National Cancer Institute®
Last Modified: March 1, 2002
UI - 11551099
AU - Rivers CA; Barton JC; Acton RT
TI - A rapid PCR-SSP assay for the hemochromatosis-associated Tyr250Stop mutation in the TFR2 gene.
SO - Genet Test 2001 Summer;5(2):131-4
AD - Department of Microbiology, University of Alabama at Birmingham, 35294, USA.
Several genes associated with hemochromatosis and primary iron overload have been identified. Mutations in the HFE gene have been detected in 60-100% of hemochromatosis patients of northern, central, and western European descent, although the frequencies of these mutations vary among racial and ethnic groups. Recently, a mutation in the gene encoding transferrin receptor-2 (exon 6, nucleotide 750 C --> G; Y250X) was detected by a PCR-restriction fragment length polymorphism (RFLP) method in Sicilians with hemochromatosis. We describe a modification of the original assay in which the sequence-specific priming PCR assay does not require the use of restriction endonuclease. The modified assay is robust and cost-efficient, and may be more useful for large-scale population studies because it can be performed rapidly on DNA extracted from buccal swabs.
UI - 11551100
AU - Hegde MR; Fawkner M; Chong B; McGaughran J; Gilbert D; Love DR
TI - Compound heterozygosity at the FMR1 gene.
SO - Genet Test 2001 Summer;5(2):135-8
AD - School of Biological Sciences, University of Auckland, and Auckland Hospital, New Zealand.
Individuals affected with Fragile X syndrome are usually characterized at the DNA level by the presence of at least 200 CGG repeats in the 5' untranslated region of the FMR1 gene; this number of repeats is defined as a full mutation. Repeats that number 50-200 usually define those with premutations and are termed unaffected carriers. We report here a compound heterozygous female who carried CGG repeats in the FMR1 gene that fall within the premutation and full mutation ranges. The former appears to have been inherited from the father, whereas the latter is an expansion of the premutation carried by the proband's mother. Therefore, the offspring of the proband will carry a significant risk of being affected with Fragile X syndrome, and the paternal uncle and any cousins should be counselled for being at risk for this syndrome.
UI - 11551108
AU - Wang ZH; Zeng B; Pastores GM; Raksadawan N; Ong E; Kolodny EH
TI - Rapid detection of the two common mutations in Ashkenazi Jewish patients with mucolipidosis type IV.
SO - Genet Test 2001 Summer;5(2):87-92
AD - Department of Neurology, New York University School of Medicine, NY 10016, USA.
Among Ashkenazi Jewish individuals with mucolipidosis IV (ML IV), two mutations in the ML IV gene, IVS3-1A --> G and delEX1-EX7, account for more than 95% of disease alleles. The reported method of genotyping for the delEX1-EX7 mutation involves a cumbersome multistep procedure. In the present study, a new simplified one-step procedure is described that detects this mutation in both patients and carriers. An improved procedure is also described for detection of the IVS3-1A --> G mutation. Using these improved procedures, we have characterized the ML IV mutant alleles in 27 patients and 95 of their relatives from 22 families, and in 123 unrelated and unaffected Ashkenazi Jewish controls. Of the 27 ML IV patients, 16 patients (59.3%) were found to be homozygous for the IVS3-1A --> G mutation and 1 patient (3.7%) homozygous for the delEX1-EX7 mutation. Additionally, 9 patients (33.3%) were compound heterozygotes for IVS3-1A --> G/delEX1-EX7. Among the 123 Ashkenazi Jewish controls, two individuals were identified as heteroallelic with one IVS3-1A --> G mutation (carrier frequency: approximately 1 in 61); none showed the delEX1-EX7 mutation. The modifications described here provide a more facile means of genotyping patients and carriers and expand the possibilities for screening at-risk populations.
UI - 11748358
AU - Chung WB; Hong SH; Kim JA; Sohn YK; Kim BW; Kim JW
TI - Hypermethylation of tumor-related genes in genitourinary cancer cell lines.
SO - J Korean Med Sci 2001 Dec;16(6):756-61
AD - Department of Dental Microbiology, College of Dentistry, Kyungpook National University, Taegu, Korea. firstname.lastname@example.org
Hypermethylation of CpG island is a common mechanism for the inactivation of tumor-related genes. In the present study, we analyzed 13 genitourinary cancer cell lines for aberrant DNA methylation of 5 tumor-related genes using methylation- specific polymerase chain reaction (MSP). GSTP1 was methylated in 5 (38.5%), E-cadherin in 1 (8%), VHL in 1 (8%), and MGMT and hMLH1 in none (0%). Six out of thirteen genitourinary cancer cell lines had methylation of at least one of five genes; 5 had one gene methylated, and, 1 had two genes methylated. Methylation of these 5 genes was not detected in any of the bladder cancer cell lines. GSTP1 was methylated in all of the 3 prostate cancer cell lines. We conclude that aberrant hypermethylation may be an important mechanism for the inactivation of cancer-related genes in kidney and prostate cancer cell lines.
UI - 11793470
AU - Herman GE; Kopacz K; Zhao W; Mills PL; Metzenberg A; Das S
TI - Characterization of mutations in fifty North American patients with X-linked myotubular myopathy.
SO - Hum Mutat 2002 Feb;19(2):114-21
AD - Children's Research Institute and the Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA. email@example.com
X-linked myotubular myopathy (MTM1) is a rare developmental disorder of skeletal muscle that is characterized by the presence of abnormal central nuclei in biopsy specimens taken from affected individuals. To date 133 different mutations have been identified in the MTM1 gene worldwide. We report here mutations detected in 50 additional U.S. families with biopsy-proven MTM1. Forty-one of the patients have not been described previously, including 18 with novel mutations. Eighty-eight percent of the mothers of sporadic cases that were studied were identified as carriers, extending the previously reported high-carrier frequency for this disorder. Clinical information collected on the majority of patients helps to further correlate genotype with phenotype, and implications of these data for genetic counseling in families are discussed. Copyright 2002 Wiley-Liss, Inc.
UI - 11793471
AU - Yamaguchi N; Kobayashi K; Yasuda T; Nishi I; Iijima M; Nakagawa M; Osame
TI - M; Kondo I; Saheki T Screening of SLC25A13 mutations in early and late onset patients with citrin deficiency and in the Japanese population: Identification of two novel mutations and establishment of multiple DNA diagnosis methods for nine mutations.
SO - Hum Mutat 2002 Feb;19(2):122-30
AD - Department of Biochemistry, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
We have recently identified SLC25A13 on chromosome 7q21.3 as the gene responsible for adult-onset type II citrullinemia (CTLN2) and found seven mutations in the SLC25A13 gene of CTLN2 patients. Most recently, the SLC25A13 mutations have been detected in neonatal/infantile patients with a type of neonatal hepatitis associated with cholestasis (NICCD). In the present study, we identified a novel mutation, E601X, in the SLC25A13 gene and established multiple DNA diagnosis methods for eight mutations by using a genetic analyzer with GeneScan and the single primer extension procedure (SNaPshot). An additional novel missense mutation (variation), E601K, was detected by SNaPshot analysis and was indistinguishable from the mutation E601X detected by the PCR/RFLP method. Multiple DNA diagnoses for the nine mutations revealed that 100 (male/female: 70/30) out of 115 CTLN2 and 38 (14/24) out of 45 NICCD patients tested were homozygotes or compound heterozygotes. The frequency of homozygotes carrying SLC25A13 mutations in both alleles is estimated to be minimally 1 in 21,000 from carrier detection (18 in 1,315 individuals tested) in the Japanese population. The differences in the gender ratio and in mutation types between CTLN2 and NICCD patients are significant. It is, however, unknown whether all homozygotes with mutated SLC25A13 in both alleles suffer from NICCD, CTLN2, both, or neither. Copyright 2002 Wiley-Liss, Inc.
UI - 11793473
AU - Dakeishi M; Shioya T; Wada Y; Shindo T; Otaka K; Manabe M; Nozaki J;
TI - Inoue S; Koizumi A Genetic epidemiology of hereditary hemorrhagic telangiectasia in a local community in the northern part of Japan.
SO - Hum Mutat 2002 Feb;19(2):140-8
AD - Department of Hygiene, Akita University School of Medicine, Akita, Japan. firstname.lastname@example.org
Hereditary hemorrhagic telangiectasia (HHT or Rendu-Osler-Weber syndrome) is an autosomal dominant disorder characterized by aberrant vascular development. We report here a genetic epidemiologic study in a county, A, in the Akita prefecture (population 1.2 million) located in northern Japan. Nine HHT patients who had been referred to tertiary-care hospitals were located in and near the study county. A total of 137 pedigree members were traced of which 81 were alive and 32 were affected by HHT. Complications associated with cerebral or pulmonary arteriovenous malformations were proven in six out of seven families. Linkage analysis in two large families revealed a weak yet suggestive linkage to the HHT1 locus (encoding endoglin; ENG). Three novel mutations were found in four families, all of which led to a frameshift: a G to C transversion at the splicing donor site of intron 3 (Inv3+1 G>C) in one family, one base pair insertion (A) at nucleotide 828 (exon 7) of the endoglin cDNA in two large families (c.828-829 ins A), and a four base pair deletion (AAAG) beginning with nucleotide 1120 (exon 8) of the endoglin cDNA (c.1120-1123 delAAAG) in one family. The insertion of A in exon 11 (c.1470-1471 insA) mutation found in one family has also been reported in a European family. No endoglin gene mutations were found in two families. The population prevalence of HHT in the county was estimated to be 1:8,000 approximately 1:5,000, roughly comparable with those reported in European and U.S. populations, which is contradictory to the traditional view that HHT is rare among Asians. We recommend that families with HHT be screened for gene mutations in order that high-risk individuals receive early diagnosis and treatment initiation that will substantially alter their clinical course and prognosis. Copyright 2002 Wiley-Liss, Inc.
UI - 11793475
AU - Kahmann S; Herter P; Kuhnen C; Muller KM; Muhr G; Martin D; Soddemann M;
TI - Muller O A non-radioactive protein truncation test for the sensitive detection of all stop and frameshift mutations.
SO - Hum Mutat 2002 Feb;19(2):165-72
AD - Max-Planck-Institut fur molekulare Physiologie, Dortmund, Germany.
A new method for mutation detection is described, which is a technical advancement of the protein truncation test. The new technique is non-radioactive and highly sensitive for detection of virtually all sequence mutations, which lead to a stop signal or to the shift of the translation frame. The method includes four steps: 1) capture of the interesting sequence copies out of the sample by binding to an immobilized complementary sequence, 2) PCR amplification of the gene fragment to be analyzed with primers coding both for amino- and carboxy-terminal tags, 3) in vitro transcription and translation, and 4) analysis of the translation products by Western blot. As an evaluation of the new method, we detected mutated gene copies at a dilution of 1 to 40 compared to the non-mutated gene. Using the method, we were able to detect a mutation in the adenomatous polyposis coli tumor suppressor gene (APC) in a stool sample of a colorectal cancer patient. This mutation could not be detected by direct sequencing of the amplified APC gene fragment. Copyright 2002 Wiley-Liss, Inc.
UI - 11793476
AU - Sodha N; Houlston RS; Williams R; Yuille MA; Mangion J; Eeles RA
TI - A robust method for detecting CHK2/RAD53 mutations in genomic DNA.
SO - Hum Mutat 2002 Feb;19(2):173-7
AD - Royal Marsden NHS Trust, Surrey, UK. email@example.com
While screening for germline CHK2 mutations in cancer cases by heteroduplex CSGE, we observed that additional PCR fragments were generated from the 3' end region of the gene that includes exons 11-14. Direct sequencing of these fragments suggested that homologous loci (possibly pseudogenes) were concomitantly being amplified. Searches of public sequence databases showed that a number of areas of the genome show a high degree of homology to exons 10-14 of the CHK2 gene. The presence of these homologous regions means that standard screening methods for detecting mutations in CHK2, based on PCR of genomic DNA, are prone to error. To circumvent this problem, we have developed a strategy, based on long-range PCR, to screen the functional copy of CHK2. Using this approach it is possible to carry out a comprehensive mutational analysis of CHK2 from genomic DNA. Copyright 2002 Wiley-Liss, Inc.
UI - 11793482
AU - Nuchprayoon I; Sanpavat S; Nuchprayoon S
TI - Glucose-6-phosphate dehydrogenase (G6PD) mutations in Thailand: G6PD Viangchan (871G>A) is the most common deficiency variant in the Thai population.
SO - Hum Mutat 2002 Feb;19(2):185
AD - Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common hereditary disorder in humans. Through a population study for G6PD deficiency using a cord blood quantitative G6PD assay in Bangkok, Thailand, we found that the prevalence of G6PD deficiency is 11.1% in Thai male (N=350) and 5.8% in female (N=172) cord blood samples. Among the neonates with hyperbilirubinemia, the prevalence of G6PD deficiency is 22.1% in males (N=140) and 10.1% in females (N=89). We developed a PCR-restriction enzyme-based method to identify G6PD Viangchan (871G>A), and searched for this and 9 other mutations in DNA from G6PD deficient blood samples. G6PD Viangchan (871G>A) was the most common mutation identified (54%), followed by G6PD Canton (1376G>T; 10%), G6PD Mahidol (487G>A; 8%), G6PD Kaiping (1388G>A; 5%), G6PD Union (1360C>T; 2.6%) and "Chinese-5" (1024C>T; 2.6%). Among 20 neonates with hyperbilirubinemia, G6PD Viangchan was also most frequently identified (60%), followed by G6PD Canton (10%), G6PD Mahidol, G6PD Union, and G6PD Kaiping (5% each). G6PD Viangchan appears from this study to be the most common G6PD mutation in the Thai population, bringing into question previous reports that G6PD Mahidol is most prevalent. G6PD Viangchan, together with G6PD Mahidol and G6PD Canton, are responsible for over 70% of G6PD deficiency in this study of Thais. With the data from other Southeast Asian ethnic groups such as Laotians, G6PD Viangchan (871G>A) is probably the most common variant in non-Chinese Southeast Asian population.Copyright 2002 Wiley-Liss, Inc.
UI - 11793484
AU - Okubo M; Horinishi A; Kim DH; Yamamoto TT; Murase T
TI - Seven novel sequence variants in the human low density lipoprotein receptor related protein 5 (LRP5) gene.
SO - Hum Mutat 2002 Feb;19(2):186
AD - Department of Endocrinology and Metabolism, Okinaka Memorial Institute for Medical Research and Toranomon Hospital, Tokyo, Japan. QFG00550@nifty.ne.jp
We identified seven novel polymorphisms in the human low density lipoprotein receptor related protein 5 (LRP5) gene. Two of them are predicted to replace amino acid in LRP5 protein (c.314A>G: Q89R and c.4037T>C: V1330A), whereas three are silent mutations in the coding region (c.2268T>C: N740N, c.3405A>G: V1119V, and c.4137C>T: D1363D) and two are polymorphisms in introns (IVS10+6T>C and IVS17-30G>A). Since LRP5 recognizes apolipoprotein E and is genetically linked with type 1 diabetes, these novel polymorphisms will be useful in genetic studies of hyperlipoproteinemia and diabetes. To our knowledge, this is the first report in the literature of sequence variants in the human LRP5 gene. Copyright 2002 Wiley-Liss, Inc.
UI - 11793485
AU - El-Hakeh J; Rosenzweig S; Oleastro M; Basack N; Berozdnik L; Molina F;
TI - Rivas EM; Zelazko M; Danielian S Wiskott-Aldrich syndrome in Argentina: 17 unique, including nine novel, mutations.
SO - Hum Mutat 2002 Feb;19(2):186-7
AD - Molecular Biology Laboratory, Hospital Nacional de Pediatria "J.P Garrahan", Buenos Aires, Argentina.
Wiskott-Aldrich syndrome (WAS), is an X-linked immunodeficiency disease caused by mutations of the WAS protein (WASP) gene, characterized by thrombocytopenia, eczema and recurrent infections. X-linked thrombocytopenia (XLT) is a milder form with only platelet abnormalities. Cumulative mutation data have revealed that WASP genotypes are highly variable among WAS patients. By SSCP analysis, we determined the location of the mutation in 23 WAS patients from 17 unrelated families with variable clinical phenotypes. Direct sequence analysis of genomic DNA showed 9 novel mutations (Q52H, G70W, 393del7, Ex 7 Ex11del, IVS 8+1G-->C, 925delG, 959ins38, 1380del8, and IVS 2+2T-->C) and 8 known mutations distributed throughout the WAS gene. This is the first report of WAS gene mutations from a Latin American country. Copyright 2002 Wiley-Liss, Inc.
UI - 11808679
AU - Parker M
TI - Genetics and the interpersonal elaboration of ethics.
SO - Theor Med Bioeth 2001 Sep;22(5):451-9
AD - The Ethox Centre, University of Oxford, Institute of Health Sciences, UK. firstname.lastname@example.org
Confidentiality in genetic testing poses important ethical challenges to the current primacy of respect for autonomy and patient choice in health care. It also presents a challenge to approaches to decision-making emphasising the ethical importance of the consequences of health care decisions. In this paper a case is described in which respect for confidentiality calls both for disclosure and non-disclosure, and in which respect for patient autonomy and the demand to avoid causing harm each appear to call both for testing without consent, and testing only with consent. This creates problems not only for clinicians, families and patients, but also for those who propose clinical bioethics as a tool for the resolution of such dilemmas. In this paper I propose some practical ways in which ethical issues in clinical genetics and elsewhere, might be addressed. In particular I call for a closer relationship between ethics and communication in health care decision-making and describe an approach to the ethics consultation that places particular emphasis on the value of interpersonal deliberation in the search for moral understanding. I reach these conclusions through an analysis of the concept of 'moral development' in which I argue that the achievement of moral understanding is a necessarily intersubjective project elaborated by moral persons.
UI - 11808680
AU - Bennett R
TI - Antenatal genetic testing and the right to remain in ignorance.
SO - Theor Med Bioeth 2001 Sep;22(5):461-71
AD - School of Law, The University of Manchester, UK. email@example.com
As knowledge increases about the human genome, prenatal genetic testing will become cheaper, safer and more comprehensive. It is likely that there will be a great deal of support for making prenatal testing for a wide range of genetic disorders a routine part of antenatal care. Such routine testing is necessarily coercive in nature and does not involve the same standard of consent as is required in other health care settings. This paper asks whether this level of coercion is ethically justifiable in this case, or whether pregnant women have a right to remain in ignorance of the genetic make-up of the fetus they are carrying. While information gained by genetic testing may be useful for pregnant women when making decisions about their pregnancy, it does not prevent harm to future children. It is argued that as this kind of testing provides information in the interests of the pregnant women and not in the interests of any future child, the same standards of consent that are normally required for genetic testing should be required in this instance.
UI - 11866650
AU - Verlinsky Y; Rechitsky S; Verlinsky O; Masciangelo C; Lederer K; Kuliev
TI - A Preimplantation diagnosis for early-onset Alzheimer disease caused by V717L mutation.
SO - JAMA 2002 Feb 27;287(8):1018-21
AD - Reproductive Genetics Institute, Chicago, IL, USA. firstname.lastname@example.org
CONTEXT: Indications for preimplantation genetic diagnosis (PGD) have recently been expanded to include disorders with genetic predisposition to allow only embryos free of predisposing genes to be preselected for transfer back to patients, with no potential for pregnancy termination. OBJECTIVE: To perform PGD for early-onset Alzheimer disease (AD), determined by nearly completely penetrant autosomal dominant mutation in the amyloid precursor protein (APP) gene. DESIGN: Analysis undertaken in 1999-2000 of DNA for the V717L mutation (valine to leucine substitution at codon 717) in the APP gene in the first and second polar bodies, obtained by sequential sampling of oocytes following in vitro fertilization, to preselect and transfer back to the patient only the embryos that resulted from mutation-free oocytes. SETTING: An in vitro fertilization center in Chicago, Ill. PATIENTS: A 30-year-old AD-asymptomatic woman with a V717L mutation that was identified by predictive testing of a family with a history of early-onset AD. MAIN OUTCOME MEASURES: Results of mutation analysis; pregnancy outcome. RESULTS: Four of 15 embryos tested for maternal mutation in 2 PGD cycles, originating from V717L mutation--free oocytes, were preselected for embryo transfer, yielding a clinical pregnancy and birth of a healthy child free of predisposing gene mutation according to chorionic villus sampling and testing of the neonate's blood. CONCLUSION: This is the first known PGD procedure for inherited early-onset AD resulting in a clinical pregnancy and birth of a child free of inherited predisposition to early-onset AD.
UI - 11742676
AU - Abuin A; Holt KH; Platt KA; Sands AT; Zambrowicz BP
TI - Full-speed mammalian genetics: in vivo target validation in the drug discovery process.
SO - Trends Biotechnol 2002 Jan;20(1):36-42
AD - Lexicon Genetics Incorporated, 4000 Research Forest Drive, The Woodlands, TX 77381, USA.
The completion of the Human Genome Project has signaled the beginning of the post-genome era, with a corresponding shift in focus from the sequencing and identification of genes to the exploration of gene function. A rate-limiting step in deriving value from this gene sequence information is determining the potential pharmaceutical applications of genes and their encoded proteins. This validation step is crucial for focusing efforts and resources on only the most promising targets. Strategies using reverse mouse genetics provide excellent methods for validating potential targets and therapeutic proteins in vivo in a mammalian model system.
UI - 11748846
AU - Elanko N; Sibbring JS; Metcalfe KA; Clayton-Smith J; Donnai D; Temple
TI - IK; Wall SA; Wilkie AO A survey of TWIST for mutations in craniosynostosis reveals a variable length polyglycine tract in asymptomatic individuals.
SO - Hum Mutat 2001 Dec;18(6):535-41
AD - Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, UK.
The human TWIST gene encodes a 202 amino acid transcription factor characterized by a highly conserved basic-helix-loop-helix motif in the C-terminal half, and a less conserved N-terminal half that has binding activity toward the histone acetyltransferase p300. Between these domains is a repeat region of unknown function that encodes the glycine-rich sequence (Gly)5Ala(Gly)5. Heterozygous mutations of TWIST were previously described in Saethre-Chotzen craniosynostosis syndrome [El Ghouzzi et al., 1997; Howard et al., 1997]. During a search for TWIST mutations in patients with craniosynostosis, we identified, in addition to 11 novel and one previously described bona fide mutations, several individuals with rearrangements of the glycine-rich region, involving either deletion of 18 nucleotides or insertion of three, 15, or 21 nucleotides. None of these rearrangements was consistently associated with clinical disease and we conclude that they are at most weakly pathogenic. The glycine stretch may serve as a flexible linker between the functional domains of the TWIST protein, and as such may be subject to reduced evolutionary constraint. Copyright 2001 Wiley-Liss, Inc.
UI - 11748305
AU - Eng C; Brody LC; Wagner TM; Devilee P; Vijg J; Szabo C; Tavtigian SV;
TI - Nathanson KL; Ostrander E; Frank TS; Steering Committee of the Breast Cancer Information Core (BIC) Consortium Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1.
SO - J Med Genet 2001 Dec;38(12):824-33
AD - Clinical Cancer Genetics and Human Cancer Genetics Programs, Comprehensive Cancer Center, and Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA. email@example.com
While sequence analysis is considered by many to be the most sensitive method of detecting unknown mutations in large genes such as BRCA1, most published estimates of the prevalence of mutations in this gene have been derived from studies that have used other methods of gene analysis. In order to determine the relative sensitivity of techniques that are widely used in research on BRCA1, a set of blinded samples containing 58 distinct mutations were analysed by four separate laboratories. Each used one of the following methods: single strand conformational polymorphism analysis (SSCP), conformation sensitive gel electrophoresis (CSGE), two dimensional gene scanning (TDGS), and denaturing high performance liquid chromatography (DHPLC). Only the laboratory using DHPLC correctly identified each of the mutations. The laboratory using TDGS correctly identified 91% of the mutations but produced three apparent false positive results. The laboratories using SSCP and CSGE detected abnormal migration for 72% and 76% of the mutations, respectively, but subsequently confirmed and reported only 65% and 60% of mutations, respectively. False negatives therefore resulted not only from failure of the techniques to distinguish wild type from mutant, but also from failure to confirm the mutation by sequence analysis as well as from human errors leading to misreporting of results. These findings characterise sources of error in commonly used methods of mutation detection that should be addressed by laboratories using these methods. Based upon sources of error identified in this comparison, it is likely that mutations in BRCA1 and BRCA2 are more prevalent than some studies have previously reported. The findings of this comparison provide a basis for interpreting studies of mutations in susceptibility genes across many inherited cancer syndromes.
UI - 11748308
AU - Fokstuen S; Myring J; Meredith L; Ravine D; Harper PS
TI - Eight years' experience of direct molecular testing for myotonic dystrophy in Wales.
SO - J Med Genet 2001 Dec;38(12):E42
UI - 11748311
AU - Gong W; Gottlieb S; Collins J; Blescia A; Dietz H; Goldmuntz E;
TI - McDonald-McGinn DM; Zackai EH; Emanuel BS; Driscoll DA; Budarf ML Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects.
SO - J Med Genet 2001 Dec;38(12):E45
UI - 11773283
AU - Geisler JP; Hatterman-Zogg MA; Rathe JA; Buller RE
TI - Frequency of BRCA1 dysfunction in ovarian cancer.
SO - J Natl Cancer Inst 2002 Jan 2;94(1):61-7
AD - Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City 52242, USA.
BACKGROUND: Ovarian cancer is one of the most common hereditary cancers in women. Mutations in the BRCA1 gene increase a woman's risk of ovarian cancer. Testing for BRCA1 mutations is cumbersome and impractical for large populations. Therefore, we developed an efficient strategy to detect various types of BRCA1 dysfunction and also determined the relative frequency of BRCA1 dysfunction in ovarian cancer. METHODS: Tumors from 221 patients with epithelial ovarian cancer were screened for loss of heterozygosity (LOH) at the BRCA1 locus. BRCA1 complementary DNA (cDNA) and genomic DNA from all cancers with BRCA1 LOH (106 tumors) or noninformative status (15 tumors) were polymerase chain reaction (PCR) amplified and analyzed for protein truncation in a coupled transcription/translation test. When truncated BRCA1 protein was detected, the BRCA1 gene from both the tumor and a paired blood sample was sequenced. When BRCA1 expression in tumor cDNA was not detected with a protein truncation test, a methylation-specific PCR was used to determine whether the promoter region of BRCA1 was methylated and thus inactivated. All statistical tests were two-sided. RESULTS: Fifty-one (23.1%) of 221 tumors had BRCA1 dysfunction, including 18 with germline mutations, 15 with somatic mutations, and 18 with monoallelic or biallelic hypermethylated promoters. By the consideration of only tumors with LOH or that were noninformative, the efficiency for detecting BRCA1 dysfunction improved to 45 (37.2%) of 121 tumors. Therefore, LOH/noninformative was a strong predictor of mutation status (Fisher's exact test, P<.001). However, this subset of tumors did not include those with BRCA1 missense mutations (estimated at six [2.7%] of 221 not detected by our method) or biallelic promoter methylation (estimated at six [2.7%] of 221). CONCLUSIONS: BRCA1 dysfunction in ovarian cancer is common and occurs via multiple mechanisms. The use of LOH, rather than a family history of ovarian cancer, as a first step in a screening strategy, followed by protein truncation testing, appears to increase the chance of identifying tumors with BRCA1 dysfunction.
UI - 11857010
AU - Bish A; Sutton S; Jacobs C; Levene S; Ramirez A; Hodgson S
TI - Changes in psychological distress after cancer genetic counselling: a comparison of affected and unaffected women.
SO - Br J Cancer 2002 Jan 7;86(1):43-50
AD - Department of Clinical Genetics, Guy's Hospital, St Thomas's Street, London SE1 9RT, UK. firstname.lastname@example.org
This study sought to examine changes in psychological distress following cancer genetic counselling. Women attending a family cancer clinic completed questionnaires before their appointment and at 2 weeks, 6 months and 12 months after their appointment. Twenty-six women were at low risk of developing breast or ovarian cancer, 76 were at moderate risk, 46 were at high risk and 46 women had previously had breast or ovarian cancer. All groups were compared with regard to measures of anxiety, depression, general psychological distress, worry about developing breast and ovarian cancer, and perceived risk of developing breast/ovarian cancer and perceived likelihood of carrying a genetic mutation. General psychological distress did not change over the course of the study and the groups did not differ on these measures. Worry about developing breast cancer and perceptions of the likelihood of carrying a genetic mutation significantly reduced following genetic counselling. On the whole women who had already had breast/ovarian cancer showed more concerns about ovarian cancer and raised perceptions of risk in comparison with the other groups, indicating the need for sensitive counselling of such women.
UI - 11838716
AU - Calzone KA; Biesecker BB
TI - Genetic testing for cancer predisposition.
SO - Cancer Nurs 2002 Feb;25(1):15-25; quiz 26-7
AD - University of Pennsylvania Cancer Center, Philadelphia 19104, USA.
The onslaught of genetic innovations in the past decade has resulted in the ongoing identification of a spectrum of genes, some of which, when mutated, result in cancer susceptibility. The impact of these discoveries on healthcare provides an opportunity to enhance health promotion and long-term health outcomes by identifying at-risk individuals before cancer develops. This provides the healthcare provider with the potential to intervene much earlier to either reduce the risk or diagnose a cancer early when the chances for effective treatment are greatest. Even though genetic testing is increasingly being employed clinically, there remains a gap between the technology and effective interventions. Genetic tests also provide information that is distinct from other tests used routinely in health promotion, because of the personal and family nature of the information. This results in unique clinical, ethical, legal, and social issues that further affect the effective diffusion of this technology clinically. This article provides an overview of the distinguishing characteristics of genetic testing, outlines the essential components of informed consent, and discusses the potential implications of testing on individuals' lives and the nurse's role in offering genetic testing.
UI - 11838717
AU - Weinrich S; Royal C; Pettaway CA; Dunston G; Faison-Smith L; Priest JH;
TI - Roberson-Smith P; Frost J; Jenkins J; Brooks KA; Powell I Interest in genetic prostate cancer susceptibility testing among african American men.
SO - Cancer Nurs 2002 Feb;25(1):28-34
AD - School of Nursing, University of Louisville, KY 40292, USA. email@example.com
Six regions for prostate cancer genes have been identified, and it is anticipated that prostate cancer susceptibility testing will be available in the future. This correlational study identified predictors for interest in prostate cancer susceptibility testing among African American men. Participants were 320 African American men from the African American Hereditary Prostate Cancer Study and the South Carolina Prostate Cancer Education and Screening Study participated. Two questions measured interest in genetic prostate cancer susceptibility testing and family history of prostate cancer. Chi-square analyses by family history as well as demographics (age, education, marital status) were performed. Most of the men (277 [87%]) indicated an interest in genetic prostate cancer susceptibility testing. Interest in undergoing testing did not vary by family history, age, or education. Marital status was the only significant demographic predictor. Men who were married were significantly more likely to respond with a "yes" to interest in prostate cancer susceptibility testing than were men who were not married. The high "yes" response rate and the men's confusion between the genetic prostate cancer susceptibility testing and prostate cancer screening highlight the need for public education once prostate cancer genes are identified and available for public testing.
UI - 11295836
AU - Kamarinos M; McGill J; Lynch M; Dahl H
TI - Identification of a novel COCH mutation, I109N, highlights the similar clinical features observed in DFNA9 families.
SO - Hum Mutat 2001 Apr;17(4):351
AD - The Murdoch Childrens Research Institute, Royal Children's Hospital, Melbourne, Australia. firstname.lastname@example.org
Hereditary hearing loss is a heterogeneous condition at both the genetic and clinical levels. We have recruited an Australian family with dominant sensorineural nonsyndromic late onset hearing loss. The hearing loss typically begins in the second or third decade of life as a high frequency loss which progresses to a severe to profound loss by the sixth to seventh decade. All affected family members presented with concomitant vestibular dysfunction. Vertigo is a less common feature. The causative gene in this family was identified as COCH which lies within the DFNA9 interval. We identified a new point mutation, 253 T>A, in the coding region of the COCH gene, changing the isoleucine 109 to an asparagine (I109N). This is a non-conservative change of an amino acid that is identical in the human, mouse and chicken sequences. The mutation was identified in all affected individuals (n=13) and all were heterozygotes. Hearing loss in this family is clinically similar to that observed in ten other DFNA9 families. However, there are some differences in the age of onset and the extent of vestibular involvement. The remarkable clinical uniformity observed between DFNA9 families is intriguing especially in light of the great phenotypic variability observed with some of the other hearing loss genes. Hum Mutat 117:351, 2001. Copyright 2001 Wiley-Liss, Inc.
UI - 11826017
AU - Kanavakis E; Traeger-Synodinos J
TI - Preimplantation genetic diagnosis in clinical practice.
SO - J Med Genet 2002 Jan;39(1):6-11
AD - Medical Genetics, University of Athens, Aghia Sophia Children's Hospital, Athens 11527, Greece. email@example.com
Preimplantation genetic diagnosis (PGD) represents an alternative to prenatal diagnosis and allows selection of unaffected IVF embryos for establishing pregnancies in couples at risk for transmitting a genetic disorder.
UI - 11870512
AU - Brain K; Norman P; Gray J; Rogers C; Mansel R; Harper P
TI - A randomized trial of specialist genetic assessment: psychological impact on women at different levels of familial breast cancer risk.
SO - Br J Cancer 2002 Jan 21;86(2):233-8
AD - Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK.
The aim was to compare the psychological impact of a multidisciplinary specialist genetics service with surgical provision in women at high risk and those at lower risk of familial breast cancer. Women (n=735) were randomized to a surgical consultation with (trial group) or without (control group) specialist genetic risk assessment and the possible offer of presymptomatic genetic testing. Participants completed questionnaires before and immediately after the consultation to assess anxiety, cancer worry, perceived risk, interest in genetic testing and satisfaction. Responses of subgroups of women stratified by clinicians as low, moderate, or high risk were analyzed. There were no significant main effects of study intervention on any outcome variable. Regardless of risk information, there was a statistically significant reduction in state anxiety (P<0.001). Reductions in cancer worry and perceived risk were significant for women at low or moderate risk (P<0.001) but not those at high risk, and satisfaction was significantly lower in the high risk group (P<0.001). In high risk women who received specialist genetic input, there was a marginally significant trend towards increased perceived risk. The effect of risk information on interest in genetic testing was not significant. Breast care specialists other than geneticists might provide assessments of breast cancer risk, reassuring women at reduced risk and targeting those at high risk for specialist genetic counselling and testing services. These findings are discussed in relation to the existing UK Calman-Hine model of service delivery in cancer genetics. DOI: 10.1038/sj/bjc/6600051 www.bjcancer.comCopyright 2002 The Cancer Research Campaign
UI - 11480785
AU - Curuk MA; Arpaci A; Attila G; Tuli A; Kilinc Y; Aksoy K; Yuregir GT
TI - Genetic heterogeneity of beta-thalassemia at Cukurova in southern Turkey.
SO - Hemoglobin 2001 May;25(2):241-5
AD - Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta 30912, USA. firstname.lastname@example.org
Beta-thalassemia is the most common genetic abnormality causing health problems worldwide. Cukurova, in the southern part of Turkey, being on the Mediterranean, is in the thalassemic belt. Since there is no cure for the disease at present, the frequency of the mutation types of beta-thalassemia must first be identified to aid in clinical follow-up and prenatal diagnosis. Carriers identified during a screening survey and patients referred to our laboratory were studied for this purpose. After routine hematological analysis molecular screening was performed by the amplification refractory mutation system and DNA sequencing. The frequency of the common mutations were: IVS-I-110 (G-->A) 57.3%, IVS-I-1 (G-->A) 8.3%, codon 39 (C-->T) 6.4%, IVS-I-6 (T-->C) 5.7%, frameshift codon 8 (-AA) 5.7%, -30 (T-->A) 4.7%, IVS-II-1 (G-->A) 3.4%, IVS-II-745 (G-->C) 2.8%, and frameshift codon 5 (-CT) 1.1%. Some rare mutations (1%) such as frameshift codon 44 (-C) 0.7%, frameshift codons 74/75 (-C) 0.7%, IVS-1-5 (G-->C) 0.7%, frameshift codons 8/9 (+G) 0.4%, frameshift codons 36/37 (-T) 0.4%, frameshif