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.

Cardiac abnormalities in a follow-up study on carriers of Duchenne and Becker muscular dystrophy.

OBJECTIVES: Cardiac involvement has been reported in carriers of dystrophin mutations giving rise to Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). The progress of these abnormalities during long-term follow-up is unknown. We describe the long-term follow-up of dilated cardiomyopathy (DCM) in DMD/BMD carriers. METHODS: A long-term follow-up study was performed among Dutch DMD/BMD carriers first analyzed in 1995. A cardiac history was taken, and all carriers were assigned a functional score to assess skeletal muscle involvement. Electrocardiography and M-mode and 2-D echocardiography were performed. DCM was defined as an enlarged left ventricle with a global left ventricle dysfunction or fractional shortening less than 28%. Slow vital capacity of the lung was measured by a hand-held spirometer. RESULTS: Ninety-nine carriers were monitored with a median follow-up of 9 years (range 7.0-10.6 years). Eleven carriers with DCM (10 DMD, 1 BMD) were identified. Nine of them developed DCM in the follow-up period. One of the patients with DCM reported in the 1995 study died of cardiac failure at age 57 years. DCM was more frequently found in carriers who were functionally symptomatic. CONCLUSION: Cardiac abnormalities in DMD/BMD carriers are progressive, as in patients with DMD/BMD.

Reproductive outcome after PGD in couples with recurrent miscarriage carrying a structural chromosome abnormality: a systematic review.

BACKGROUND: Preimplantation genetic diagnosis (PGD) has been stated to improve live birth rates compared with natural conception in couples with recurrent miscarriage (RM) carrying a structural chromosome abnormality. It is unclear to what extent this claim can be substantiated by evidence. A systematic review of the literature was performed on the reproductive outcome of these couples after natural conception or after PGD. METHODS: MEDLINE, EMBASE and the Cochrane database were searched until April 2009. Trials, patient series and case reports describing reproductive outcome in couples with RM carrying a structural chromosome abnormality after natural conception and/or after PGD were included. Since no randomized controlled trials or non-randomized comparative studies were found, separate searches for both groups were conducted. Primary outcome measure was live birth rate per couple. Secondary outcome measure was miscarriage rate per couple. RESULTS: Four observational studies reporting on the reproductive outcome of 469 couples after natural conception and 21 studies reporting on the reproductive outcome of 126 couples after PGD were found. After natural conception, live birth rate per couple varied between 33 and 60% (median 55.5%) after parental chromosome analysis; miscarriage rate ranged from 21 to 40% (median 34%). After PGD, live birth rate per couple varied between 0 and 100% (median 31%) after parental chromosome analysis; miscarriage rate ranged from 0 to 50% (median 0%). CONCLUSIONS: Currently, there are insufficient data indicating that PGD improves the live birth rate in couples with RM carrying a structural chromosome abnormality.

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.

Inherited unbalanced structural chromosome abnormalities at prenatal chromosome analysis are rarely ascertained through recurrent miscarriage.

OBJECTIVE: To determine the mode of ascertainment of inherited unbalanced structural chromosome abnormalities detected at prenatal chromosome analysis. METHODS: From the databases of three centres for clinical genetics in the Netherlands, all cases of inherited unbalanced structural chromosome abnormalities detected at prenatal chromosome analysis in the period 1992-2000 were selected. The mode of ascertainment was identified by examining the reason for prenatal chromosome analysis and the reason for parental chromosome analysis of the first structural chromosome abnormality detected within the family. RESULTS: Totally 56 cases of inherited unbalanced structural chromosome abnormalities were detected at prenatal chromosome analysis. Only one case was ascertained through two previous miscarriages (2%). The main modes of ascertainment were a previous child with an unbalanced karyotype (48%), congenital abnormalities at ultrasound examination (20%), and advanced maternal age (9%). The remaining cases had a different mode of ascertainment. CONCLUSION: Inherited unbalanced structural chromosome abnormalities detected at prenatal chromosome analysis are rarely ascertained through two or more miscarriages.

[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.

A comparison of counselee and counselor satisfaction in reproductive genetic counseling.

Important insights in the process of genetic counseling can be provided by establishing levels of satisfaction. The aim of our study was to compare counselees' and counselors' satisfaction with the initial consultation in reproductive genetic counseling and to gain insight into the factors associated with their contentment. One hundred and fifty-one women and 11 counselors participated in this study. Pre-test questionnaires included counselees' socio-demographic, physical and psychological characteristics, i.e. their degree of worry, expectations, preferred participation in decision making and experienced degree of control. Post-visit questionnaires asked for counselees' and counselors' satisfaction, counselees' participation in decision making and counselees' Perceived Personal Control (PPC). Little difference was found between counselees' and counselors' overall visit-specific satisfaction (mean 79 vs 74, respectively, on a visual analogue scale from 0 to 100). The correlation between counselees' and counselors' satisfaction was medium sized (r = 0.26, p < 0.01). Counselees' satisfaction was positively associated with being pregnant and with their post-visit PPC. Counselors' satisfaction was positively associated with counselees' post-visit PPC. No other counselee and counselor related variables appeared to be associated with satisfaction, nor was the duration of the consultation. Our findings suggest that, although both groups were satisfied with the consultation, counselees and counselors do not always have equal perceptions of the consultation process and may form their evaluation in different ways. In the assessment of quality of care, evaluation of both counselees' and counselors' satisfaction deserves more attention.

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.

[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.

Management of recurrent miscarriage: evaluating the impact of a guideline.

BACKGROUND: Little is known on the actual diagnostic and therapeutic management of recurrent miscarriage and the impact of introducing guidelines on this topic. The objective of this study was to evaluate any changes in the management of recurrent miscarriage among Dutch gynaecologists after the introduction of the Dutch guideline 'Recurrent Miscarriage' in 1999. METHODS: Questionnaires were sent to all practices for obstetrics and gynaecology in the Netherlands. Data concerned definition, diagnosis and treatment of recurrent miscarriage. Results were compared with a similar study conducted before the introduction of the guideline and with the recommendations in the guideline. RESULTS: The response rate was 83%. Regarding gestational age, only 3% of the respondents used the definition as advised in the guideline. After the introduction of the guideline, thrombophilia factors were tested more frequently, anticoagulants were prescribed more frequently and more respondents reported to correct uterine malformations. Therapies not described in the guideline, e.g. donor insemination and oocyte donation, were still applied. CONCLUSIONS: The adherence to the Dutch guideline 'Recurrent Miscarriage' was rather poor, presumably due to guideline-related as well as physician-related barriers. Too many diagnostic tests and ineffective therapeutic interventions were performed. This study demonstrates the importance of appropriate implementation and revision.

['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.

Mutations in the testis-specific NALP14 gene in men suffering from spermatogenic failure.

BACKGROUND: Because of the common use of ICSI and the potential genetic aetiology of spermatogenic failure, concern has been raised about transmitting genetic disorders to ICSI offspring. However, to date, in only approximately 15% of all cases of spermatogenic failure, an underlying genetic cause can be identified. We have previously established an association between spermatogenic failure and chromosomal region 11p15. In this study, we set out to explore whether NALP14, a gene recently mapped to 11p15, has a function in spermatogenesis and whether mutations in NALP14 can cause spermatogenic failure. METHODS: We applied two different multiple tissue northern (MTN) blots to determine tissue specificity of NALP14 and performed immunohistochemistry on human testis with anti-NALP14 antiserum. To determine imprinting status of NALP14, we tested the expression pattern of two single-nucleotide polymorphisms (SNPs) in human testis. Finally, we performed a mutation screen of the NALP14 gene in 157 men with azoospermia or severe oligozoospermia by direct sequencing; 158 normospermic men served as controls. RESULTS: NALP14 was, as are the three other genes in 11p15, exclusively expressed in testis. Within the testis, the NALP14 protein was mainly expressed in A dark spermatogonia, mid and late spermatocytes and spermatids. The mutation screen revealed five mutations that occurred only in the patient group. One of these unique mutations introduced an early stop codon in the NALP14 sequence, predicted to result in a severely truncated protein. CONCLUSION: Our data suggest that NALP14 has a function in spermatogenesis and that mutations in this gene might cause spermatogenic failure.

[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.

[The disquieting consequences of granting patents on human genes for healthcare and scientific research in The Netherlands]. / De zorgwekkende gevolgen van het octrooieren van humane genen voor de gezondheidszorg en het wetenschappelijk onderzoek in Nederland.

The granting of a patent by the European Patent Office to Myriad Genetics on the sequence of the BRCA-1 gene in 2001 prompted the Dutch Minister of Healthcare and the Minister of Education, Culture and Science to ask for advice. The Royal Netherlands Academy of Arts and Science (KNAW) prepared a report in 2003 entitled: 'The consequences of granting patents on human genes for scientific research in The Netherlands'. Another recommendation (by Van de Bunt) entitled: 'A code of gene patenting' was also published in 2003. The KNAW report recommends, among others: a redefinition of the 'research exemption' and renewed discussion on a 'grace period'. The Van de Bunt report concludes, among other things, that some holders of gene patents cause unwanted side effects, but that the patent system itself provides sufficient possibilities to prevent these side effects. In a comment on both reports, the Dutch Ministry of Healthcare concluded: 'There is no reason to change the current patent system'. One should be more critical, however, and favour the possibility of a 'diagnostic exemption' in which DNA-diagnostics would be excluded from patenting.

[Invasive prenatal diagnosis in the Netherlands, 1991-2000: number of procedures, indications and abnormal results detected]. / Invasieve prenatale diagnostiek in Nederland, 1991-2000: aantallen ingrepen, indicaties, en gevonden afwijkingen.

OBJECTIVE: To provide an overview of invasive prenatal diagnosis in the Netherlands during the period 1991-2000 and to analyse potential trends. DESIGN: Retrospective. METHOD: The annual results from all 13 Dutch centres for invasive prenatal diagnosis over the period 1991-2000 were combined and described, with particular emphasis on indications, number and type of invasive procedures, and number and type of abnormal results. RESULTS: The percentage of pregnancies in which invasive prenatal diagnostics were carried out increased from 5% in 1991 to 6% in 1996 and remained at the same level until 2000. 'Maternal age' was the main reason for prenatal testing (69.2-73.3% of procedures). However, the number of pregnant women aged 36 or over increased by 69.9%. An abnormal result was found in an average of 4.7% of procedures, rising from 3.6% in 1991 to 5.4% in 2000. In 70.8% of cases with abnormal results, the pregnancy was terminated. Important trends were the relative decrease of cordocentesis (-82%) and chorionic villi biopsy (-18%) in favour of amniocentesis (+48%), and a strong decrease in the number of amniocentesis procedures on indication of increased risk of neural tube defect. CONCLUSION: The total number of invasive prenatal diagnostic procedures remained stable. However, there was an important decrease in the percentage of pregnant women aged 36 or over who underwent invasive prenatal diagnosis without previous prenatal screening.

[From gene to disease; primary open-angle glaucoma and three known genes: MYOC, CYP1B1 and OPTN]. / Van gen naar ziekte; primair openkamerhoekglaucoom en 3 bekende genen: MYOC, CYP1B1 en OPTN.

Primary open-angle glaucoma (POAG) is a group of multifactorial diseases that affects 1.5% of the population. If untreated, the disease leads to irreversible damage to the visual system. The clinical features of POAG are excavation of the optic disc and visual field defects, probably due to degeneration of retinal ganglion cells. Important risk factors for POAG are older age, elevated intraocular pressure, the presence of POAG in relatives, and still largely unknown molecular genetic factors. The clinical, genetic and pathological heterogeneity most likely reflects the complex heterogeneous situation at the molecular level. The three genes known to be involved in POAG (MYOC, CYP1B1 and OPTN) account for up to 18% of the POAG cases. These findings result in new possibilities for the presymptomatic molecular diagnosis of POAG.