National Cancer Institute®
Last Modified: September 1, 2002
UI - 12161610
AU - De Baere E; Lemercier B; Christin-Maitre S; Durval D; Messiaen L;
TI - Fellous M; Veitia R FOXL2 mutation screening in a large panel of POF patients and XX males.
SO - J Med Genet 2002 Aug;39(8):e43
UI - 11876475
AU - Powell SM
TI - Direct analysis for familial adenomatous polyposis mutations.
SO - Mol Biotechnol 2002 Feb;20(2):197-207
AD - Division of Gastroenterology, University of Virginia Health System, Charlottesville 22908, USA. firstname.lastname@example.org
The spectrum of disease causing mutations is immense. It just so happens that the overwhelming majority of genetic alterations in the APC gene with leads to adenomatous polyposis coli generate truncated gene products. This observation lead to the development of the in vitro synthesis protein assay (protein truncation test) which is a sensitive method to detect these truncated gene products from patient samples. This article describes the assay to detect truncated proteins for the APC gene, which can also be applied to other disease causing genetic alterations which commonly lead to truncations such in HNPCC, von Hippel-Lindau, osteogenesis imperfecta, retinoblastoma, BCRAI, beta-thalassemia, hemophilia B, Duchenene and Becker muscular dystrophy.
UI - 11881908
AU - Isaacs C; Peshkin BN; Schwartz M; Demarco TA; Main D; Lerman C
TI - Breast and ovarian cancer screening practices in healthy women with a strong family history of breast or ovarian cancer.
SO - Breast Cancer Res Treat 2002 Jan;71(2):103-12
AD - Department of Medical Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20007-2197, USA. email@example.com
Studies in women with a family history of cancer demonstrate a wide variability in the uptake of cancer screening measures. Little data exist regarding the breast and ovarian cancer screening practices of women who are members of hereditary breast cancer families. In order to address this issue, we examined the screening behaviors and the determinants of screening in a clinic based group of 216 women with a strong family history of breast or ovarian cancer who were participating in a free genetic counseling and testing research program. At baseline, prior to obtaining genetic counseling or testing, 50% of women ages 30-39, 83% of those age 40-49, 69% of those 50-64, and 53% of those >65 reported having a mammogram in the prior year. Adherence to mammography recommendations was correlated with age, number of relatives with breast cancer, and income. Twenty percent of participants had at least one CA- 125 performed and 31 % had ever obtained a screening ultrasound. Having at least one relative with ovarian cancer was very strongly associated with ovarian cancer screening [OR = 12.3, 95% CI = 4.6-33 for CA-125; OR=4.9, 95% CI=2.4, 10.1 for ultrasound]. No association between cancer worries/distress and either breast or ovarian cancer screening was found. In conclusion, the breast and ovarian screening uptake in healthy women from hereditary breast cancer families is suboptimal, even for women over age 50, for whom annual mammography is clearly indicated. These findings indicate a need for better education about screening guidelines for high-risk women.
UI - 11890312
AU - Satagopan JM; Verbel DA; Venkatraman ES; Offit KE; Begg CB
TI - Two-stage designs for gene-disease association studies.
SO - Biometrics 2002 Mar;58(1):163-70
AD - Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. firstname.lastname@example.org
The goal of this article is to describe a two-stage design that maximizes the power to detect gene-disease associations when the principal design constraint is the total cost, represented by the total number of gene evaluations rather than the total number of individuals. In the first stage, all genes of interest are evaluated on a subset of individuals. The most promising genes are then evaluated on additional subjects in the second stage. This will eliminate wastage of resources on genes unlikely to be associated with disease based on the results of the first stage. We consider the case where the genes are correlated and the case where the genes are independent. Using simulation results, it is shown that, as a general guideline when the genes are independent or when the correlation is small, utilizing 75% of the resources in stage 1 to screen all the markers and evaluating the most promising 10% of the markers with the remaining resources provides near-optimal power for a broad range of parametric configurations. This translates to screening all the markers on approximately one quarter of the required sample size in stage 1.
UI - 11961686
AU - Vehmas S
TI - Is it wrong to deliberately conceive or give birth to a child with mental retardation?
SO - J Med Philos 2002 Feb;27(1):47-63
AD - University of Jyvaskyla, Finland. email@example.com
This paper discusses the issues of deciding to have a child with mental retardation, and of terminating a pregnancy when the future child is known to have the same disability. I discuss these problems by criticizing a utilitarian argument, namely, that one should act in a way that results in less suffering and less limited opportunity in the world. My argument is that future parents ought to assume a strong responsibility towards the well-being of their prospective children when they decide to reproduce. The moral point in cases in which our acts affect the well-being of future children should be expressed strictly in terms of parents' culpability. Future children thus do not have current moral standing but presently living persons have current obligations to consider the presumable effects of their actions on future people. I will also argue that there are morally significant differences between 'selective contraception' and selective abortion.
UI - 12114481
AU - Nichols WC; Pankratz N; Uniacke SK; Pauciulo MW; Halter C; Rudolph A;
TI - Conneally PM; Foroud T Linkage stratification and mutation analysis at the Parkin locus identifies mutation positive Parkinson's disease families.
SO - J Med Genet 2002 Jul;39(7):489-92
AD - Division of Human Genetics, Children's Hospital Medical Center, Cincinnati, OH, USA. firstname.lastname@example.org
UI - 12114482
AU - Splendore A; Jabs EW; Passos-Bueno MR
TI - Screening of TCOF1 in patients from different populations: confirmation of mutational hot spots and identification of a novel missense mutation that suggests an important functional domain in the protein treacle.
SO - J Med Genet 2002 Jul;39(7):493-5
UI - 12114489
AU - MacDonald DJ; Choi J; Ferrell B; Sand S; McCaffrey S; Blazer KR; Grant
TI - M; Weitzel JN Concerns of women presenting to a comprehensive cancer centre for genetic cancer risk assessment.
SO - J Med Genet 2002 Jul;39(7):526-30
UI - 12114490
AU - McAllister M; O'Malley K; Hopwood P; Kerr B; Howell A; Evans DG
TI - Management of women with a family history of breast cancer in the North West Region of England: training for implementing a vision of the future.
SO - J Med Genet 2002 Jul;39(7):531-5
UI - 12147820
AU - Friedenberg RM
TI - Genetic testing.
SO - Radiology 2002 Aug;224(2):316-9
AD - Department of Radiological Sciences, University of California, Irvine Medical Center, Orange, USA. email@example.com
UI - 11911650
AU - Angelastro JM; Ryu EJ; Torocsik B; Fiske BK; Greene LA
TI - Blue-white selection step enhances the yield of SAGE concatemers.
SO - Biotechniques 2002 Mar;32(3):484, 486
AD - Department of Pathology, Columbia University, College of Physicians and Surgeons, Center for Neurobiology and Behavior, New York, NY 10032, USA. firstname.lastname@example.org
UI - 10380820
AU - Hansson MG
TI - Ethical management of hereditary cancer information.
SO - Acta Oncol 1999;38(3):305-8
AD - Department of Public Health and Caring Sciences, Academic Hospital, Uppsala, Sweden.
Genetic diagnosis yields information that is highly relevant for both the patient and the genetic relatives of the patient. In this article two ethical problems are discussed. Under what conditions should hereditary cancer information be given to a relative? It is suggested that in order to answer this question, three factors have to be considered and a balance struck: the seriousness of the condition, the existence of treatment or prevention and the reliability of the diagnosis. The second issue discussed in the article relates to the psychosocial effects of giving hereditary cancer information. It is argued that ethical management of clinical practice requires that further attention must be given to the psychosocial effects on both the individual and the family.
UI - 12167832
AU - Williamson R; Duncan R
TI - DNA testing for all.
SO - Nature 2002 Aug 8;418(6898):585-6
AD - Murdoch Children's Research Institute, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia. email@example.com
UI - 11764096
AU - Tzetis M; Kanavakis E; Tsezou A; Ladis V; Pateraki E; Georgakopoulou T;
TI - Kavazarakis E; Maragoudaki E; Karpathios T; Kitsiou-Tzeli S Gilbert syndrome associated with beta-thalassemia.
SO - Pediatr Hematol Oncol 2001 Dec;18(8):477-84
AD - Medical Genetics, University of Athens, Aghia Sophia Children's Hospital, Greece.
The authors investigated whether the considerable variability in serum bilirubin levels (STB) found in transfusion-dependent beta-thalassemia, beta-thal intermedia, and heterozygous beta-thalassemia individuals could be related to the coexistence of Gilbert syndrome (GS). The promoter region [A(TA)nTAA] of the bilirubin UDP-glucuronosyltransferase gene (UGT1A1) was analyzed in a total of 128 beta-thalassemia individuals (108 transfusion-dependent beta-thal patients, 20 very mild beta-thal intermedia) and in 33 beta-thal heterozygotes. The control group consisted of 70 healthy children with no history of anemia. The frequency of GS genotype (TA)7/(TA)7 did not differ significantly between the groups studied. A significant difference was observed between serum bilirubin levels (STB) and GS genotypes (TA)7/(TA)7 and (TA)6/(TA)7 and also between (TA)7/(TA)7 and (TA)6/(TA)6 for all groups examined. These results confirm that the (TA)7/(TA)7 GS genotype is one of the factors accounting for the hyperbilirubinemia observed in beta-thalassemia major, intermedia, and heterozygous individuals.
UI - 11809257
AU - Ahr A; Karn T; Solbach C; Seiter T; Strebhardt K; Holtrich U; Kaufmann M
TI - Identification of high risk breast-cancer patients by gene expression profiling.
SO - Lancet 2002 Jan 12;359(9301):131-2
We previously used DNA array analyses in the molecular profiling of breast cancers. By cluster analysis of 55 patients, we identified a subpopulation of breast cancers-designated class A-that contained a high number of nodal-positive tumours and that had frequently developed distant metastases at the time of diagnosis. We have now analysed follow-up data from these patients. We found that, despite a median of only 23.5 months of follow-up, 11 of 22 patients in class A progressed to metastatic disease, and three of five patients classified as having a nodal status of N0 in this subpopulation developed distant metastases. Our analysis identifies breast-cancer patients with a high risk of disease recurrence, and could act as a first step towards improved patient-adapted therapy.
UI - 9415688
AU - Benkendorf JL; Reutenauer JE; Hughes CA; Eads N; Willison J; Powers M;
TI - Lerman C Patients' attitudes about autonomy and confidentiality in genetic testing for breast-ovarian cancer susceptibility.
SO - Am J Med Genet 1997 Dec 19;73(3):296-303
AD - Department of Obstetrics and Gynecology, Georgetown University Medical Center, Washington, DC 20007, USA.
The identification of BRCA1 and BRCA2, two breast-ovarian cancer susceptibility genes, has brought many ethical and social issues to the forefront. This paper presents the results of a survey assessing the attitudes of 238 unaffected first-degree relatives of women with breast or ovarian cancer regarding the ethical issues of autonomy and confidentiality as they relate to BRCA1/2 testing. Baseline knowledge about BRCA1/2 and ethnic and psychosocial characteristics of our study population were examined to determine their association with women's attitudes. The majority of women (86-87%) felt that health care providers should not disclose the results of genetic tests for breast-ovarian cancer susceptibility to insurance companies or employers without written consent; however, only 56-57% felt that written consent should be required for a spouse or immediate family to receive this information. Ninety-eight percent of the women surveyed agreed that genetic testing for breast-ovarian cancer risk should be voluntary. Likewise, most women (95%) agreed that a person should be able to have genetic testing against a doctor's recommendation and 88% of the women surveyed agreed that parents should be able to consent to genetic susceptibility testing on behalf of their minor children. African American women were less concerned than Caucasian women about the protection of confidentiality in families, they were more likely to agree that an individual should still have access to testing when their physicians recommended against it, and they were more supportive of parents' rights to consent to genetic predisposition testing on behalf of their minor children. Women with coping styles characterized by higher optimism were more likely to favor access to genetic testing when a physician recommended against it, and to support parents' rights to consent to testing of their minor children. Therefore, the setting and manner in which genetic counseling and testing are delivered must be appropriately tailored to reflect these attitudinal differences and preferences.
UI - 10815363
AU - Schoonmaker MM; Bernhardt BA; Holtzman NA
TI - Factors influencing health insurers' decisions to cover new genetic technologies.
SO - Int J Technol Assess Health Care 2000 Winter;16(1):178-89
AD - Johns Hopkins Medical Institutions, USA.
OBJECTIVE: To examine the relative importance of factors influencing health insurers' coverage of new genetic technologies. METHODS: A national survey in which the decision makers for private health insurers were asked whether they would cover cystic fibrosis (CF) carrier screening, testing for genetic susceptibility to breast cancer (BRCA test), and medical costs of a clinical trial of gene therapy for CF under a variety of conditions. RESULTS: Respondents' coverage of the two tests and of medical costs of clinical trials was low at the time of the study (4%-15.5% of insurers). Their coverage of CF carrier screening and BRCA testing would be increased significantly if the group tested was restricted to those at high risk, if detection rates were higher and costs lower, and if testing was endorsed by a national professional group or consensus conference. Coverage of the medical costs of a trial of CF gene therapy would be significantly more likely if the trial was restricted to children or adults with severe CF, safety and effectiveness was proven, and therapy could be administered in a regional hospital or an outpatient setting rather than in a research hospital. CONCLUSIONS: Health insurers play a critical role in the diffusion of new genetic technologies. The validity of genetic tests and the safety and effectiveness of new therapies are primary factors influencing health insurers' coverage. Lower costs and approval of professional groups are other factors associated with increased coverage.
UI - 12082905
AU - Boylan M
TI - Genetic testing.
SO - Camb Q Healthc Ethics 2002 Summer;11(3):246-56
AD - Marymount University, USA.
UI - 11300730
AU - Johansson C; Smedh C; Partonen T; Pekkarinen P; Paunio T; Ekholm J;
TI - Peltonen L; Lichtermann D; Palmgren J; Adolfsson R; Schalling M Seasonal affective disorder and serotonin-related polymorphisms.
SO - Neurobiol Dis 2001 Apr;8(2):351-7
AD - Neurogenetics Unit, Karolinska Institutet and Karolinska Hospital, Stockholm, S-171 76, Sweden. firstname.lastname@example.org
Disturbances in central serotonergic systems have been hypothesized to be involved in seasonal affective disorder (SAD). Association between SAD and the shorter allele of the serotonin transporter promoter repeat length polymorphism (5-HTTLPR) has been reported in an American sample. We have genotyped 82 SAD patients and 82 healthy controls from Sweden, Finland, and Germany for this and five other polymorphisms in the genes coding for serotonin receptors 5-HT2A and 5-HT2C, tryptophan hydroxylase and white. No associations with SAD or seasonality (seasonal variations in mood and behavior) were detected. Although minor effects cannot be excluded, our results suggest that these polymorphisms do not play a major role in the pathogenesis of SAD in the northern European population. Copyright 2001 Academic Press.
UI - 12212516
AU - Conte-Devolx B; Niccoli-Sire P; Groupe d'Etude des Tumeurs a Calcitonine
TI - [Polyadenomatoses: type 2 multiple endocrine neoplasms]
SO - Presse Med 2002 Aug 10;31(26):1224-30
AD - Service d'Endocrinologie-Maladies Metaboliques, Hopital de la Timone 13385 Marseille. email@example.com
FROM A CLINICAL POINT OF VIEW: Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant, inherited multiglandular disease with familial and individual age-related penetration and variable expression. A medullary thyroid carcinoma (MTC) is always concomitant to MEN2 and associated in varying proportion with pheochromocytoma (50%) and hyperparathyroidism (5 to 20%). PROGNOSTIC DATA: The prognosis of MEN2 is related to the carcinological evolution of MTC, which depends mainly on the stage of discovery and the quality of the first surgical treatment, emphasizing the need for early diagnosis. THE IMPORTANCE OF THE ERT GENE: The identification of mutations in proto-oncogene RET, responsible for the various forms of the disease allows subjects at risk in a family circle to be identified and early screening of various endocrine damage, notably MTC, should be performed. Biological explorations in all persons carrying this mutation would permit diagnosis and surgical treatment of the endocrine lesions, before their clinical manifestation.
UI - 12109281
AU - Borelli S
TI - [Skin manifestations of diseases of the gastrointestinal tract]
SO - Schweiz Rundsch Med Prax 2002 Jun 5;91(23):1029-36
AD - Abteilung Dermatologie, Kantonsspital Aarau. firstname.lastname@example.org
Diseases of the gut frequently show skin symptoms. These can give first and important clues in regard to diagnosis. In general the etiology can be divided into genetic disorders, chronic inflammation, drug reaction, infectious diseases or related to malignancy. In genetic disorders increasing knowledge about the involved genes is available, allowing prenatal diagnosis and screening of clinically not affected family members. Especially in cancer prone syndromes early diagnosis and preventive treatment is crucial. Inflammatory bowel diseases show a high prevalence, therefore necessitating the knowledge of skin complications such as pyoderma gangrenosum, Sweet syndrome and erythema nodosum. Gastrointestinal malignancies may metastasize into the skin or may produce typical paraneoplastic changes.
UI - 12188452
AU - Sangwatanaroj S; Yanatasneejit P; Sunsaneewitayakul B; Sitthisook S
TI - Linkage analyses and SCN5A mutations screening in five sudden unexplained death syndrome (Lai-tai) families.
SO - J Med Assoc Thai 2002 Jun;85 Suppl 1():S54-61
AD - Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Sudden Unexplained Death Syndrome (SUDS) (or in Thai Lai-tai) share the same ECG pattern as Brugada Syndrome: RSR' and ST segment elevation in V1 to V3. Brugada Syndrome is a genetic disorder with the inheritance pattern of autosomal dominant (using the ECG pattern and unexplained sudden death as phenotype) and the cardiac sodium channel gene (SCN5A) mutations caused this syndrome. To determine whether SUDS was associated with the same mutations as Brugada Syndrome, the authors performed a linkage studies on 5 SUDS families with the Brugada Syndrome ECG pattern and found one family could not be excluded from linkage to SCN5A. However, the direct sequencing in 8 reported mutations on exon 5, 12, 17, 18 and 28 in this family failed to demonstrate the mutations. It was concluded that SUDS mutations maybe a novel mutation different from previously reported mutations, further genetic studies in SCN5A and other candidate genes might elucidate the molecular basis of SUDS.
UI - 12192099
AU - Miturski R; Bogusiewicz M; Ciotta C; Bignami M; Gogacz M; Burnouf D
TI - Mismatch repair genes and microsatellite instability as molecular markers for gynecological cancer detection.
SO - Exp Biol Med (Maywood) 2002 Sep;227(8):579-86
AD - Second Department of Gynecological Surgery, University School of Medicine, Lublin, Poland. email@example.com
Due to major developments in genetics over the past decade, molecular biology tests are serving promising tools in early diagnosis and follow-up of cancer patients. Recent epidemiological studies revealed that the risk for each individual to develop cancer is closely linked to his/her own genetic potentialities. Some populations that are defective in DNA repair processes, for example in Xeroderma pigmentosum or in the Lynch syndrome, are particularly prone to cancer due to the accumulation of mutations within the genome. Such populations would benefit from the development of tests aimed at identifying people who are particularly at risk. Here, we review some data suggesting that the inactivation of mismatch repair is often found in endometrial cancer and we discuss molecular-based strategies that would help to identify the affected individuals in families with cases of glandular malignancies.
UI - 10205265
AU - Wirth B; Herz M; Wetter A; Moskau S; Hahnen E; Rudnik-Schoneborn S;
TI - Wienker T; Zerres K Quantitative analysis of survival motor neuron copies: identification of subtle SMN1 mutations in patients with spinal muscular atrophy, genotype-phenotype correlation, and implications for genetic counseling.
SO - Am J Hum Genet 1999 May;64(5):1340-56
AD - Institute of Human Genetics, Wilhelmstrasse 31, D-53111 Bonn, Germany. firstname.lastname@example.org
Problems with diagnosis and genetic counseling occur for patients with autosomal recessive proximal spinal muscular atrophy (SMA) who do not show the most common mutation: homozygous absence of at least exon 7 of the telomeric survival motor neuron gene (SMN1). Here we present molecular genetic data for 42 independent nondeleted SMA patients. A nonradioactive quantitative PCR test showed one SMN1 copy in 19 patients (45%). By sequencing cloned reverse-transcription (RT) PCR products or genomic fragments of SMN1, we identified nine different mutations in 18 of the 19 patients, six described for the first time: three missense mutations (Y272C, T274I, S262I), three frameshift mutations in exons 2a, 2b, and 4 (124insT, 241-242ins4, 591delA), one nonsense mutation in exon 1 (Q15X), one Alu-mediated deletion from intron 4 to intron 6, and one donor splice site mutation in intron 7 (c.922+6T-->G). The most frequent mutation, Y272C, was found in 6 (33%) of 18 patients. Each intragenic mutation found in at least two patients occurred on the same haplotype background, indicating founder mutations. Genotype-phenotype correlation allowed inference of the effect of each mutation on the function of the SMN1 protein and the role of the SMN2 copy number in modulating the SMA phenotype. In 14 of 23 SMA patients with two SMN1 copies, at least one intact SMN1 copy was sequenced, which excludes a 5q-SMA and suggests the existence of further gene(s) responsible for approximately 4%-5% of phenotypes indistinguishable from SMA. We determined the validity of the test, and we discuss its practical implications and limitations.
UI - 11546830
AU - Liu T; Chen J; Salahshor S; Kuismanen S; Holmberg E; Gronberg H;
TI - Peltomaki P; Lindblom A Screening families with endometrial and colorectal cancers for germline mutations.
SO - J Med Genet 2001 Sep;38(9):E29
UI - 12187189
AU - Bratt O
TI - Hereditary prostate cancer: clinical aspects.
SO - J Urol 2002 Sep;168(3):906-13
AD - Unit for Urology, Helsingborg Hospital, Sweden.
PURPOSE: We review the current epidemiological and genetic knowledge regarding hereditary prostate cancer, and outline its clinical implications. MATERIALS AND METHODS: Published articles on hereditary prostate cancer were identified using the MEDLINE data base. RESULTS: A risk of prostate cancer, particularly early onset disease, is strongly affected by family history (number of relatives with prostate cancer and their age at diagnosis). A family history of prostate cancer increases the positive predictive value of prostate specific antigen testing and, hence, heredity should always be assessed when deciding whether to perform biopsies in a man with a prostate specific antigen level of 3 to 10 ng./ml. Epidemiological studies indicate that dominantly inherited susceptibility genes with high penetrance cause 5% to 10% of all prostate cancer cases, and as much as 30% to 40% of early onset disease. More than a half dozen chromosome loci that may comprise such genes have of major importance had been cloned. Most likely, environmental factors and comparatively common variants of several other genes affect prostate cancer risk in families with or without multiple cases of the disease. On average, hereditary prostate cancer is diagnosed 6 to 7 years earlier than sporadic prostate cancer, but does not otherwise differ clinically from the sporadic form. As a consequence of the earlier onset, a greater proportion of men with hereditary prostate cancer die of the disease than those with nonhereditary prostate cancer. At present, the only clinically applicable measure to reduce prostate cancer mortality in families with hereditary disease is screening, with the aim of diagnosing the disease when it is still in a curable stage. CONCLUSIONS: Hereditary susceptibility is now considered the strongest risk factor for prostate cancer and has profound clinical importance. The genetic mechanism behind such susceptibility has turned out to be more complex than initially thought, and will probably not be completely understood for many years to come.
UI - 11325775
AU - Evans JP; Skrzynia C; Burke W
TI - The complexities of predictive genetic testing.
SO - BMJ 2001 Apr 28;322(7293):1052-6
AD - Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. email@example.com
UI - 11983341
AU - Bonk T; Humeny A; Sutter C; Gebert J; von Knebel Doeberitz M; Becker CM
TI - Molecular diagnosis of familial adenomatous polyposis (FAP): genotyping of adenomatous polyposis coli (APC) alleles by MALDI-TOF mass spectrometry.
SO - Clin Biochem 2002 Mar;35(2):87-92
AD - Institut fur Biochemie, Emil-Fischer-Zentrum, Universitat Erlangen-Nurnberg, Fahrstrasse 17 D-91054, Erlangen, Germany.
OBJECTIVES: Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited colorectal cancer predisposition syndrome caused by germ line mutations in the adenomatous polyposis coli gene (APC). For prophylactic colectomy, timely identification of patients at risk is urgent. Here, matrix assisted laser desorption ionization - time of flight - mass spectrometry (MALDI-TOF-MS) genotyping is offered for an efficient molecular diagnosis of APC germline mutations. DESIGN AND METHODS: The four most frequent APC germ line mutations (three deletions, one point mutation) were genotyped by allele specific elongation and termination of extension primers. The extension products generated were analyzed by MALDI-TOF-MS. RESULTS: Following PCR amplification and allele specific primer extension reactions MALDI-TOF-MS allowed the unambiguous identification of informative nucleic acid fragments corresponding to distinct genotypes or mutants even in duplex assays. Results were confirmed by DNA-sequencing. CONCLUSIONS: Due to its high molecular resolution and accuracy, this method is highly suitable as an alternative for clinical APC genotyping.
UI - 12111297
AU - Kobayashi T; Mori H; Okuma Y; Dickson DW; Cookson N; Tsuboi Y; Motoi Y;
TI - Tanaka R; Miyashita N; Anno M; Narabayashi H; Mizuno Y Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome 17.
SO - J Neurol 2002 Jun;249(6):669-75
AD - Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. firstname.lastname@example.org
Association between clinical characteristics and types of the tau gene mutation has been observed in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). P301L mutation seldom causes parkinsonism as a leading symptom; instead it usually causes personality changes with aggressiveness and disinhibition. We experienced two patients of FTDP-17 from separate families (designated as patient 1 from family 1 and patient 2 from family 2). They had P301L mutation in common. However, their phenotypes were distinct from each other. Aggressive behaviors and disinhibition were the main symptoms in patient 1, whereas parkinsonism was the most prominent feature in patient 2. Their genotypes of the tau gene were different at three sites, i. e. in exon 6, in intron segment before exon 10, and in exon 13, though they do not bring amino acid change. Patient 1 had more prevalent C/C, C/C, and rare T/C respectively. Patient 2 had less prevalent T/T, A/A, and more prevalent T/T respectively. These findings suggest two things. Firstly, they do not share a common founder for P301L mutation. Secondly, either of the two less prevalent genotypes observed in patient 2 may be the factor to modify the phenotype of P301L mutation into those unusual clinical features with prominent parkinsonism. Accumulation of information as to phenotype-genotype association will settle this hypothesis.
UI - 12196647
AU - de Jong BA; Huizinga TW; Zanelli E; Giphart MJ; Bollen EL; Uitdehaag BM;
TI - Polman CH; Westendorp RG Evidence for additional genetic risk indicators of relapse-onset MS within the HLA region.
SO - Neurology 2002 Aug 27;59(4):549-55
AD - Department of Clinical Epidemiology, LUMC, Leiden, The Netherlands.
BACKGROUND: Human leukocyte antigen (HLA)-DR2 carriership is associated with an increased risk for MS. Genome searches using microsatellite markers have consistently shown that additional genetic factors contribute to susceptibility for MS. OBJECTIVE: To identify loci within the HLA region that predispose to relapse-onset MS independently of HLA-DR2. METHOD: A case-control study involving 159 patients with definite relapse-onset MS and 273 control subjects was conducted. Six highly polymorphic microsatellite markers encoded within the HLA-C to DR region, that is, D6S1014, D6S273, TNFa, MIB, C1_2_5, and C1_3_2, three single-nucleotide tumor necrosis factor (TNF) promoter gene polymorphisms at positions -238, -308, and -376, and HLA-DR2 carriership were typed. RESULTS: These data confirmed the well-known association between the HLA-DR2 haplotype and relapse-onset MS, yielding an odds ratio (OR) of 3.6 (95% CI: 2.4 to 5.4; p < 0.0001). Multivariate analyses revealed that C1_3_2*354 was also associated with an increased risk for developing relapse-onset MS independently of HLA-DR2 (OR: 2.0; 95% CI: 1.2 to 3.1; p = 0.004). This allele is encoded within an ancestral haplotype that is highly linked to HLA-DR3. The joint effect of this ancestral haplotype and HLA-DR2 resulted in an OR of 8.7 (95% CI: 2.7 to 29; p < 0.0001) to develop relapse-onset MS. In addition, a protective risk factor was found: carriers of TNFa*107 had a 0.5-fold lower risk to develop relapse-onset MS (95% CI: 0.3 to 0.9; p = 0.026). CONCLUSION: Within the HLA region, other loci besides HLA-DR2 haplotype modulate susceptibility for relapse-onset MS.
UI - 10830907
AU - Judson H; van Roy N; Strain L; Vandesompele J; Van Gele M; Speleman F;
TI - Bonthron DT Structure and mutation analysis of the gene encoding DNA fragmentation factor 40 (caspase-activated nuclease), a candidate neuroblastoma tumour suppressor gene.
SO - Hum Genet 2000 Apr;106(4):406-13
AD - Molecular Medicine Unit, University of Leeds, St James's University Hospital, UK.
We have characterised the DFFB gene, encoding the active subunit of the apoptotic nuclease DNA fragmentation factor (DFF40). DFFB maps to 1p36, near the imprinted putative tumour suppressor gene TP73. The DFFA gene (encoding the inhibitory DFF45 subunit) also maps to 1p36.2-36.3, and we show by FISH that DFFB lies distal to DFFA. We have also mapped a processed DFFB pseudogene to chromosome 9. DFFB itself has seven coding exons spanning 10 kb. Exhaustive mutation screening of 41 neuroblastomas and other tumours in which a 1p36 tumour suppressor gene is implicated showed no tumour-specific mutations. A coding region polymorphism was used to demonstrate uniformly biallelic expression in human fetal DFFB transcripts. Since the putative neuroblastoma tumour suppressor gene in distal 1p36 is predicted to be maternally expressed, the lack of imprinting and absence of somatic mutations in DFFB indicate that it is probably not the neuroblastoma tumour suppressor gene.
UI - 11723754
AU - Maat-Kievit JA; Losekoot M; Roos RA
TI - [From gene to disease; HD gene and Huntington disease]
SO - Ned Tijdschr Geneeskd 2001 Nov 3;145(44):2120-3
AD - Erasmus Universitair Medisch Centrum, afd. Klinische Genetica, Westzeedijk 112, 3016 AH Rotterdam. email@example.com
Huntington's disease (HD) is a late onset, incurable, autosomal dominantly-inherited, progressive neuropsychiatric disease, characterised by chorea, changes in personality, mood and behaviour, and dementia. Huntington's disease is a clinical diagnosis. The advent of DNA diagnosis has made predictive, prenatal and preimplantation testing possible for at-risk persons or asymptomatic carriers. The prevalence is estimated to be 3-10/100,000 among individuals of European descent; HD is less common in other ethnic groups. Huntington's disease is caused by an expanded trinucleotide CAG repeat in the HD gene on chromosome 4. The gene encodes for the protein huntingtin, with an as yet unknown function. The mutated huntingtin has an elongated stretch of glutamines which leads to a gain of function such as overactivity, excitotoxicity, or to interactions with other proteins.
UI - 12160747
AU - Pennetta G; Hiesinger P; Fabian-Fine R; Meinertzhagen I; Bellen H
TI - Drosophila VAP-33A directs bouton formation at neuromuscular junctions in a dosage-dependent manner.
SO - Neuron 2002 Jul 18;35(2):291-306
AD - Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
Aplysia VAP-33 (VAMP-associated protein) has been previously proposed to be involved in the control of neurotransmitter release. Here, we show that a Drosophila homolog of VAP-33, DVAP-33A, is localized to neuromuscular junctions. Loss of DVAP-33A causes a severe decrease in the number of boutons and a corresponding increase in bouton size. Conversely, presynaptic overexpression of DVAP-33A induces an increase in the number of boutons and a decrease in their size. Gain-of-function experiments show that the presynaptic dose of DVAP-33A tightly modulates the number of synaptic boutons. Our data also indicate that the presynaptic microtubule architecture is severely compromised in DVAP-33A mutants. We propose that a DVAP-33A-mediated interaction between microtubules and presynaptic membrane plays a pivotal role during bouton budding.
UI - 12149436
AU - Li J; Protopopov A; Wang F; Senchenko V; Petushkov V; Vorontsova O;
TI - Petrenko L; Zabarovska V; Muravenko O; Braga E; Kisselev L; Lerman MI; Kashuba V; Klein G; Ernberg I; Wahlestedt C; Zabarovsky ER NotI subtraction and NotI-specific microarrays to detect copy number and methylation changes in whole genomes.
SO - Proc Natl Acad Sci U S A 2002 Aug 6;99(16):10724-9
AD - Microbiology and Tumor Biology Center, Karolinska Institute, 171 77 Stockholm, Sweden.
Methylation, deletions, and amplifications of cancer genes constitute important mechanisms in carcinogenesis. For genome-wide analysis of these changes, we propose the use of NotI clone microarrays and genomic subtraction, because NotI recognition sites are closely associated with CpG islands and genes. We show here that the CODE (Cloning Of DEleted sequences) genomic subtraction procedure can be adapted to NotI flanking sequences and to CpG islands. Because the sequence complexity of this procedure is greatly reduced, only two cycles of subtraction are required. A NotI-CODE procedure can be used to prepare NotI representations (NRs) containing 0.1-0.5% of the total DNA. The NRs contain, on average, 10-fold less repetitive sequences than the whole human genome and can be used as probes for hybridization to NotI microarrays. These microarrays, when probed with NRs, can simultaneously detect copy number changes and methylation. NotI microarrays offer a powerful tool with which to study carcinogenesis.
UI - 12197465
AU - Roche PA
TI - The genetic revolution at work: legislative efforts to protect employees.
SO - Am J Law Med 2002;28(2-3):271-83
AD - Boston University School of Public Health, USA.
UI - 12202036
AU - Tapon N; Harvey KF; Bell DW; Wahrer DC; Schiripo TA; Haber DA; Hariharan
TI - IK salvador Promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines.
SO - Cell 2002 Aug 23;110(4):467-78
AD - Massachusetts General Hospital Cancer Center, Building 149, 13th Street, Charlestown 02129, USA.
The number of cells in an organism is determined by regulating both cell proliferation and cell death. Relatively few mechanisms have been identified that can modulate both of these processes. In a screen for Drosophila mutations that result in tissue overgrowth, we identified salvador (sav), a gene that promotes both cell cycle exit and cell death. Elevated Cyclin E and DIAP1 levels are found in mutant cells, resulting in delayed cell cycle exit and impaired apoptosis. Salvador contains two WW domains and binds to the Warts (or LATS) protein kinase. The human ortholog of salvador (hWW45) is mutated in three cancer cell lines. Thus, salvador restricts cell numbers in vivo by functioning as a dual regulator of cell proliferation and apoptosis.
UI - 11524259
AU - Soria JM; Baiget M; Castano L; Tejada MI; Perez-Nanclares G; Fontcuberta
TI - J Genetic risk factors for thrombosis in a Basque population and its possible contribution to the analysis of a complex disease such as thrombophilia.
SO - Haematologica 2001 Aug;86(8):889-90
UI - 12211263
AU - Buchanan A; Califano A; Kahn J; McPherson E; Robertson J; Brody B
TI - Pharmacogenetics: ethical issues and policy options.
SO - Kennedy Inst Ethics J 2002 Mar;12(1):1-15
AD - Department of Philosophy, University of Arizona, Tucson, AZ, USA.
Pharmacogenetics offers the prospect of an era of safer and more effective drugs, as well as more individualized use of drug therapies. Before the benefits of pharmacogenetics can be realized, the ethical issues that arise in research and clinical application of pharmacogenetic technologies must be addressed. The ethical issues raised by pharmacogenetics can be addressed under six headings: (1) regulatory oversight, (2) confidentiality and privacy, (3) informed consent, (4) availability of drugs, (5) access, and (6) clinicians' changing responsibilities in the era of pharmacogenetic medicine. We analyze each of these categories of ethical issues and provide policy approaches for addressing them.
UI - 11994765
AU - Dehaghani AS; Amirzargar A; Farjadian S; Ghaderi A
TI - HLA-DQBl alleles and susceptibility to cervical squamous cell carcinoma in Southern Iranian patients.
SO - Pathol Oncol Res 2002;8(1):58-61
AD - Shiraz University of Medical Sciences, Medical School, Department of Obstetrics and Gynecology, Shiraz, Iran.
The association of HLA class II with various autoimmune diseases has been extensively investigated. Despite the importance and functions of HLA genes in the evolution of cancer, the allele specific association of HLA molecules in cancer patients has not been well investigated. In this study the HLA-class II alleles frequency was investigated in Iranian patients with cervical squamous cell carcinoma. HLA typing was carried out by PCR amplification using sequence specific primers (PCR-SSP). DRB1, DQA1 and DQB1 typing was performed for 23 patients. The allele frequencies were calculated and compa