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ABSTRACT: X-linked agammaglobulinaemia (XLA) is a primary immunodeficiency caused by a mutation in the gene encoding Bruton's tyrosine kinase (BTK). The classical presentation of XLA consists of the almost complete absence of B-lymphocytes and immunoglobulins in the peripheral blood leading to severe, mainly bacterial, upper and lower respiratory-tract infections already in early childhood. Irrespective of the kind of BTK-gene mutation the phenotype of XLA can be very diverse. Two 9-year-old cousins with the same BTK-gene mutation illustrate this phenotypical diversity. One boy had a classical presentation and was on maintenance treatment with intravenous immunoglobulins and prophylactic antibiotics to control his infections. Without any prophylactic treatment, his cousin had no abnormal infectious course despite very low B-lymphocyte counts and immunoglobulin levels in the blood. The mechanisms underlying the phenotypical diversity of XLA have not been clarified. Gene polymorphisms affecting the innate immune system may play a role.
Nederlands tijdschrift voor geneeskunde 06/2004; 148(21):1053-6.
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ABSTRACT: Recently, we and others reported instability in the (C)8 repeat in exon 5 of MSH6 as a preferential target for somatic mutations in tumours from MSH6 germline mutation carriers. Here, we report that in 45% of tumours from MLH1, MSH2 and MSH6 germline mutation carriers no sequence change in the (C)8 repeat of MSH6 was found upon DNA sequencing analysis of PCR products with a shift in electrophoresis mobility. Using "standard" PCR primers a high frequency of instability (50-86%) of the (C)8 repeat was found, but using a modified PCR reverse primer, accomplishing modulation of non-templated addition of adenine during in vitro PCR amplification by the Taq polymerase, a markedly lower frequency of instability was found in tumours from MLH1, MSH2 and MSH6 mutation carriers (6, 13 and 40%, respectively). Furthermore, a significant difference of the frequency of instability of the (C)8 repeat in tumours from MSH6 mutation carriers was found compared to MLH1, MSH2 mutation carriers. These results might have important implications for the detection of instability of other short mononucleotide repeats, e.g. TGFbetaRII, BAX, IGFRII, PTEN, BRCA2.
Oncogene 10/2001; 20(43):6241-4. · 6.37 Impact Factor
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ABSTRACT: Hereditary paragangliomas or glomus tumors are usually benign slow-growing tumors in the head and neck region. The inheritance pattern of hereditary paraganglioma is autosomal dominant with imprinting. Recently, we have identified the SDHD gene encoding subunit D of the mitochondrial respiratory chain complex II as one of the genes involved in hereditary paragangliomas. Here, we demonstrate that two founder mutations, Asp92Tyr and Leu139Pro, are responsible for paragangliomas in 24 and 6 of the 32 independently ascertained Dutch paraganglioma families, respectively. These two mutations were also detected among 20 of 55 isolated patients. Ten of the isolated patients had multiple paragangliomas, and in eight of these SDHD germline mutations were found, indicating that multicentricity is a strong predictive factor for the hereditary nature of the disorder in isolated patients. In addition, we demonstrate that the maternally derived wild-type SDHD allele is lost in tumors from mutation-carrying patients, indicating that SDHD functions as a tumor suppressor gene.
Genes Chromosomes and Cancer 08/2001; 31(3):274-81. · 3.31 Impact Factor
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A Wagner,
Y Hendriks,
E J Meijers-Heijboer,
W J de Leeuw,
H Morreau,
R Hofstra,
C Tops,
E Bik, A H Bröcker-Vriends,
C van Der Meer,
D Lindhout,
H F Vasen,
M H Breuning,
C J Cornelisse,
C van Krimpen,
M F Niermeijer,
A H Zwinderman,
J Wijnen,
R Fodde
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ABSTRACT: Hereditary non-polyposis colorectal cancer (HNPCC) is the most common genetic susceptibility syndrome for colorectal cancer. HNPCC is most frequently caused by germline mutations in the DNA mismatch repair (MMR) genes MSH2 and MLH1. Recently, mutations in another MMR gene, MSH6 (also known as GTBP), have also been shown to result in HNPCC. Preliminary data indicate that the phenotype related to MSH6 mutations may differ from the classical HNPCC caused by defects in MSH2 and MLH1. Here, we describe an extended Dutch HNPCC family not fulfilling the Amsterdam criteria II and resulting from a MSH6 mutation. Overall, the penetrance of colorectal cancer appears to be significantly decreased (p<0.001) among the MSH6 mutation carriers in this family when compared with MSH2 and MLH1 carriers (32% by the age of 80 v >80%). Endometrial cancer is a frequent manifestation among female carriers (six out of 13 malignant tumours). Transitional cell carcinoma of the urinary tract is also relatively common in both male and female carriers (10% of the carriers). Moreover, the mean age of onset of both colorectal cancer (MSH6 v MSH2/MLH1 = 55 years v 44/41 years) and endometrial carcinomas (MSH6 v MSH2/MLH1 = 55 years v 49/48 years) is delayed. As previously reported, we confirm that the pattern of microsatellite instability, in combination with immunohistochemical analysis, can predict the presence of a MSH6 germline defect. The detailed characterisation of the clinical phenotype of this kindred contributes to the establishment of genotype-phenotype correlations in HNPCC owing to mutations in specific mismatch repair genes.
Journal of Medical Genetics 06/2001; 38(5):318-22. · 6.36 Impact Factor
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ABSTRACT: A retrospective study was performed to explore carrier testing among women who were possible or obligate carriers of the haemophilia gene. Knowledge of the possibility of carrier testing and use of carrier testing were studied separately. In our exploration we were guided by the diffusion theory and the Health Belief Model. Logistic regression analysis showed that four factors were statistically significant related to knowledge of carrier testing: information via mass media, a haemophilic relative in the nuclear family rather than in the extended family, medical severity of haemophilia, and information from the patients' organization. For those women acquainted with carrier testing two of the four factors just mentioned were significantly related to the utilization of carrier testing i.e. having a haemophilic relative in the nuclear family and the medical severity of the haemophilia. In addition the following factors were associated: attitude towards abortion because of haemophilia, educational level, and marital status. Notwithstanding the prominent function of the mass media and the patients' organization, the respondents themselves stated that relatives, especially parents and sisters, were the most important source of information on genetic counselling and carrier testing.
Social Science [?] Medicine 10/1993; 37(5):639-48. · 2.70 Impact Factor
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ABSTRACT: Developments in DNA technology have provided a novel means of carrier detection and prenatal diagnosis of hemophilia A and B. The collection of a large set of data has enabled us to evaluate the present feasibility and reliability of a diagnosis at the gene level and its contribution to methods already available. Since 1984, 533 potential and obligate carriers belonging to 170 families with hemophilia have been referred to us. By the combined use of pedigree analysis, coagulation assays, and DNA (RFLP) analysis, certainty about the carrier status has been markedly increased for the potential carriers. Although RFLP analysis revealed the possible origin of the mutation in many families with an isolated patient, uncertainty remained for quite a number of their female relatives because of the possible occurrence of germline mosaicism. Forty-one women requested prenatal diagnosis during one or more pregnancies. The short time interval between pregnancies, even after abortion of an affected fetus, proved that first-trimester prenatal diagnosis has become an acceptable option for women at risk. Recently, efficient methods for direct identification of mutations have been developed, and they may allow a definite diagnosis for all families with hemophilia in the near future.
Annals of Hematology 02/1992; 64(1):2-11. · 2.62 Impact Factor
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ABSTRACT: Coagulation and RFLP data from 41 families with an isolated haemophilia A patient were used to estimate the sex ratio of mutation frequencies (nu/mu). Based on the results of coagulation assays in all the female relatives investigated, nu/mu was estimated to be 12.1 by the maximum likelihood method (95% confidence interval 3.8 to 62.5). In order to avoid the possible influence of germline mosaicism, an additional analysis was performed in which only the results in the mothers and grandmothers of an isolated patient were included. The nu/mu ratio was then estimated to be 5.2 (95% confidence interval 1.8 to 15.1). Because an estimate of nu/mu based on all available RFLP data can easily be biased in favour of males, we set up a model in which only information on the grandparental derivation of the patient's X chromosome was used, irrespective of the generation in which the mutation actually occurred. In this way nu/mu was estimated to be minimally 4. The probability of carriership for mothers of an isolated haemophilia A patient amounts to 86% with a sex ratio of 5.2. Although this would imply that 14% of the mothers are not carriers of the disease in the classical sense, they may be mosaic for the mutation and, therefore, also at risk of transmitting the mutation more than once.
Journal of Medical Genetics 11/1991; 28(10):672-80. · 6.36 Impact Factor
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ABSTRACT: Adequate replacement therapy in haemophilia has been available for two decades. This has led to considerable improvements in the life expectancy and physical status of haemophilia patients. A study was conducted to investigate whether this has also led to improvements in quality of life. With this aim, information was obtained from 935 Dutch haemophiliacs by mailed questionnaires on relationships, marriage, family life and employment. Haemophilia patients were less often married than men in the general population (13% fewer) and had a lower total number of children (30% lower, 17% for those who were married). Twenty-two per cent of the patients were not employed and received an income from the disability funds. While severity of haemophilia, joint damage and age increased the risk of disability, it was noted that home treatment was associated with a 50% reduction in this risk. Remarkably, haemophilia patients did not differ from the general population in their view of the quality of their own health. The results of this study show a positive influence of modern haemophilia treatment on quality of life. At present, AIDS overshadows all optimistic feelings one may have about this field. However, the results described here demonstrate the benefits that can be achieved with adequate replacement therapy, and justify the expectation of further improvements in the near future.
Journal of Internal Medicine 01/1991; 228(6):633-40. · 5.48 Impact Factor
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ABSTRACT: A hereditary disease with excess mortality such as haemophilia is maintained in the population by the occurrence of new cases, i.e. mutations. In haemophilia, mutations may arise in female or male ancestors of a 'new' patient. The ratio of the mutation frequencies in males over females determines the prior risk of carriership of the mother of an isolated patient. An estimate of this prior risk is required for the application of Bayes' theorem to probability calculations in carriership testing. We have developed a method to estimate the sex ratio of the mutation frequencies; it does not depend on the assumption of genetic equilibrium, nor require an estimate of the reproductive fitness of haemophilia patients and carriers. Information from 462 patients with severe or moderately severe haemophilia A was gathered by postal questionnaires in a survey that included practically all Dutch haemophiliacs. Pedigree analysis was performed for the 189 patients of these 462, who were the first haemophiliacs in their family. By the maximum likelihood method, the ratio of the mutation frequencies in males and females was estimated at 2.1, with a 95% confidence interval of 0.7-6.7. In addition, we performed a meta-analysis of all published studies on the sex ratio of the mutation frequencies. When the results of six studies were pooled, it was estimated that mutations originated 3.1 times as often in males as in females. The 95% confidence interval was 1.9-4.9. This implies that 80% of mothers of an isolated patient are expected to be haemophilia carriers.
Human Genetics 01/1991; 86(2):139-46. · 5.07 Impact Factor
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ABSTRACT: Experiences with and attitudes toward carrier testing and prenatal diagnosis were evaluated among 549 potential and obligate carriers of hemophilia. Almost everybody considered carrier testing to be useful. Forty-nine percent had been tested for carriership, 10% had only received limited information, and 41% had not been tested and had never received information about the heredity of hemophilia. More married women, women with severe hemophilia in their family, and women closely related to a patient with hemophilia had been tested for carriership than others. Lack of information about the probability of carriership for female relatives and a similar ignorance of the possibility of carrier testing were important reasons for not having been tested. Eleven percent of the women with one or more children had undergone prenatal diagnosis in the past. Thirty-one percent of the study population would favour prenatal diagnosis with the implication of a potential abortion in early pregnancy and half of them would choose this option even in late pregnancy. Most of the women who objected to prenatal diagnosis did so because they did not consider hemophilia to be a sufficiently serious disorder to justify an abortion.
American Journal of Medical Genetics 10/1990; 37(1):147-54.
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ABSTRACT: We found a partial deletion of the clotting factor VIII gene of about 2000 bp, spanning exon 5 and part of intervening sequence 4 and 5 in an isolated patient with severe haemophilia A. The mother of the patient, who appeared to be a non-carrier on the basis of coagulation assays and restriction fragment length polymorphism analysis in the family, turned out to be a mosaic for the deletion, not only in her germ cells, but also in various somatic cells. These findings suggest that the mutation is the result of an event in early embryogenesis. If mosaicism for a mutation, either gonadal or somatic, proves to be a common phenomenon in human genetics, it is imperative to reconsider genetic risks for (future) sibs of any apparently new mutant of a hereditary disease.
Human Genetics 09/1990; 85(3):288-92. · 5.07 Impact Factor
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ABSTRACT: Mortality figures were calculated for a group of 717 Dutch haemophiliacs over the period 1973-86. Follow-up was on average 10.9 years; no patients were lost to follow-up. The data were compared to the general male population by actuarial methods and patient-year analysis. Forty-three patients died, while 20 deaths were expected in a hypothetical group of non-haemophiliacs of the same age distribution. Hence, overall mortality was 2.1 times higher than in the general population. This leads to a calculated life expectancy of 66 years, as compared to 74 years in the general male population. Mortality did not differ much by severity of haemophilia. A possibly beneficial effect of prophylaxis on longevity was observed. Haemorrhage occurred in half of all deaths and among these traumatic bleeding was the most prevalent. The number of deaths due to ischaemic heart disease was significantly lower (80% reduction) than expected and therefore the authors conclude that haemophilia offers protection against ischaemic heart disease. Cancer mortality was significantly higher (2.5 times) than expected.
British Journal of Haematology 02/1989; 71(1):71-6. · 4.94 Impact Factor
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ABSTRACT: We evaluated the feasibility, reliability, and acceptability of prenatal diagnosis of haemophilia A by DNA analysis of chorionic villi. Twenty-two women at risk to transmit the abnormal gene were referred for prenatal diagnosis, two of them twice. Two of the 22 women appeared to be non-carriers by DNA analysis. In one of these women, the results were known only after chorionic villus sampling had been carried out. Thirteen of the twenty carriers were heterozygous for an intragenic (Bc1I or XbaI) marker; six women were only heterozygous for the extragenic DXS52 (St14) locus. One of the women was homozygous for all the presently known DNA markers within or closely linked with the factor VIII locus. Twelve of the 22 fetuses at risk were male, ten were female. Seven of the 12 male fetuses were shown to be affected and were subsequently aborted. Four male fetuses appeared to be not affected. In one case, the diagnosis was made by use of an extragenic marker. The woman rejected fetal blood sampling to confirm the diagnosis. After birth, a normal factor VIII level was found in three of the four cases. The fourth pregnancy is still continuing. In one of the 12 male fetuses, no diagnosis at the gene level was possible. DNA analysis is expected to provide maximum certainty as to the phenotype of the fetus for approximately 60 per cent of the women; for another 37 per cent a rate of misdiagnosis of 4-5 per cent applies. In only 3 per cent of the cases will no diagnosis at the gene level be possible as yet. The new possibility of a prenatal diagnosis in the first trimester of pregnancy enabled some of these women to have a family of their own and was appreciated in particular by the women who underwent fetoscopy in an earlier pregnancy.
Prenatal Diagnosis 08/1988; 8(6):411-21. · 2.11 Impact Factor
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Thrombosis and Haemostasis 03/1988; 59(1):122. · 5.04 Impact Factor
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ABSTRACT: We performed DNA analysis in 20 families with haemophilia A in order to evaluate its usefulness for carrier detection and prenatal diagnosis. The polymorphic BclI site within intron 18 of the factor VIII gene and the extragenic TaqI and BglII polymorphic sites which are detected by the random DNA probes designated St14 and DX13, respectively, were investigated for. Two events of recombination were found between the St14 and the haemophilia A locus in 51 informative meioses. In one of these recombinant meioses crossing over had also occurred between the DX13 and the haemophilia A locus. No further crossovers between the DX13 and the haemophilia A locus were found in 20 informative meioses. Segregation analysis of the polymorphic markers and the deleterious mutation within the families allowed a diagnosis at the gene level for 52 out of 57 potential carriers. The new method considerably decreased the uncertainty about carriership for seventeen of the nineteen women with a probability of carriership between 5% and 95% based on pedigree analysis and factor VIII assays. In seven cases chromosome and DNA analysis of a chorionic villus biopsy was carried out. Three of the fetuses were female, four were male. Three of the male fetuses had inherited the normal maternal X-chromosome and were, therefore, not affected. For another male fetus no diagnosis at the gene level was possible since the mother was homozygous for all the known restriction fragment length polymorphisms within or closely linked with the haemophilia A locus.
Thrombosis and Haemostasis 05/1987; 57(2):131-6. · 5.04 Impact Factor
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ABSTRACT: Two patients with partial monosomy of the short arm of chromosome 8 are described. Their clinical features were very similar. Comparison with previously reported patients confirms the existence of an 8p- syndrome. The importance of cytogenetic investigations in all infants with major congenital heart defect and facial dysmorphism or microcephaly or both is stressed.
Journal of Medical Genetics 05/1986; 23(2):153-4. · 6.36 Impact Factor
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ABSTRACT: We analysed DNA from individuals of five families with haemophilia B, including nineteen potential carriers. A gene-specific probe was used to reveal a TaqI restriction-fragment length polymorphism. Segregation analysis of the polymorphic marker and the deleterious mutation within families allowed diagnosis at the gene level for 16 out of the 19 potential carriers, two proving to be carriers and 14 non-carriers. The obvious advantage is that lyonisation, which is a limiting factor when gene product (clotting factor IX) measurements are used for carrier detection, does not interfere with this procedure and that the result is a definitive diagnosis instead of a risk estimate. The method also permits prenatal diagnosis on chorionic villi in the first trimester of pregnancy. Restriction-fragment length analysis, based upon the probe and restriction enzyme used in this study, will be informative for approximately 45% of the individuals at risk of carrying or transmitting the haemophilia B mutation.
Thrombosis and Haemostasis 09/1985; 54(2):506-9. · 5.04 Impact Factor
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ABSTRACT: We describe a family with translocation (8;13) (p21;q22), in which both unbalanced products of adjacent-1 segregation occurred. Two members of the family have partial trisomy 8p with partial monosomy 13q; two others have partial monosomy 8p with partial trisomy 13q. The latter are both phenotypically normal, which is a highly unusual observation. One of these is, in addition, a carrier of a de novo balanced translocation between chromosomes 2 and 19. The risk for unbalanced progeny is discussed.
Clinical Genetics 06/1985; 27(5):487-95. · 3.13 Impact Factor
