Knowledge and perceived risks in couples undergoing genetic testing after recurrent miscarriage or for poor semen quality.

Couples with recurrent miscarriage (RM) and men with poor semen quality may undergo genetic testing as part of the diagnostic work-up. This study explored their knowledge and perception of genetic testing, evaluated psychological wellbeing and identified associated variables. A prospective questionnaire study was conducted in seven clinical genetics centres and referring gynaecological departments in couples with RM or poor semen quality. Questionnaires were completed before disclosure of genetic test results. Main outcome measures were knowledge, perceived risk, anxiety and depression. Of 439 participants, 256 were not aware genetic testing was part of the diagnostic work-up. One-third (36% RM, 33% poor semen quality) indicated they had not received information about the genetic test from their doctor. Perceived risk of receiving an abnormal genetic test result was higher than objective risk. Anxiety was highly correlated with perceived risk. Women with RM were more anxious than women in the poor semen quality group or men (P<0.01). These couples undergoing genetic testing have a suboptimal understanding of the nature of testing, overestimate the risks of receiving an abnormal result and some show high levels of anxiety. The results of this study can be used to improve patient counselling before genetic testing.

Consecutive or non-consecutive recurrent miscarriage: is there any difference in carrier status?

BACKGROUND: Carrier status of a structural balanced chromosome abnormality is associated with recurrent miscarriage. There is, at present, no evidence of the impact of the sequence of preceding pregnancies on the probability of carrier status. The aim of our study was therefore to examine whether the history of consecutive versus non-consecutive miscarriages in couples with two or more miscarriages has any impact on the probability of carrying a chromosome abnormality. METHODS: A nested case-control study was performed in six centres for clinical genetics in the Netherlands. Couples referred for chromosome analysis after two or more miscarriages were included: 279 couples with a carrier of a structural chromosomal abnormality and 428 non-carrier couples who served as controls. Univariable and multivariable logistic regression analyses, corrected for known risk factors for carrier status, were performed. The main outcome measure was the probability of carrier status. RESULTS: Two hundred and fifty-six of 279 (92%) carrier couples and 381 of 428 (89%) non-carrier couples had experienced consecutive miscarriages (P = 0.21). A history of two or three consecutive miscarriages did not alter the probability of carrier status when compared with two [odds ratio (OR) 0.90, 95% confidence interval (CI) 0.48-1.7] or three (OR 0.71, 95% CI 0.39-1.3) non-consecutive miscarriages. CONCLUSIONS: The sequence of preceding pregnancies is not a risk factor for carrier status. Therefore, couples with miscarriages interspersed with healthy child(ren) should be managed the same as couples with consecutive miscarriages regarding chromosome diagnosis.

Development of guideline-based quality indicators for recurrent miscarriage.

Recurrent miscarriage (RM) is a multifactorial clinical problem. Guidelines have been published to guide evidence-based clinical practice in RM. To measure adherence to these guidelines in daily practice and to monitor quality of care delivered in RM patients, indicators are necessary. This study aimed to develop a set of valid quality indicators for RM and to explore the relationship between evidence level of guideline recommendations and their acceptance rate as quality indicators. Expert opinions of 11 gynaecologists were used to appraise all guideline recommendations. The systematic RAND-modified Delphi method was used to develop the indicator set from the Dutch guideline on RM. The acceptance rate as indicator of the initial recommendations was assessed per evidence level. A representative set of 23 key recommendations was selected out of 39 guideline recommendations, covering diagnostic tests, lifestyle, therapy and counselling. All recommendations of evidence level A (high) and D (consensus based) were accepted as indicators, while 64% of level B and 22% of level C was accepted. In conclusion, this study generated a set of 23 quality indicators for care in couples with RM. The selection of all consensus-based recommendations subscribes the general importance of these recommendations for gynaecologists.

Psycho-social counselling in predictive genetic testing for cancer: the association between number of supportive sessions and client characteristics as assessed by psycho-social workers.

Given the increased demand on genetic services, it is important to identify clients who may require relatively more extensive psychosocial support. This paper describes which client characteristics, as assessed in the first psycho-social counselling session, were associated with requiring relatively more psycho-social support (> or = 3 sessions) in the process of predictive testing for cancer. The study population consisted of 244 counselees for hereditary cancer. Data were derived from an electronic data-base, used by psycho-social workers for the systematic registration of relevant details of each counselling session. Data were analysed for two respective groups: (A) patients who had a known mutation in the family and (B) patients with an as yet unknown mutation in the family. Results show that two or more psychosocial sessions were given if the information derived from the first session indicated the client to have childhood experiences with cancer (in group A), to experience the family role and/or the psychological impact as burdensome (in both groups) or to experience the social impact as burdensome (in group B). We conclude that the first assessment by a psychosocial worker already provides valuable information on the psychological support needs of patients. These findings provide insight into possible problem areas for clients dealing with predictive genetic testing.

Genetic counselling for familial conditions during pregnancy: a review of the literature published during the years 1989-2004.

BACKGROUND: Genetic counselling for familial conditions during pregnancy may have some disadvantages, such as time pressure and induced worry. However, little is known about the reasons for and consequences of this timing of genetic counselling. OBJECTIVE: The objective of this study was to provide an overview of research aimed at the counselee's reasons for seeking genetic counselling during pregnancy and the medical-technical and procedural consequences thereof. METHODS: We searched the databases Medline and PsycINFO for primary research papers, reviews and case reports, published from 1989 to June 2004. RESULTS: No papers could be retrieved which explicitly addressed our research questions. However, 34 papers, out of a total of 399 papers, covered issues with some relevance to our research questions. Limited knowledge and alertness towards genetics and a greater apparent relevance of genetic issues during pregnancy seemed to explain, at least partly, the timing of referral during pregnancy. Literature on the consequences of this timing for the quality of the genetic counselling process appeared to be scarce. These consequences, therefore, remain unclear. CONCLUSION: In the literature, little attention is paid to the various aspects of the timing of genetic counselling for familial conditions during pregnancy. More research on this issue is important, with a view to improving the care of pregnant women and their children.

[The optimal treatment of chronic heart failure with beta-blockers may be dependent upon the genetic background of the patient]. / Optimale behandeling met bètablokkers bij chronisch hartfalen mogelijk afhankelijk van de genetische achtergrond van de patiënt.

Pharmacogenetics, which aims at the development of'personal pills', is an attractive field in modern medicine. However, the results obtained in the last few years are somewhat disappointing. Recently, a genetic polymorphism was discovered in the treatment of chronic heart failure with beta-blockers. An in-vitro study revealed a hypersensitivity of the Arg389 variant in the beta1-adrenergic receptor to the beta-blocker carvedilol. Interestingly, this polymorphism also has ethnic aspects: the allele frequency of the Arg389 variant is 20% lower in Negroes than in Caucasians. If this result can be confirmed in other studies, one should consider testing for this polymorphism before carvedilol is prescribed. The manufacturer of carvedilol might well consider offering to test the patient's DNA for this polymorphism.

[Risk factors for structural chromosomal abnormality in > or = 2 miscarriages, as an instrument for selective karyotyping]. / Risicofactoren voor structurele chromosoomafwijking bij > or = 2 miskramen als instrument voor selectieve karyotypering.

OBJECTIVE: To identify additional risk factors and the corresponding probability of carrying a chromosome abnormality in couples with two or more miscarriages. DESIGN: Nested case-control study. METHOD: In 6 centres for clinical genetics in the Netherlands, data were collected from couples referred for karyotyping after 2 2 miscarriages from 1992-2000. Factors influencing the probability of carrier status were examined. The corresponding probability of carrier status was calculated for the various combinations of these factors. RESULTS: In total 279 carrier couples and 428 non-carrier couples were included. 4 independent factors influencing the probability of carrier status were identified: a younger maternal age at the time of second miscarriage, a history of > or = 3 miscarriages, a history of > 2 miscarriages in a brother or sister of either partner, and a history of> 2 miscarriages in parents of either partner. The calculated probability of carrier status in couples referred for chromosome analysis after two or more miscarriages, varied between 0.5-10.2%. In 18% of couples included, the risk was found to be so low (< 2.2%), that in couples with comparable risk factors, it may not be necessary to perform karyotyping. CONCLUSION: This study demonstrated that the probability of carrier status in couples with > or = 2 miscarriages is modified by additional factors. Selective chromosome analysis would result in a more effective referral policy and therefore decrease the number of chromosome analyses and lower the costs.

['Multifactorial disorders in the genomics era'; notes on a recent report from The Royal Netherlands Academy of Arts and Sciences]. / 'Multifactoriële aandoeningen in het genomics-tijdperk'; kanttekeningen bij een recent rapport van de Koninklijke Nederlandse Akademie van Wetenschappen.

The Royal Netherlands Academy of Arts and Sciences (KNAW) has issued a report entitled 'Multifactorial diseases in the genomics era'. It makes two major recommendations. The ministers of Science, Health and Economic Affairs are advised to (a) to take steps to ensure the development, evaluation and implementation of advanced high-throughput technologies in order to improve the international position of the Netherlands, and (b) to actively promote the setting up of one or more general biobanks in the Netherlands that should contain biological samples and data from parts of the population and that are not restricted to a single disorder. The report fails to address some important aspects of biobanks, such as the registration of the ethnicity of patients and controls. In addition monogenetic subvariants in multifactorial disease are not mentioned.

[DNA-analysis in hereditary cancer: the importance of a reliable family history]. / DNA-diagnostiek bij erfelijke kanker: het belang van betrouwbare familiegegevens.

Three patients, a 45-year-old man, a 51-year-old woman and a 43-year-old woman, wanted to know whether they had a hereditary predisposition for cancer. The family of patient A fulfilled the clinical diagnostic criteria for hereditary non-polyposis colorectal carcinoma (HNPCC). The family of patient B fulfilled the clinical diagnostic criteria for hereditary breast/ovarian cancer (HBOC). The family of patient C did not completely fulfil the criteria for HBOC since only two family members had a confirmed diagnosis of breast cancer. In all three families, DNA-mutation analysis was performed. In families A and B no mutation was found. However, based on the family history, the diagnosis of hereditary cancer was made and recommendations for surveillance were given. After extensive counselling, one member of family B eventually decided to have prophylactic surgery performed. A few years later, a pathogenic mutation in BRCA2 was found in family B. In family C, an unclassified variant was found in BRCA1. Further investigations in the family were not possible, due to a lack of co-operation from family members. It is important to obtain a thorough and complete family history. When DNA-analysis remains inconclusive or if an unclassified variant is found, recommendations for surveillance will be based on this family history.

Prenatal diagnosis in the Netherlands. Dutch Working Party of Prenatal Diagnosis.

Prenatal invasive diagnosis of genetic conditions in the Netherlands is well organised, based on uniform indications and has a sound financial structure. Facilities for fetal karyotyping and DNA analysis are available in the 8 academic centres. Prenatal diagnosis of metabolic diseases is mainly carried out in Rotterdam. Amniocentesis, transcervical and transabdominal chorionic villus sampling are carried out in all centres, including 4 subcentres. The national Working Party on Prenatal Diagnosis started in 1985 and is a useful platform for all obstetricians and geneticists involved in prenatal diagnosis.

A placental diploid cell line is not essential for ongoing trisomy 13 or 18 pregnancies.

Viable trisomy 13 or 18 pregnancies may be supported by the presence of a diploid cell line, confined to the outer layer of the placenta (cytotrophoblast). To establish the presence of diploid cells we investigated five random biopsies from placentas of trisomy 13 (n = 8) and trisomy 18 cases (n = 6) of newborn infants and terminated pregnancies by means of fluorescence in situ hybridisation on interphase nuclei (n = 100). In 12 of these 14 placentas (including all five liveborns) 80% or more of the analysed nuclei showed three spots, suggestive of the presence of a full trisomy. In the other two placentas (both cases of trisomy 18) mosaicism was detected at most investigated sites. Thus, in contrast with earlier studies, these results show that a significant diploid cell line present in the placenta, confined to the trophoblast, is not a pre-requisite for intrauterine survival in the investigated cases.

Cardiac involvement in carriers of Duchenne and Becker muscular dystrophy.

A cross-sectional study in a cohort of DNA proven carriers of Duchenne (DMD) and Becker (BMD) muscular dystrophy was undertaken with the following objectives: (1) to estimate the frequency of electrocardiographic (ECG) and echocardiographic abnormalities; (2) to establish the proportion of carriers with dilated cardiomyopathy and (3) to assess possible associations between dilated cardiomyopathy and genotype. One hundred and twenty nine DMD and BMD carriers, aged 18-60 years, were traced through the files of the central register kept at the department of Human Genetics in Leiden. Investigations included full medical history, physical examination, ECG and two-dimensional and M-mode echocardiographic examination. Forty-seven percent had ECG changes. Thirty-six percent (DMD 41%, BMD 27%) had at least one abnormality as is usually found in the male patients. Echocardiographic examination was abnormal in 36% (DMD 38%, BMD 34%). Dilated cardiomyopathy was found in seven DMD carriers (8%), and in none of BMD carriers. In addition, 18% had left ventricle dilatation (DMD 19%, BMD 16%). Only 38% had a completely normal investigation of the heart. We found no association between genotype and cardiac manifestations. Our study underlines that cardiac involvement is part of the dystrophinopathies. Carriers should be told about the increased risk of this complication when asking genetic advice. It also implicates that a complete cardiological evaluation should be performed at least once in all carriers. If left ventricle dilatation or dilated cardiomyopathy is present a yearly follow up is needed, in order to start timely therapy.

A novel gamma-sarcoglycan mutation causing childhood onset, slowly progressive limb girdle muscular dystrophy.

Limb girdle muscular dystrophy is a heterogeneous group of disorders. One autosomal recessive subtype, LGMD2C, has been linked to chromosome 13, and is caused by gamma-sarcoglycan deficiency in muscle. This report describes a novel missense mutation identified in a large consanguineous Dutch family with LGMD. This mutation leads to reduction of gamma-sarcoglycan, and gives rise to a childhood-onset, slowly-progressive dystrophy.

Absence of deleted in azoospermia (DAZ) genes in spermatozoa of infertile men with somatic DAZ deletions.

OBJECTIVE: To determine the presence or absence of the deleted in azoospermia (DAZ) gene clusters in the Y-bearing spermatozoa in semen of severely oligozoospermic men or in testicular biopsy samples of azoospermic men with somatic DAZ deletions. DESIGN: Prospective study. SETTING: Academic hospital. PATIENT(S): Nineteen patients attending our clinics for therapeutic intracytoplasmic injection of sperm. INTERVENTION(S): Peripheral blood lymphocytes were used to obtain somatic DNA for analysis using the polymerase chain reaction. Analysis of chromosomes X and Y and the detection of the DAZ gene clusters were carried out with the fluorescence in situ hybridization technique in spermatozoa remaining after intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Presence or absence of the DAZ gene clusters in matched somatic DNA and Y-bearing spermatozoa. RESULT(S): Seven patients appeared to have a somatic DAZ deletion. Three-color fluorescence in situ hybridization showed that all Y-bearing spermatozoa examined from these men carried the same deletion. CONCLUSION(S): The DAZ deletions present in the seven men would all have been transmitted if they had fathered sons through artificial fertilization techniques using the sperm cells examined in this study.

A critical analysis of 75 therapeutic abortions.

An analysis is presented of the first 75 therapeutic abortions based on the results of laboratory investigations on midtrimester amniotic samples from 2816 pregnancies. The reasons for the abortions were: chromosome aberration (n = 36), male fetus at risk for X-linked disorder (n = 23), neural tube defect (n = 14), and metabolic disorders (n = 2). An estimation was made of the life expectancy of these 75 fetuses if no termination of pregnancy had taken place. We estimate that a maximum of about 40% of the aborted fetuses would have resulted in malformed children at the age of 1 year, or in boys developing serious disabilities during infancy. Financial (cost-benefit analysis) and psychologic aspects are discussed.

Genetic counseling for hereditary cancer: a pilot study on experiences of patients and family members.

Recent advances in the identification of genetic abnormalities associated with certain types of cancer have stimulated the development of screening and counseling programs for hereditary and familial forms of cancer. In 1995, such a program was established in a collaboration between three familial cancer clinics in Amsterdam. Given the potential impact of genetic screening and counseling on the psychosocial health of participants, it was considered essential that the program be evaluated from its inception to determine the participants' satisfaction with the services provided. A pilot study was initiated in which individuals who received genetic counseling for cancer were asked to provide feedback on the perceived quality of the services provided, and to identify areas in which additional services may be required. Preliminary results based on 36 counseled individuals indicated generally high levels of satisfaction with the care provided by the clinical geneticist and with the procedures at the familial cancer clinics. Several areas were identified that deserve additional attention: (1) the role of the family doctor in the genetic counseling; (2) communication of information regarding the possible impact of genetic counseling and testing on daily life; (3) communication between the clinical geneticist and other health care workers, and (4) psychosocial support during and after the process of genetic counseling.

Bilateral renal agenesis (Potter's syndrome) in two consecutive infants.

Bilateral renal agenesis is a relatively rare congenital anomaly; its frequency is 1 : 3000-4000 deliveries, with a remarkable predominance of male infants. This anomaly is most often found in combination with characteristic facial features ('Potter's face') and pulmonary hypoplasia, the combination being known as Potter's syndrome. In the course of pregnancy an increasing oligohydramnios becomes manifest; during labor, virtual absence of amniotic fluid is found in most cases. This oligohydramnios should alert the obstetrician to suspect Potter's syndrome; serial ultrasonography may confirm the diagnosis. Most affected children are born alive but die within a few hours due to respiratory difficulties caused by the pulmonary hypoplasia. Despite the remarkable facial characteristics of these infants, it was only in a small minority that the diagnosis was considered before autopsy. This stresses the need for a full post-mortem examination in all cases of perinatal death. The etiology is still uncertain, though multifactorial inheritance is the most likely. As a consequence, the recurrence risk is not negligible; the small number of 'familial occurrence' observations, however, does not allow estimation of a risk figure. Genetic counseling is indicated in any family giving birth to a child with bilateral renal agenesis. A family is described in which two consecutive male infants with bilateral renal agenesis were born alive and survived 19 and 38 h.

Severe congenital skin defects in a newborn. Case report and relevance of several obstetrical parameters.

The clinical, laboratory, histologic and autopsy findings are reported from a live-born male infant with severe congenital skin defects (CSD) who survived for 2 days. The family history revealed consanguinity of the (Turkish) parents. The patient was compared with 10 cases from the literature with the most severe form of CSD. The combination of severe CSD, parental consanguinity and gastrointestinal atresia was found in 3 of these 11 cases, including our own patient. Differentiation from an atypical form of epidermolysis bullosa, complicated by pyloric atresia, is difficult. The mechanism of the (prenatally detected) elevated amniotic fluid alpha 1-fetoprotein (AFP) level is discussed. The finding of a balanced 13q14q chromosome translocation in the infant and his mother is considered a coincidence.

A patient with a de novo t (6;9) and an interstitial duplication of (9)(q21.2q22.1).

We report on a 4-year-old child with psychomotor retardation, general hypotonia and only mild dysmorphic features. Her chromosome constitution was 46,XX, t (6;9) (q27;q22.1), dup (9) (q21.2q22.1). This de novo interstitial duplication was confirmed using fluorescence in situ hybridisation (FISH) with band-specific probes. This is the second report of a patient with an interstitial duplication of this region of the long arm of chromosome 9. It is concluded that in a child with an abnormal phenotype and a de novo (apparently) balanced translocation, the possibility of a small duplication or deletion should be considered.

[Use of genetics in the Dutch health care system; a memorandum from the Dutch Minister of Health, Welfare and Sports to the Dutch Parliament]. / De toepassing van genetica in de gezondheidszorg; een nota van de minister van Volksgezondheid, Welzijn en Sport aan de Tweede Kamer.

In the memorandum entitled 'The application of genetics in health care', which was sent to the Dutch Parliament in December 2000, the Minister of Health, Welfare and Sport responded to four proposals she had received from the Health Council of the Netherlands during the previous three years. These proposals included reports on in vitro fertilisation, DNA diagnostics, clinical genetic testing and genetic counselling, and pharmacogenetics. Legal aspects dominate the section on the consumer's/patient's position: detailed legal guidelines are provided for difficult family-related issues in genetic counselling. For genetic counselling and clinical genetic testing, permission from the Minister of Health is still required. Criteria have been provided for the public funding of these activities in the shorter term. Clinical geneticists have been asked to develop guidelines for a number of clinical situations, which include predictive genetic testing and genetic testing in children. Moreover both medical and laboratory professionals have already initiated a number of self-regulatory measures. The Minister has adopted most of the proposals received, which means that for the foreseeable future, there is a clearly regulated framework for the responsible use of genetics within the Dutch healthcare system.