reform movement that redefines management practices as well as relationships between consumers/physicians and primary care/specialty care providers emphasizes the need to address issues of how best to ensure the delivery of high quality cost effective genetic services in this changing environment. For this reason, a survey of managed health care programs operating under the premise of "cost containment and quality assurance" was developed. The survey was administered to medical directors of managed care programs. The results, while limited to a selective group in a relatively small geographic area, demonstrate that the medical directors making decisions about the reimbursement of genetic services are limited in their training/knowledge in the area of genetics, rely on the primary care physicians to determine when a referral for genetic services is required, are not aware of the training of genetic professionals and feel that the health care professionals who provide services should be licensed and/or certified. Based on this information, the following conclusions were made and recommendations generated. The results of this pilot study indicate that family physicians, internists and obstetricians will be the most likely points of referral for genetic testing and genetic counseling inquiries in managed health plans, that genetic professionals are individuals with unique expertise and provide specialized services and that the genetic counselor would serve as an excellent "case



manager" and, therefore, allow the delivery of comprehensive quality health care in the managed care system. Based on these findings, genetic professionals must market their services, educate HMOs, employers and the community about genetic services, work toward the licensure of genetic counselors, modify and implement CPT codes and educate themselves concerning the Managed Health Care infrastructure. There is a need to further address and investigate an effective and quality delivery of genetic services in a managed health care system. The time to address this issue is now as the drive for health care cost containment has brought managed health care to the forefront of the delivery of health services.

The Attitudes and Practices of New England Obstetrical Health Professionals Towards Multiple Marker Maternal Serum Screening K. Ormond, A. Guttmacher, E. KIoza, M. DiMaio, E. Rawnsley, K. McGowan, and C. Waiters

University of Vermont, Burlington, Vermont The use of maternal serum alpha-fetoprotein (MS-AFP) and, more recently, multiple marker maternal serum screening (MSS), including various combinations of AFP, hCG, and uE3, have provided obstetrical practice with a minimally invasive method of detecting pregnancies that are at increased risk for Down syndrome or neural tube defects. Many publications have discussed patients' attitudes, knowledge and anxiety regarding MS-AFP and multiple marker MSS. Other literature has suggested that physician attitudes affect patient attitudes and acceptance of screening. However, virtually no literature addresses the thoughts and practices of medical professionals toward MS-AFP or multiple marker MSS. We have assessed the attitudes and practices of physicians and certified nurse midwives (CNMs) in the six New England states (Vermont, New Hampshire, Maine, Massachusetts, Connecticut, and Rhode Island). A mail survey assessed attitudes dealing with how health professionals provide information about screening and results, as well as medical professionals' attitudes toward screening and related issues. Questionnaires were mailed to 289 CNMs and 442 physicians across New England chosen by random sampling. Replies were received from 290 (40%), with 238 completed by health professionals currently practicing obstetrics. Fifty-four percent of respondents were CNMs (N = 127), and 43% (N = 102) were physicians. For most measures, there were no significant differences between states. Regarding MSS practices, 100% of respondents offered serum screening to some patients, with 86.6% offering "triple marker screening" (AFP, hCG, uE3). The most common factors influencing to whom serum screening was offered included general professional standards (49%), more specific group practice standards (46%), and the patient's age (23%). Thirty-seven percent of respondents offer MSS to all patients. Information regarding MSS is usually provided via verbal discussion (94%) and pamphlet information (72%). While 84% of all respondents feel that women should be offered MSS during pregnancy, physicians were more likely than CNMs to believe women should have MSS during pregnancy (p = .0005). Physicians were more likely than CNMs to feel MSS is cost-effective (p = .0005) and useful to patient management (p = .0001). Physicians were also more likely to agree that their own attitudes influenced their patients' decision-making (p = .001). Additional information regarding practices around MSS during pregnancy, and the attitudes of health professionals toward MSS will also be presented.



The South Carolina Neural Tube Defect Surveillance, Prevention and Research Project: A Summary of the First Three Years E. Pearson, L. Hammond, and A. Stahl University of South Carolina Medical School, Department of Obstetrics and Gynecology, Division of Clinical Genetics, Columbia, South Carolina 29203 In October 1992, with support from the U.S. Centers for Disease Control and Prevention (CDC), the three genetic centers in South Carolina (SC) and the SC Department of Disabilities and Special Needs initiated the SC Neural Tube Defect (NTD) Surveillance, Prevention and ResearchProject. The objectives of this project are to: identify all NTD cases in the state; obtain detailed information from mothers of NTD cases; enroll these women in a primary prevention program using folic acid supplements; evaluate the impact of the prevention program and project supported educational campaigns on the reduction of NTDs and awareness of folic acid therapy; and conduct a case-control study in collaboration with the CDC and Texas Health Department. At the time of the NSGC 14th annual Education Conference, 3 years of this study will have been completed. Surveillance findings from 1992-1994 will include the number of NTD affected pregnancies, how ascertainment was made, geographic distribution of cases within the state, types of NTD lesions, pregnancy outcomes, and current folic acid status. Efforts in South Carolina to publicize and promote use of folic acid by all women include print brochures; professional, lay, and school lectures; a statewide conference; educational videotapes; and public service announcements on radio and television.

An Education and Counseling Hierarchy for BRCA1 Susceptibility Testing and Cancer Prevention: Optimizing Resources and Meeting the Demand B. Peshkin, J. Benkendorf, C. Hughes, and C. Lerman Georgetown University Medical Center, Washington, D.C. 20007 The recent identification of a major breast and ovarian cancer susceptibility gene, BRCA1, is dramatically heightening our understanding of the genetic basis of these cancers. Concomitantly, the anticipation of a readily available test is having a pervasive impact on professionals and consumers. In response to the high public expectation and demand, we have developed and implemented an education and counseling hierarchy for BRCA1 susceptibility testing and cancer prevention. This research model is designed to meet and study the multiple needs of women of various risk groups. A randomized trial of standard pre-test education with or without counseling is offered to women who have no personal history of cancer, but at least one first-degree relative (FDR) with breast and/or ovarian cancer. This population, while at increased risk for breast and/or ovarian cancer, is at a low risk for having a predisposing mutation in a cancer susceptibility gene. Yet, they are known to have a significant level of cancer anxiety and interest in testing. High risk women meeting specific criteria based on personal and family history of breast and/or ovarian cancer are triaged directly to formal, individualized genetic counseling with the option of possible testing. This option is not available to the low risk women; however, as a measure of their readiness for testing they are offered the opportunity to provide a blood sample for storage and future testing. The standard education model (SE), which forms the core of each approach, consists of general information about cancer risk and personal risk factors, an explanation of the BRCA1 susceptibility gene and dominant



inheritance, an outline of the benefits, risks, and limitations of BRCA1 testing, and information about screening and prevention for breast and ovarian cancers. This is similar to the informed consent model practiced by many physicians. The education with counseling (SE+C) intervention adds a more classical genetic counseling component in which participants' experiences with familial cancer, their personal cancer worries, support systems, and coping strategies are elicited. Participants are also asked to explore the ramifications various testing decisions and outcomes might have for them. Finally, the high risk women who are triaged to the cancer genetic counselor will receive all of the components of SE+C, plus a complete risk assessment which includes a pedigree analysis. If a living proband is available they are also offered, counseled about, and consented for mutation analysis. The results will then be disclosed in a second counseling session. In order to study the effectiveness of each intervention, participants receive a baseline interview prior to their visit, as well as several follow-up interviews in the 12 months thereafter. These pre- and post-intervention interviews utilize standardized psychometric measures to assess knowledge and attitudes about BRCA1 testing, psychological well-being, coping styles, and health behaviors. Sociodemographic data and personal risk information, including family history are gathered at baseline. These data will be used to assess the effectiveness of each intervention on decision-making, health behaviors, and well-being. In addition, we hope to correlate the information gathered at baseline, including ethnicity, with various outcomes. This may elucidate critical information about individuals seeking testing that can then be used as a mechanism for selecting the most appropriate education and counseling strategies, minimizing the incidence of adverse outcomes, facilitating decision-making, and maximizing informed consent. Our hierarchical model and triage pathway will be presented, along with preliminary outcome data. As we forge into a new era of molecular and preventive medicine, this program will establish a new paradigm for optimizing the use of limited genetic counseling resources in the delivery of genetic susceptibility testing for other common multifactorial adult-onset conditions. It will be incumbent upon a heterogeneous group of providers to responsibly allocate these services and resources to an immense group of eager and interested consumers. This work is supported by NIMH/NCHGR R 0 1 MH/HG54435.

Multiple Marker Screening and the Detection of Fetal Turner Syndrome C. Ruiz, F. Lamm, and S. Hart

The Bowman Gray School of Medicine of Wake Forest University, WinstonSalem, North Carolina 27157 The measurement of maternal serum levels of AFP, hCG, and uE3 in conjunction with maternal age has been used as a prenatal screen for fetal Down syndrome. Recent reports have suggested that the levels of these markers may also be altered in other fetal anenploidies such as trisomy 18 and Turner syndrome. We report our experience regarding the levels of MSAFP, hCG, and uE3 in 11 cases of fetal Turner syndrome. The purpose of this study was to determine if there is a specific pattern of maternal serum markers associated with fetal Turner syndrome. The results were also correlated with the ultrasound finding of hydrops. Results from all maternal serum samples assayed between January 1989 and April 1995 and their respective outcomes were reviewed. During that time period, 12 pregnancies were identified as having Turner syndrome either prenatally or postnatally. MSAFP and hCG levels were available in ten of the 12 pregnancies. In the twelfth pregnancy, screening was performed prior to the addition of hCG and uE3 to the assay. Since a sample was not available for a retrospective analysis of hCG and uE3, this pregnancy was eliminated from the analysis. The sample from the eleventh pregnancy was assayed retrospectively for hCG and uE3. Of the ten remaining pregnancies, three had uE3 levels assayed at the time of screening while seven



had uE3 assayed retrospectively. Eight of the 11 (73%) cases of fetal Turner syndrome were identified as a result of a positive Down syndrome screen using a combination of MSAFP, hCG, and maternal age. Only three (27%) of the 11 pregnancies would have been placed at increased risk for Down syndrome using a combination of all three markers in conjunction with maternal age. The median values of MSAFP, hCG, and uE3 in these 11 cases of fetal Turner syndrome were 0.72 MoM, 3.25 MoM, and 1.02 MoM, respectively. Of the 11 pregnancies, four were found to be associated with hydrops prenatally. The median values of MSAFP, hCG, and uE3 in the hydropic pregnancies were 0.83 MoM, 6.42 MoM, and 0.58 MoM, respectively, whereas the median values in nonhydropic pregnancies were 0.68 MoM, 2.86 MoM, and 1.31 MoM, respectively. As has been previously reported, the levels of MSAFP were slightly reduced in pregnancies affected with Turner syndrome. In addition, hCG levels were found to be increased in fetal Turner syndrome, but more so in hydropic pregnancies. Unlike previous reports, our study revealed that the levels of uE3 remain relatively unchanged in fetal Turner syndrome. These results suggest there is a nonrandom association between maternal serum analytes, AFP and hCG, and fetal Turner syndrome. Based on these findings, fetal Turner syndrome may be identified prenatally as a result of an increased risk for Down syndrome using MSAFP and hCG. More data is necessary to assess the relative contribution of uE3 in the detection of fetal Turner syndrome.

Is Directiveness in Cancer Risk Counseling Ever Appropriate? K. A. Schneider and D. Marnane Division of Cancer Epidemiology and Control, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 Nondirectiveness is a hallmark of genetic counseling. The ability to provide management options in an unbiased, value-neutral manner allows individuals to make decisions which are best for them. Yet being nondirective is not easy, as each of us struggles with our own biases and as clients continually ask for advice in difficult situations. Cancer risk counseling is one subspecialty which offers opportunities for directiveness; the question is whether this is ever appropriate. To learn the extent of directiveness that exists in current cancer risk counseling practices, we sent surveys to the 77 genetic counselors listed in the 1994 NSGC membership directory as having an interest in cancer genetics. Of the 56 counselors that responded, 42 (75%) counselors stated that they are currently providing cancer risk counseling, with the majority providing counseling about Breast-Ovarian Cancer syndrome, (76%), Neurofibromatosis (67%), and Hereditary Colon Cancer syndromes (55%). Cancer risk counselors typically work with a team of other health professionals, yet the majority indicated that they routinely discuss DNA testing, cancer surveillance, and prevention options with clients. We were interested in learning whether there were any situations in which genetic counselors would, in fact, feel comfortable being directive to clients. All respondents who were currently providing or planning to provide cancer risk counseling were asked to complete these questions; 50 did so. For a situation involving a female client with a strong family history of breast cancer who had never had a mammogram, 41 (82%) felt comfortable recommending (rather than suggesting) a mammogram. When asked about a client with a family history of lung cancer who was a heavy smoker, about half the counselors would advise him to stop smoking and about half would discuss his risks in a more general way. Counselors were then asked their responses to a situation where a client with early-onset breast cancer refused to inform her two halfsisters about their potential increased risks. In this situation, there was less uniformity of responses. About half stated that they would explain the importance of disclosure to their client and hope she acts upon it, while 15 (30%) stated that they would tell their client that they feel compelled to inform her physician about the increased risks for her half-sisters. Genetic



counselors were also asked their opinions about statements regarding the appropriateness of directiveness in specific situations. The majority of counselors believed that it was appropriate for counselors to advise clients to follow standard American Cancer Society guidelines. Many, but not all, counselors did feel that it was inappropriate to advise clients regarding DNA testing options, prophylactic surgery, or disclosing information to other family members. Clearly, there are aspects of cancer risk counseling which differ from counseling for other disorders. Cancer risk counseling involves some situations where directiveness may be appropriate, but also has situations where this would clearly be the wrong approach. The challenge for genetic counselors providing cancer risk counseling is to recognize the specific situations which might warrant utilizing a more directive approach.

Maternal Serum Biochemical Screening for Down Syndrome and Smoking: Should Adjustments Be Made? T. Snell, R. Best, K. Brooks, and J. Edwards University of South Carolina, Two Richland Medical Park, Suite 103, Columbia, South Carolina 29203. The primary purpose of this study was to investigate the association between maternal cigarette smoking during pregnancy and its effect on serum levels of alpha-fetoprotein and human chorionic gonadotropin, and to determine the validity of adjusting these serum levels for smoking status when screening for fetal Down syndrome. In addition, the study population was analyzed to search for an effect of racial variation on serum human chorionic gonadotropin levels. Information on smoking status and maternal race was obtained from 2008 women who had undergone routine maternal serum screening. Serum levels of alpha-fetoprotein and human ehorionic gonadotropin were classified into four groups according to smoking status and maternal race and compared. For the statistical analyses, the MoMs of these levels were transformed to logarithmic values to achieve approximate normality of distributions. Individual risk estimates for fetal Down syndrome were analyzed before and after correcting human chorionic gonadotropin MoMs for the effect of smoking. The mean logO0 ) alpha-fetoprotein MoMs in women who smoked was not significantly different from those women who did not smoke (p = 0.9806). However, the mean log(10) human chorionic gonadotropin MoMs of women who smoked was 12.2% lower than those of women who did not smoke (p = 0.0205). Maternal race was not found to have a significant effect on serum human chorionic gonadotropin levels (p = 0.0560). Women who smoked were 16% less likely to be classified as high risk for fetal Down syndrome than were nonsmokers before the human chorionic gonadotropin MoMs were adjusted for the effect of smoking (8.35% and 7.0%, respectively), despite a higher average a priori risk. The net effect of adjusting the human chorionic gonadotropin MoMs for smoking status was to increase the overall rate of high risk classification for fetal Down syndrome from 7.68% to 8.35% (using a Down syndrome risk cutoff of 1 in 270). Because women who smoked during pregnancy were less likely to be classified as high risk for fetal Down syndrome, the), were also less likely to be offered amnioeentesis. Human chorionic gonadotropin levels are a more accurate predictor for fetal Down syndrome than other maternal serum markers used for this screening; thus, it is important that corrections for the effect of smoking be performed to improve the accuracy of maternal serum screening. More research must be done to analyze the effect of maternal cigarette smoking on the overall detection rate of fetal Down syndrome.



Health Locus of Control and Prenatal Diagnosis Decision Making R. D. Stott, H. Temple, and R.E. Zinberg

Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029 Each year genetic technology confronts the public with a greater number of genes or genetic conditions that can be screened for or diagnosed. Studies show that individuals who choose genetic testing have an increased sense of risk; both from the testing procedure itself, and from the potential knowledge it can reveal. In the future, genetic services will be available to more people. We believe that comprehensive genetic counseling should be a part of these services. Recently, the role of, and the meaning of, nondirectiveness in genetic counseling has come under renewed scrutiny. Although "nondirectiveness" is the standard for genetic counseling few studies have examined what the perceived benefit of this counseling is for the client. We are currently studying women undergoing prenatal diagnosis to better understand the client's perceptions of risks and benefits with the goal of providing improved genetic counseling services for people choosing genetic testing. Our study tries to answer the following questions: What factors go into the decision to use genetic services? What are the relationships between health locus of control, health values and the decision to pursue prenatal diagnosis? What is the proper role of counseling in the decision making process? We are interviewing a multi-ethnic group of 150 women, from diverse socioeconomic backgrounds who come to our large tertiary care center to receive counseling for amniocentesis or CVS because of age related risks or parental concern. Clients are surveyed both prior to counseling and after receiving the results of the tests. The pre-counseling survey uses Wallston's Multidimensional Health Locus of Control scale. Clients are also given a survey that assesses health values, and elicits which factors were most important in choosing prenatal diagnosis. A short questionnaire is used after results are received to determine the level of satisfaction with the counseling given. The clients' satisfaction with the counseling will be correlated with their health locus of control (internal vs. external) and health values. This study will help us to re-examine how clients make health decisions and explore the impact of nondirective counseling on that decision-making process.

Ethical Analyses for a Policy Decision on Prenatal Diagnosis for BRCA-1 C. Sun McGill University, Division of Medical Genetics, Montreal, Quebec, Canada BRCA-1 is the first gene isolated for hereditary breast and ovarian cancer. A recent enquiry about prenatal diagnosis for BRCA-1 prompted discussion within our department. A hypothetical case was presented as an exercise to five graduate students in bioethics and the ensuing analyses illustrate different approaches to making a policy decision for prenatal diagnosis for cancer genes. Case. A 32-year-old woman known to be a BRCA-1 carrier called to enquire about prenatal diagnosis for her next pregnancy. She was told that her risk for breast cancer is 85% to age 70 and her risk for ovarian cancer is 50%. Her maternal grandmother died of breast cancer at 60, her mother died of ovarian cancer at 45, and her two sisters died of breast cancer at ages 30 and 37. Three students decided to offer prenatal testing on the basis of reproductive autonomy. For these students, the woman's right to make reproductive decisions outweighed possible harms that might he incurred to the woman or the



fetus. A recurring thread woven into this complex analysis is the controversy surrounding the moral status of the fetus. In taking a casuistic (case by case) perspective, one student found compelling arguments to offer prenatal diagnosis for BRCA-1. However, on a policy level, the student reasoned that offering testing may be the first step down a slippery slope to discrimination on the basis of genetic status. Another student decided against offering prenatal testing because of moral implications for society. He argued that late-onset genetic testing places emphasis on end-of-life decisions rather than more important values of day-to-day life. Using a narrative and experiential approach, he also discussed how we underestimate people's ability to cope with burdens. The above analyses illuminate the difficulty in making a policy decision regarding prenatal diagnosis for BRCA-1. From the individual's perspective, it is compelling to offer prenatal testing in order to promote the principles of autonomy and beneficence. However, on a societal level, there are considerations that the casuistic approach may not address. I am indebted to Frank Carnevale, Wendy Morton, Derrick Aarons, Kristin Saville, and Rosalyn Macey for the lively and challenging discussion.

Genetics of Narcolepsy H. Temple, R. Goldberg, M. Goswani, R. Kuchalapati, and M. Thorpy

Sleep-Wake Disorders Center, Montefiore Medical Center-Albert Einstein College of Medicine, Bronx, New York Narcolepsy is a neurological condition related to a dysfunction of brainstem sleep-wake mechanisms and is expressed as a tetrad of four major symptoms: excessive daytime sleepiness with irresistible episodes of sleep, emotionally induced weakness (cataplexy), sleep paralysis, and hypnogogic hallucinations. The prevalence of narcolepsy in the United States is approximately 50/100,000 and worldwide prevalence figures have been reported from a high of 160/100,000 in Japan to 0.23/100,000 in Israel. It has equal sex distribution with onset typically in the second decade of life--the highest incidence occurring between 15 and 25 years of age. Severe psychosociaI stress is experienced by the affected person. In adolescence the symptoms cause the sufferer embarrassment, academic difficulties, to feel loss of self-worth, and to avoid social situations in which the symptoms will be apparent. In adult life, there are additional concerns involving career choice, safety, and marital relationships. The disorder is diagnosed by history, age of onset, and sleep studies (ICSD, 1990). Genetic factors have long been recognized as important in its pathogenesis. This is based on reported clustering of narcolepsy in families and more recent reports from Japan, France, and England of close to 100% association between the major histocompatibility complex ( M H C ) D r 1 5 ( D R B l * 1501)/DQb6(DQBI*0602), subsets of the HLA-DR2/DQW1 phenotype, and narcolepsy. Two modes of inheritance have been proposed: an autosomal dominant mode with incomplete penetrance and a multifactorial mode with genetic and environmental factors. For many rare diseases, linkage analysis has been successful in locating the disease gene, therefore, a strategy to identify the geue(s) involved in human narcolepsy/cataptex3, was developed. Sixteen probands with narcolepsy documented by formal sleep studies and with a family history positive for narcolepsy were interviewed in person or by phone. Permission was obtained to contact affected living relatives. In many cases, relatives had not had formal sleep studies and the Ullanlinna Narcolepsy Scale was used for evaluation. Seven families with three generations of living affected individuals were asked to participate. An additional ten individuals who are the only affected people in their families were also asked to participate. Two sets of identical twins, one set concordant and one set nonconcordant for narcolepsy, and one nonconcordant set of fraternal twins were also included. Blood was obtained and linkage analysis was used to study a battery of polymorphic markers (STRP-short tandem repeat polymorphism) looking for potential candidate genes. To coordinate and encourage additional research in this disor-



der, a National Registry for Narcolepsy has been established at Montefiore Medical CenterAlbert Einstein College of Medicine, Bronx, New York.

Implementation of a Screening Program for Detection of Individuals at Risk for Cancer Based on Family History A. Tutera, J. Edwards, S. Smith, and S. Young

University of South Carolina, Division of Genetics, Department of Obstetrics and Gynecology, Columbia, South Carolina 29203 With the identification of genes predisposing individuals to hereditary breast, colon, ovarian, and endometrial cancers, cancer risk assessment based on family history may soon become standard of care in oncology practices. The Division of Genetics at the University of South Carolina Department of Obstetrics and Gynecology is conducting a 6-month pilot project to determine the feasibility of screening patients for positive family history of cancer. All patients attending one of three oncology clinics in Columbia or Greenville, South Carolina are asked to complete a one page, double-sided family history questionnaire. Completed questionnaires are collected weekly at which time they are reviewed by a PhD geneticist, genetic counselor, and oncologist. Based on this review, the questionnaires are subdivided into three categories; sporadic, familial, or hereditary cancers. The questionnaires which reveal seemingly sporadic cancer cases are returned to the referring oncologist with a cover letter indicating that based on the information obtained, no further follow-up is recommended at this time. Patients whose questionnaires reveal potential familial or hereditary cancers are contacted (given their signed consent) via telephone by a genetic counselor. The genetic counselor takes a complete, threegeneration pedigree and ascertains the patient's questions and concerns. If appropriate, genetic consultation is offered. The goals of this pilot project are to determine the proportion of patients with sporadic vs. hereditary/familial cancers in our population, to determine the need and/or desire for genetic services, to ascertain patient's questions and concerns, and to provide genetic counseling to at-risk individuals. Other goals include monitoring cost effectiveness of this screening protocol and exploring reimbursement issues.

Expanding Roles: Genetic Counseling for Adult Males with Congenital Bilateral Absence of the Vas Deferens (CBAVD) W. R. Uhlmann

University of Michigan, Ann Arbor, Michigan Genetic counselors can expand their roles by providing genetic counseling to urology patients who have been diagnosed with congenital bilateral absence of the vas deferens (CBAVD). While CBAVD is found in most males with cystic fibrosis, it is also a cause of infertility in healthy males with no clinical features of this disease. It has been found that a significant proportion of healthy males with CBAVD have at least one, if not two, detectable cystic fibrosis (CF) mutations. Pregnancies have been achieved in couples involving a mate with CBAVD by utilizing microscopic epididymal sperm aspiration (MESA) in combination with in vitro fertilization (IVF). Genetic testing for cystic fibrosis has become part of the recommended work-up for couples prior to undergoing MESA-IVF because of the increased risk for having a child with etassic cystic fibrosis. Genetic counselors can effectively work with these couples to help them understand the genetics of CBAVD,the distinction between having



CF mutations vs. classic CF, and the limitations of genetic testing. Since January 1994, we have worked closely with a urologist at our center and have provided genetic counseling for his patients with CBAVD. As of April 1995, nine patients with CBAVD and their partners have been counseled. Genetic testing for cystic fibrosis was performed by a laboratory that analyzes 32 CF mutations. Four CBAVD patients had one detectable CF mutation (3-AF508; 1-AI507), three patients had no detectable CF mutations, and two patients declined testing. All female partners were negative for the 32 CF mutations. The implications of these results and strategies for counseling this patient population will be presented.

Atypical Adult Cystic Fibrosis Patients: Genetic Counseling Challenges K. Valverde, H. Temple, and F. Gilbert CF Center, St. Vincent's Hospital and Medical Center, New York, New York Cystic Fibrosis (CF) has historically been a disease diagnosed early in childhood by an abnormal sweat test leading to progressive pulmonary disease, pancreatic insufficiency and a reduced life expectancy. The discovery of the gene responsible for CF and the availability of direct mutation analysis has enabled identification of individuals who have two CF mutations with atypical phenotypes. Current practices of offering CF cartier screening to pregnant patients may identify adults with a CF genotype who are minimally affected. We report a 42year-old woman seen for preamniocentesis counseling based upon her advanced maternal age. During the counseling session, population screening for CF was discussed and she elected to be carrier tested. The results indicate that she is a compound heterozygote AFS08/I148T. She has been diagnosed and treated for asthma, is pancreatic sufficient, and had been a professional dancer until this pregnancy. Her partner was screened and his CF carrier risk has been reduced to 1 in 220. The baby was born and his sweat test was normal. Her brother has also been identified as a CF carrier. This information prompted him and his wife to seek genetic counseling during her current pregnancy. This case illustrates the importance of providing comprehensive counseling prior to CF carrier screening. It underscores the fact that there is considerable variability in the clinical picture of CF. This ease presented distinctly different counseling issues than those usually encountered when CF is diagnosed in childhood. Case 2 is that of a 51-year-old woman who was diagnosed with CF at the age of 37. She is pancreatic sufficient with moderate pulmonary disease. Her daughter was seen for genetic counseling during her second pregnancy. The daughter's experience with CF led her to believe that it is a disease which does not significantly impact upon one's life. This produced tremendous tension in the family when the mother wanted her son-in-law who is of Ashkenazi Jewish ancestry to be carrier tested. The couple decided against testing. These two cases illustrate the fact that we must recognize CF as a disease which has a patient population where almost half of the individuals registered with the CF Foundation are over 21 years of age. As genetic counselors we must be prepared to counsel adult CF patients with regard to the variability of the disease, presentation and clinical course, reproductive issues, and the uncertainty of living with a disease which might give a reduced life expectancy.

Preconceptional Health Education: Making It Relevant Nancy W. Warren, J. Beeman, and P. Matillar* Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, Ohio 45229



In the U.S., more than half of all pregnancies are either unintended, unwanted, or earlier than desired. For teens, an estimated 82% of pregnancies are unintended. African Americans, individuals of low socioeconomic statos, and low education levels all face increased risks of having a low birthweight baby. Achieving optimal health in the preconceptional and interconceptional time period is important, especially for women at higher risk of poor pregnancy outcome. A model preconceptional health education program will be described which addresses goals 5.10 and 14.12 of Healthy People 2000: "Increase to at least 60% the proportion of primary care providers who provide age-appropriate preconception care and counseling." In order to reach a wide population, this train-the-trainer program involved 30 dietitians working in the 16 sites of the Hamilton Count)" WlC Program. This WlC Program serves 21,400 clients per year. Approximately 20% of the clients are low income women of childbearing age and about two-thirds are Black. The dietitians serve a large number of high-risk women on an ongoing basis, so that trust and rapport is developed. The dietitians attended two workshops in preconceptional health: (1) a half-day lecture series by a multidisciplinary faculty, and (2) hands-on training in the use of an interactive curriculum, Start Healthy, developed to teach individuals of low educational levels preconceptional health awareness. By means of pre- and post-training evaluation tests, WIC dietitians increased their knowledge in preconceptional health level by 18%, with the average post-test score being 92%. In the last 6 months of 1994, WIC dietitians used the curriculum at mandatory educational programs for WlC recipients and also in one-to-one counseling sessions. Overall, 338 programs reached 1211 clients.

Counseling for Breast, Colon, and Other Inheritable Cancers: Results of a Survey of NSGC and ABMG D. C. Wertz The Shriver Center, 200 Trapelo Road, Waltham, Massachusetts 02254 We surveyed the views of 1538 persons who were either full members of NSGC or certified by ABMG with regard to ethical issues arising in cancer counseling, using an anonymous questionnaire. 1018 (66%) responded. Most were certified in genetic counseling or clinical genetics (98%), and saw patients (85%); 50% were master's-level genetic counselors and 71% were women. Preliminary analysis (n = 802) of responses to a case vignette on breast cancer suggests that a sizeable minority (39%) would override the confidentiality of a 40-year-old woman with a breast cancer gene in order to warn her 42-year-old sister, against the patient's wishes. Sixty-eight percent would encourage the patient's 20-year-old daughter to be tested. Fewer would encourage the patient's 13-year-old daughter to be tested now (21%) or would suggest prophylactic double mastectomy for the 40-year-old patient (15%). In the case vignette, all family members belonged to the same HMO and could be located easily. About 35% of respondents had counseled for inherited breast cancer. In a case describing a patient with Li-Fraumeni syndrome who refuses disclosure to relatives at risk (not mentioned as belonging to the same HMO), about half (48%) would respect the patient's confidentiality. The rest would tell relatives only if they asked (28%), tell relatives without their asking (13%), or let the referring doctor decide (11%). Most (90%) thought that a man dying of presumed familial colon cancer should bank his DNA for the benefit of descendants, but comparatively few (25%) thought a public agency should pay for the banking or that DNA banks should require pre-banking agreements from donors allowing access to blood relatives (27%). The majority (70%) thought that children

Abstracts of papers presented at the Fourteenth Annual Education Conference : Conditions that affect adults.

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