[Rapid prenatal diagnosis of chromosomal abnormalities; limitations and possibilities].
Explore the source record for details and available documents.
Chromosome Aberrations↗
Biomedical subjects
N J Leschot
Publications and source records attributed to N J Leschot.
['Multifactorial disorders in the genomics era'; notes on a recent report from The Royal Netherlands Academy of Arts and Sciences].
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.
Biomedical Research↗
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.
Amino Acid Sequence↗
[DNA-analysis in hereditary cancer: the importance of a reliable family history].
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.
Adult↗
[The disquieting consequences of granting patents on human genes for healthcare and scientific research in The Netherlands].
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.
Biomedical Research↗
[Invasive prenatal diagnosis in the Netherlands, 1991-2000: number of procedures, indications and abnormal results detected].
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.
Adult↗
[From gene to disease; primary open-angle glaucoma and three known genes: MYOC, CYP1B1 and 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.
Age Factors↗
Heterogeneous nuclear ribonucleoprotein G-T (HNRNP G-T) mutations in men with impaired spermatogenesis.
The genetic cause of male subfertility due to impaired spermatogenesis is unknown in the majority of cases, but the general assumption is that it is a complex disorder. The aim of this study was to determine whether mutations occur in the HNRNP G-T gene in men with idiopathic impaired spermatogenesis. The heterogeneous nuclear ribonucleoprotein G-T (HNRNP G-T) gene is located in chromosomal region 11p15 that has been shown to be associated with impaired spermatogenesis. It is a member of the hnRNP gene family and is predominantly expressed in pachytene spermatocytes and round spermatids, where it is thought to affect splicing and signal transduction. We identified eight single nucleotide variants in our patient group of 153 subfertile men by sequencing the HNRNP G-T gene. Two of the mutations, R100H and G388del, did not occur in a control group of 143 normozoospermic men. The R100H mutation causes loss of a conserved arginine, thereby affecting a putative site of methylation possibly required for RNA-binding. Interestingly, this mutation was inherited from the mother. The G388del mutation causes loss of one non-conserved glycine located in a glycine stretch at the end of the protein that is not a known functional motif or domain. Our data show that HNRNP G -T mutations are not a frequent cause of impaired spermatogenesis. Nevertheless, the R100H mutation detected suggests that in some men mutations in the HNRNP G-T gene can cause impaired spermatogenesis.
Amino Acid Sequence↗
Clinical relevance of diagnosing structural chromosome abnormalities in couples with repeated miscarriage.
BACKGROUND: The annual number of parental karyotypes in cases of repeated miscarriage is increasing gradually in The Netherlands. The efficiency of offering parental karyotyping in couples with repeated miscarriage has not been evaluated before, especially not for the group with miscarriages at advanced maternal age. METHODS: A historical cohort study and nested case-control study were conducted, including couples with at least two miscarriages. Data were retrieved from medical records and telephone interviews. The obstetric follow-up was recorded for > or =2 years after the parental chromosome analysis. Data were analysed to compare ratios of carrier/non-carrier couples in whom maternal age was > or =36 or <36 years at the second, third or fourth and more miscarriage. A projected prevalence of carrier status of a structural chromosome abnormality was calculated by extrapolating the number of included patients to the original level of the total screening population. RESULTS: Forty-one couples with carrier status of a structural chromosome abnormality and 74 couples without carrier status were included. No unbalanced offspring arose after the detection of a structural chromosome abnormality. The risk of being a carrier was not significantly lower (as might be expected) when women were > or =36 years. Ascertainment after two, three, or four and more miscarriages did not change these findings. CONCLUSIONS: Karyotyping of 1324 couples ascertained for repeated miscarriage did not yield an unbalanced fetal chromosome pattern after the ascertainment of parental carrier status. In women with advanced maternal age, the frequency of carrier status was not lower than in younger women.
Abortion, Habitual↗
Genetic counseling for familial conditions during pregnancy: an analysis of patient characteristics.
Reproductive genetic counseling for a familial genetic risk factor preferably takes place before conception. However, of the women with a family history of genetic conditions who attend our department of clinical genetics, about 10-20% attend for the first time during a pregnancy. The current study aims to explore patient-related factors that may affect this late timing of reproductive genetic counseling. Consecutive pregnant (n = 100) and non-pregnant (n = 84) women visiting the department of clinical genetics for a genetic risk factor which was not age related completed a questionnaire immediately prior to the consultation. The questionnaire asked for (a) background characteristics, i.e. socio-demographic, obstetric, and disease characteristics (b) cognitive factors, i.e. initiative of referral, knowledge of the risk factor involved, risk perception, worry, child wish, attitudes toward abortion, and preferred participation in decision making, and (c) reasons for the timing of the consultation and for seeking genetic counseling. Pregnant women appeared to be higher educated, considered their children more often as healthy and were less often affected themselves, as compared to non-pregnant women. They also estimated their chance of having an affected child as lower, and they worried less. Furthermore, the initiative for referral was taken less often by the pregnant woman herself and more often by a medical worker. There were no major differences between the two study groups in knowledge, perceived severity of the risk factor, child wish, attitudes toward abortion, desired participation in decision making, and reasons to seek genetic counseling. Women indicated no specific reasons for their timing of referral for reproductive genetic counseling, e.g. during vs before pregnancy. Our data suggest that this timing of referral is not influenced predominantly by the women's level of knowledge. Rather, women's estimation of genetic risks and their degree of worry, which may be in accordance with the actual risk figures, seem to play a role in seeking genetic counseling. Although further studies are required, a more active role of health care providers seems warranted if we want to prevent genetic counseling for familial genetic conditions during pregnancy as much as possible.
Attitude to Health↗
Genetic knowledge and counselling skills of Dutch cardiologists: sufficient for the genomics era?
AIMS: Genetic scientific knowledge is growing rapidly but how this affects clinical practice is unclear. We investigated the levels of knowledge, practical skills and clinical genetic practices of Dutch cardiologists. METHODS AND RESULTS: A survey was designed to assess cardiologists' experience with genetic aspects of hypertrophic cardiomyopathy, self-reported genetic knowledge, and genetic skills in general and aimed at this disease. In addition, cardiologists' opinions on five possible measures for improvement were obtained. STUDY POPULATION: all Dutch cardiologists (n=643). Median number of patients suffering from hypertrophic cardiomyopathy per cardiologist is five. Forty-one percent of respondents do not give information about genetics to all their patients. Cardiologists rarely initiate DNA tests for hypertrophic cardiomyopathy. Only 38% refer patients to clinical geneticists. Self-reported knowledge levels are low (average score 3.3-5.1, 0-10 scale). Cardiologists with an established working relationship with a clinical geneticist report significantly higher levels of knowledge. Clinical guidelines, education and improved collaboration with clinical geneticists are preferred. CONCLUSION: Dutch cardiologists' genetic knowledge and clinical genetic practice levels are insufficient. As a result, clinical genetic care for patients with hypertrophic cardiomyopathy is poor. Improvements proposed include advancement of knowledge (education, professional guidelines) and structural measures (working relationships, multidisciplinary outpatient clinics). Collaboration of cardiologists and clinical geneticists is urgently needed to optimise cardiogenetic patient care.
Adult↗
[Prenatal diagnosis for hereditary predisposition to mammary and ovarian carcinoma--defining a position].
Prenatal testing for a BRCA mutation, the hereditary trait for mammary and ovarian carcinoma, with the intention of selective termination of pregnancy in case of a female carrier is a controversial ethical issue. Based on a review of the (limited) medical literature as well as of Dutch policy statements relating to this subject, the following conclusions and recommendations are proposed: (a) the decision to opt for prenatal BRCA testing and selective termination of pregnancy in case of a BRCA mutation in the foetus cannot immediately be judged unacceptable from an ethical point of view; (b) prenatal BRCA testing is morally defensible only in case of a female foetus and if the parents at least have the intention to terminate the pregnancy if the foetus is a carrier, although the final decision is in any case up to the parents only; (c) prental testing for a BRCA mutation should only be done after extensive counselling of the parents, during which not only the medical genetic aspects but also the ethical aspects of prenatal BRCA testing are discussed.
Abortion, Eugenic↗
[Prenatal genetic counseling in pregnancy: the importance of (early) timely referral ].
Three women aged 34, 23 and 39 years, who were respectively, 14, 12 and 8 weeks pregnant, requested genetic counselling due to grave genetic diseases in their families. The first woman chiefly wanted to be prepared; an investigation revealed no abnormalities and a healthy child was born. The second needed time to assimilate the information provided and terminated the pregnancy. For the third woman genetic screening was not possible in the short term and furthermore acceptation of the pregnancy was the biggest problem; she gave birth to a healthy child. In the Netherlands, about 800 to 1600 women every year request prenatal genetic counselling when they are already pregnant. The disadvantages of this late timing are the disquiet and uneasiness, the lost options and the time pressure under which difficult decisions have to be taken. Causes of this are a lack of genetic knowledge and psychosocial aspects. Ideally, genetic counselling that deals with reproductive issues should take place prior to conception.
Abortion, Eugenic↗
[Use of genetics in the Dutch health care system; a memorandum from the Dutch Minister of Health, Welfare and Sports to the Dutch Parliament].
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.
Ethics, Medical↗
FISH analysis of fetal nucleated red blood cells from CVS washings in cases of aneuploidy.
OBJECTIVE: In chorionic villus sampling (CVS) the chromosome analysis is inconclusive in 1-2% of the samples. In many cases follow-up amniocentesis is performed. Fetal nucleated red blood cells (FNRBCs) are present in washings of chorionic villus samples. We wanted to establish whether analysis of these true fetal cells, using fluorescence in situ hybridization (FISH), could support the CVS karyotype. METHODS: We analysed washings of first trimester chorionic villi from non-mosaic 45,X (n=6) and full trisomy 18 cases (n=7). FNRBCs were identified by immunostaining and FISH was performed with chromosome-specific probes for X, Y and 18. RESULTS: In all 13 samples FNRBCs were present (between 4 and 30 cells per sample). Five cases of monosomy X showed one X signal in 89-100% of the nuclei; in the other case 50% of the nuclei displayed one signal. In the trisomy 18 cases three spots were seen in 60-100% of the cells. CONCLUSION: The CVS aneuploidy was confirmed in FNRBCs in all samples, so FISH on FNRBCs can be used in cases of non-mosaic numerical chromosomal abnormalities. This test can confirm a CVS diagnosis of monosomy X or trisomy 18 and thus minimize the risk for false-positive diagnoses. An additional invasive test may be prevented.
Aneuploidy↗
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.
DNA↗
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.
Adult↗
[The heartache of muscular dystrophy].
Duchenne and Becker muscular dystrophy are caused by a mutation in the dystrophin gene, located on the short arm of the X chromosome. Three so called dystrophinopathy patients, a women aged 54 and two men aged 23 and 21 years, suffered from a severe dilated cardiomyopathy. Such a cardiomyopathy can develop in both carriers and patients. In addition, it is often more important for prognosis than muscle weakness. For these two reasons it is important to screen both groups for (early) cardiological abnormalities. If these are present, regular follow-up is necessary to start timely therapy. When cardiological investigations yield normal results, it is advised to screen carriers with a five-year interval. Dystrophinopathy patients should be checked every year, because the cardiomyopathy sometimes develops and deteriorates over a short period of time. Patients with dilated cardiomyopathy and with a positive family history for dilated cardiomyopathy, muscle weakness or high serum creatine kinase activity should be screened for a mutation in the dystrophin gene.
Adult↗