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PubMed2002

Genetic screening using the colour change of a PNA-DNA hybrid-binding cyanine dye.

As the relationship between human genes and various malfunctions and diseases becomes revealed at an ever-increasing pace, the need arises for the development of rapid genetic screening methods for diagnostic purposes. Genetic diseases show great diversity. Some are caused by a few characteristic localised mutations, while others arise from a large number of variations. Hence, it is unlikely that a single, general diagnostic method that applies to all cases will ever exist. Instead, a combination of methods is frequently applied. Here we propose the use of a dramatic colour change that a cyanine dye, 3,3'-diethylthiadicarbocyanine, displays upon binding to DNA-PNA duplexes. This method could become an inexpensive, fast and simple genetic screening test by visual inspection, with no need for complicated equipment. Our results demonstrate that this diagnostic method may be sufficiently sensitive to discriminate between even a fully complementary and a single mutation DNA sequence.

Base Sequence↗
PubMedDate not supplied

Newborn genetic screening: ethical and social considerations for the nineties.

As we head into the next decade, the impact of the use of genetic screening programs for immunological surveillance purposes (such as for HIV) and for possible DNA typing should not be underestimated. The authors present ten principles which seek to reaffirm the basic tenents of neonatal screening programs -- the benefit of newborns. These principles are both protective and yet open to the complex ethical and social considerations raised by such new uses of newborn genetic screening programs.

Coercion↗
PubMed2004

Development of an interactive computer-assisted instruction (ICAI) program for patient prenatal genetic screening and carrier testing for use in clinical settings.

Educating patients on prenatal genetic screening and carrier testing in a timely and effective manner is faced with barriers including, providers' limited knowledge, and little time available to spend discussing screening and testing during a visit. This paper describes the use of cognitive response interviews (CRI) and usability testing (UT) in the development of an interactive computer assisted instruction (ICAI) program for use by prenatal patients in clinical settings. Lessons learned during the program development process included simplification of content and adaptation of navigational features in response to observations and interviews of a sample of patients representing the intended population. The resulting program functions as a targeted patient education program that maintains the level of medical information needed, as specified by professional practices guidelines, in a patient friendly format. In addition, this ICAI program functions as a research tool that can collect data on program effectiveness. Researchers developing other patient education programs will benefit from the lessons learned during development of this ICAI program by considering rephrasing of content to fit patient understanding, and adding navigational features to help further facilitate effective program use.

Adult↗
PubMed2004

[Predictive genetic screening for type-1 diabetes in the Hungarian population].

INTRODUCTION: In the modern genetic era the principles of genetic screening are being changed. In addition to diagnostic screening for rare monogenic diseases, predictive screening for common polygenic conditions, like type 1 diabetes, will be more widely implemented. The majority of the genetic background of type 1 diabetes is encoded by the HLA DQ and DR genes, selected variants of which could be used as screening markers. However, risk conferred by various HLA genotypes shows considerable ethnic variation, therefore population-specific screening markers need to be established. AIMS: The aim of this study was to describe a screening strategy based on risk-defining HLA DRB1-DQA1-DQB1 markers to identify individuals at risk for type 1 diabetes in the Hungarian population. METHODS: HLA genotypes of 149 consecutively diagnosed children with type 1 diabetes (age at diagnosis 0-14, mean 8.8 +/- 4.2 years) and 177 randomly selected healthy schoolchildren were studied. Allele-specific polymerase chain reaction method was used for HLA typing. The diagnostic sensitivity, specificity and predictive value of diabetes associated DRB1-DQA1-DQB1 alleles were analysed in a step-wise strategy. RESULTS: The highest diagnostic sensitivity was detected when DQB1 typing was complemented by DQA1 typing on DQB1*0201 positive samples with additional DRB1*04 subtyping in DQB1*0302 carriers. The combination of the following markers gave a relative risk of 28.9 (95% confidence interval: 15.9-52.7, p = 10(-6): DQB1*0201/0302-DQA1*0301,0501-b (b not equal to DRB1* 0403), DQB1*0302/x-DRB1*0401,0402 (not equal to DQB1*0201, 0301,0602,0603), DQB1*0301/0302-DRB1*0401,0404, DQB1*0304/s (s = any DQB1 alleles), DQB1*0201/y-DQA1*0501/a (y not equal to DQB1*0301,0302,0602, 0603,0604, a not equal to DQA1*0201). The diagnostic sensitivity, specificity and positive predictive values for this marker combination were 79.2%, 88.7%, and 1.1%, respectively. CONCLUSIONS: Using HLA DRB1-DQA1-DQB1 markers predictive genetic screening for type 1 diabetes is feasible in the Hungarian population with high diagnostic sensitivity and specificity. At present, such a screening for individuals at risk for type 1 diabetes in the general population is recommended only as part of prospective studies on the natural history or prevention of disease. To increase the positive predictive value of the model, pancreas beta-cell autoantibodies need to be measured and followed in the high-risk cohort.

Adolescent↗
PubMed1997

Genetic screening: a comparative analysis of three recent reports.

Three recent reports on genetic screening published in the United Kingdom, Denmark and the Netherlands are discussed. Comparison of the Dutch report with the Danish and the Nuffield reports reveals that the Dutch report focuses on the aim of enlarging the scope for action, emphasising protection of autonomy and self-determination of the screenee more than the other two reports. The three reports have in common that the main concern is with concrete issue such as stigmatisation, discrimination, protection of the private sphere and issues linked with labour and insurance. Some potential long term consequences, however, tend to be neglected or underestimated. These omissions are pointed out.

Advisory Committees↗
PubMed2005

[Rapid genetic screening of Leber's hereditary optic neuropathy with mtDNA G11778A mutation by AS-PCR with whole blood].

OBJECTIVE: Rapid Genetic Screening of Leber's hereditary optic neuropathy (LHON) with mtDNA G11778A mutation by allele-specific polymerase chain reaction (AS-PCR) with whole blood. METHODS: Whole blood with anticoagulant was used as a template of AS-PCR for the analysis of LHON with mtDNA G11778A point mutation. The amplified DNA fragment was directly observed by electrophoretogram with ethidium bromide stained. RESULTS: The accuracy was 100% by using this method in 24 blood samples tested, and the specific of PCR of which used whole blood as template was better than one of the purified mtDNA. The reliability of the method for screening of LHON with mtDNA G11778A mutation was checked by double-blind test in 22 blood samples. CONCLUSION: This method does not need purified DNA from blood and only required one step of PCR. Thus, it is very simple, rapid and accurate for the clinical genetic screening of LHON with mtDNA G11778A point mutation.

DNA, Mitochondrial↗
PubMedDate not supplied

Balancing risks and benefits of deception in assessing genetic screening utilization.

OBJECTIVE: To advocate that research using intentional deception is sometimes appropriate. METHODS: A deception paradigm created to assess utilization of genetic screening for alcoholism susceptibility is reviewed in the context of competing ethical obligations and objections to the procedure. CONCLUSIONS: The paradigm is ethically defensible, it generates useful knowledge about future utilization of alcoholism screening by college students, and it exposes participants to no more than minimal risk. The use of deception to address questions related to predictive genetic screening will require investigators to balance protection of participants with the need to advance knowledge.

Alcoholism↗
PubMed1985

Epidemiologic evaluation of screening for risk factors: application to genetic screening.

To assess the usefulness of screening for risk factors, we derived arithmetic relationships between screening parameters (sensitivity, specificity, and positive predictive value PPV) and risk factor frequency, disease frequency and relative risk. We evaluated these relationships in the special case of genetic markers and disease susceptibility. It can be shown that even in the face of very large relative risks, sensitivity and positive predictive value are affected by the relative magnitude of disease and genetic marker frequencies. When the genetic marker is less frequent than the disease, PPV increases with increasing relative risk but sensitivity remains low. When the genetic marker is more frequent than the disease, sensitivity increases with increasing relative risk but PPV remains low. When marker and disease frequencies are equal, both PPV and sensitivity increase with increasing relative risks, but very high relative risks (greater than 100) have to be obtained for rare diseases. Depending on the goals of the screening program, these relationships can be used to predict the relative magnitudes of false positives (low PPV) and false negatives (low sensitivity). This approach can be generalized to evaluate nongenetic risk factors in screening programs as well.

Epidemiologic Methods↗
PubMed2000

Genetic screens in mammalian cells by enhanced retroviral mutagens.

Genetic approaches such as retrovirus-mediated mutagenesis and cDNA expression libraries have contributed greatly to our understanding of signal transduction in mammalian cells. However, previously described methods for retroviral insertional mutagenesis are hindered by low mutagenesis rates and difficulties in cloning mutated genes. cDNA expression library methods are usually cell-type dependent and bias towards abundant and short messages. With the near completion of the genome projects, alternative genetic methods are needed where large numbers of genes can be more easily isolated and biochemically studied. We have developed a novel retrovirus-mediated genetic screening method in cultured cells. To achieve efficient and regulated mutagenesis, we constructed Enhanced Retroviral Mutagen (ERM) vectors that contained several engineered sequences (e.g., an ERM Tag and a splice donor) controlled by a tetracycline-responsive promoter. Endogenous genes can thus be randomly activated and tagged in a conditional system. NIH3T3 cells were used to screen for focus-forming genes using the ERM strategy. We showed that these added sequences increased the screening efficiency by >10-fold, and allowed more direct identification of the genes targeted. Sequence analysis of approximately 10% of the >600 focus clones recovered revealed both known oncogenes and novel factors such as protein kinases and GTP/GDP exchange proteins. The ERM strategy should help to facilitate large-scale gene identification in diverse pathways and integrate both genetic (with the completion of the genome projects) and functional information more readily.

3T3 Cells↗
PubMedDate not supplied

Preimplantation genetic screening and human implantation.

In recent years, preimplantation genetic screening (PGS) has been used and recommended to increase the implantation rate in older women or in couples with previous assisted reproduction (ART) failures, to try to increase pregnancy rates in couples with recurrent abortions, to prevent the transmission of chromosome anomalies to the offspring of carriers of balanced chromosomal rearrangements, or even to try to decrease the incidence of trisomic births in older women. So far, PGS has contributed to increase the implantation rate in older women; however, the rate of clinical pregnancies has not increased, either in older women or in couples with previous ART failures. In couples with recurrent abortions, the pregnancy rate seems to increase, but only when the woman is young (< or =35). In carriers of balanced reorganizations, the prognosis is poor. Attempts to decrease the birth of trisomic children to older women are difficult to evaluate. This absence of relevant results is not related to the technique itself, which is quite safe, but to other still largely unknown factors.

Abortion, Habitual↗
PubMed1999

Rapid genetic screening for hemochromatosis using automated SSCP-based capillary electrophoresis (SSCP-CE).

Hereditary hemochromatosis (HHC) represents an autosomal recessive disease in which increased iron absorption causes iron overload and irreversible tissue damage. The recently detected association between two point mutations in the HFE gene on chromosome 6p and HHC has made it possible to screen for the disease before the onset of irreversible tissue damage. Conventional genetic testing is based on restriction fragment-length polymorphisms (RFLP) using two endonuclease recognition sites in codon 63 or 282, respectively. In this study, we have adapted single-strand conformation polymorphism analysis for capillary electrophoresis (SSCP-CE) to detect homozygote or heterozygote point mutations. Two HFE gene fragments spanning codons 63 and 282 were amplified by a duplex PCR using genomic DNA from peripheral blood or from tissue sections of paraffin-embedded liver biopsies as template. Thereby, rapid genotyping of both HFE mutations was achieved with a single PCR, omitting the need of further analysis by restriction digest. Eighty-five patients with liver disease and/or suspected iron overload were genotyped using SSCP-CE, and all results were verified by conventional RFLP analysis. In summary, SSCP-CE proved to be a reliable, cost-effective, sensitive and rapid method for genotyping HFE mutations. This method will further facilitate high-throughput genetic screening using capillary array electrophoretic devices.

Adult↗
PubMed2006

A chemical genetic screen for cell cycle inhibitors in zebrafish embryos.

Chemical genetic screening is an effective strategy to identify compounds that alter a specific biological phenotype. As a complement to cell line screens, multicellular organism screens may reveal additional compounds. The zebrafish embryo is ideal for small molecule studies because of its small size and the ease of waterborne treatment. We first examined a broad range of known cell cycle compounds in embryos using the mitotic marker phospho-histone H3. The majority of the known compounds exhibited the predicted cell cycle effect in embryos. To determine whether we could identify novel compounds, we screened a 16 320-compound library for alterations of pH3. This screen revealed 14 compounds that had not been previously identified as having cell cycle activity despite numerous mitotic screens of the same library with mammalian cell lines. With six of the novel compounds, sensitivity was greater in embryos than cell lines, but activity was still detected in cell lines at higher doses. One compound had activity in zebrafish embryos and cell lines but not in mammalian cell lines. The remaining compounds exhibited activity only in embryos. These findings demonstrate that small molecule screens in zebrafish can identify compounds with novel activity and thus may be useful tools for chemical genetics and drug discovery.

Animals↗
PubMed1998

Surgical decision-making affected by clinical and genetic screening of a novel kindred with von Hippel-Lindau disease and pancreatic islet cell tumors.

OBJECTIVE: We report a unique, previously undescribed multigeneration kindred with von Hippel-Lindau (VHL) disease in whom clinical or genetic screening led to the detection of surgically resectable neoplastic disease in several family members. SUMMARY BACKGROUND DATA: Patients with VHL disease have a propensity to develop neoplasms of several different organ sites. Retinal angiomas, cerebellar and spinal hemangioblastomas, solid organ cysts, and renal carcinoma are common lesions; pheochromocytomas and pancreatic islet cell tumors occur less frequently but are important causes of morbidity and mortality. METHODS: A detailed pedigree was constructed based on clinical screening and family history that describes the development of pancreatic islet cell tumors in four of five female siblings. VHL mutation analysis was performed in an attempt to determine if genotype-phenotype correlations could be made in this interesting family. RESULTS: The age of onset of VHL-associated neoplasms for three affected siblings was in the third decade of life and in the fourth decade for the fourth sibling. The mother of the four siblings affected with pancreatic tumors developed bilateral pheochromocytomas in the seventh decade of life; she has no pancreatic or kidney tumors. We identified maternal transmission of a missense mutation in codon 238 in exon 3 of the VHL gene in the four affected siblings with pancreatic islet cell tumors. Mutation screening on unaffected family members showed no abnormalities in the VHL gene. Interestingly, one of the four affected siblings had no evidence of VHL on her initial clinical screening evaluation; however, she was followed closely because of her mutated VHL gene. Four years after initial screening, she developed two pancreatic islet cell tumors and a premalignant renal cyst. CONCLUSIONS: Clinical and genetic screening for VHL in this family had a significant impact on surgical management by detecting early-stage islet cell tumors or pheochromocytomas. Furthermore, we conclude that the preponderance of pancreatic islet cell tumors in this family cannot be explained by a strict genotype-phenotype correlation. This suggests that additional genetic abnormalities, possibly on chromosome 3p where the VHL gene is located, may be responsible for the variety of VHL-associated neoplasms.

Adenoma, Islet Cell↗
PubMed1994

Perspectives in genetic screening. Principles and implications.

Recent advances in genetic identification and characterization of a number or hereditary disorders have led to increased possibilities for genetic testing and screening. The context and methods of screening are important given that identification of otherwise healthy persons as being presymptomatic or at increased risk for genetic diseases may have serious consequences for their future lifestyle, employment, and insurability. This article examines general principles for genetic screening, including goals, delivery issues, and professional and lay responses to screening and counseling, and recommends areas in which social psychological research on screening is needed.

Cost-Benefit Analysis↗
PubMed1998

[Attitude to genetic screening for familial hypercholesterolemia].

Familial hypercholesterolemia causes premature cardiovascular disease. Genetic screening of patients' relatives who have already been diagnosed has proved to be more efficient than screening in a general population. Privacy laws in Norway forbid physicians to directly contact persons with genetic disorders who are not their own patients. We examined attitudes towards this type of screening in a representative sample of the Norwegian population and a group of patients with familial hypercholesterolaemia. In both groups the majority showed a positive attitude towards physicians contacting relatives directly to detect individuals with familial hypercholesterolaemia. In both groups the majority wanted to know whether, based on the diagnosis of relatives, they might also be affected. Both groups wanted this information regardless of the risk of their being affected. We conclude that the privacy laws should be amended to conform with the attitudes of the population and the patients, thus enabling physicians to contact relatives directly.

Attitude to Health↗
PubMed1996

Genetic screening in hereditary multiple endocrine neoplasia type 1: absence of a founder effect among Japanese families.

Ten Japanese families with hereditary multiple endocrine neoplasia type 1 (MEN1) were examined. Five DNA polymorphic markers on the long arm of chromosome 11 were analyzed for genetic screening of MEN1 in members of affected families, and disease carriers were identified before clinical manifestations. Unlike MEN1 families in Newfoundland or in Tasmania, no consistent haplotypes were segregated with the disease in the Japanese families when defined by 5 nearby markers. The identification of asymptomatic disease carriers is of substantial clinical importance for early management, genetic counseling and to avoid unnecessary screening for non-disease carriers. However, genetic screening of family members by polymorphic markers could be useful only to each family, and no generally applicable markers were found for Japanese subjects with MEN1.

Adult↗
PubMed1983

Necessity of formal genetic screening in artificial insemination by donor.

After observing abnormal offspring following artificial insemination by donor, several authors recently have proposed intensive genetic screening of donors. The screening would be beyond that practiced by most infertility specialists. To determine the necessity for formal genetic investigation of donors, the authors analyzed the outcome of artificial insemination pregnancies in which donors were screened with careful medical and family histories, but were not subjected to formal pedigree analysis, karyotyping, or extensive metabolic screening. Fewer than 10% of potential donors were disqualified for genetic reasons. The study, limited to ascertaining the presence or absence of overt anomalies evident at birth, showed that such malformations were not more frequent in artificial insemination pregnancies (1.7%) than in controls (2.3%). It is concluded that extensive and formalized genetic screening is probably not necessary provided a thorough medical history is obtained. In addition, a practical approach to identifying donors at increased risk for siring abnormal offspring is offered.

Adult↗