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PubMed2005

Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.

CONTEXT: In long QT syndrome (LQTS), disease severity and response to therapy vary according to the genetic loci. There exists a critical need to devise strategies to expedite genetic analysis. OBJECTIVE: To perform genetic screening in patients with LQTS to determine the yield of genetic testing, as well as the type and the prevalence of mutations. DESIGN, PATIENTS, AND SETTING: We investigated whether the detection of a set of frequently mutated codons in the KCNQ1, KCNH2, and SCN5A genes may translate in a novel strategy for rapid efficient genetic testing of 430 consecutive patients referred to our center between June 1996 and June 2004. The entire coding regions of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 were screened by denaturing high-performance liquid chromatography and DNA sequencing. The frequency and the type of mutations were defined to identify a set of recurring mutations. A separate cohort of 75 consecutive probands was used as a validation group to quantify prospectively the prevalence of the recurring mutations identified in the primary LQTS population. MAIN OUTCOME MEASURES: Development of a novel approach to LQTS genotyping. RESULTS: We identified 235 different mutations, 138 of which were novel, in 310 (72%) of 430 probands (49% KCNQ1, 39% KCNH2, 10% SCN5A, 1.7% KCNE1, and 0.7% KCNE2). Fifty-eight percent of probands carried nonprivate mutations in 64 codons of KCNQ1, KCNH2, and SCN5A genes. A similar occurrence of mutations at these codons (52%) was confirmed in the prospective cohort of 75 probands and in previously published LQTS cohorts. CONCLUSIONS: We have developed an approach to improve the efficiency of genetic screening for LQTS. This novel method may facilitate wider access to genotyping resulting in better risk stratification and treatment of LQTS patients.

Algorithms↗
PubMed2005

What should we want to know about our future? A Kantian view on predictive genetic testing.

Recent advances in genomic research have led to the development of new diagnostic tools, including tests which make it possible to predict the future occurrence of monogenetic diseases (e.g. Chorea Huntington) or to determine increased susceptibilities to the future development of more complex diseases (e.g. breast cancer). The use of such tests raises a number of ethical, legal and social issues which are usually discussed in terms of rights. However, in the context of predictive genetic tests a key question arises which lies beyond the concept of rights, namely, What should we want to know about our future? In the following I shall discuss this question against the background of Kant's Doctrine of Virtue. It will be demonstrated that the system of duties of virtue that Kant elaborates in the second part of his Metaphysics of Morals offers a theoretical framework for addressing the question of a proper scope of future knowledge as provided by genetic tests. This approach can serve as a source of moral guidance complementary to a justice perspective. It does, however, not rest on the-rather problematic--claim to be able to define what the "good life" is.

Ethical Theory↗
PubMed1999

Psychosocial impact of genetic testing in familial medullary-thyroid carcinoma: a multicentric pilot-evaluation.

BACKGROUND: Many crucial problems are associated with the diagnosis of inherited cancer susceptibility. One of the most important is related to the psychosocial consequences of the knowledge by the patients and their relatives of their own genetical status. Little data are available in the literature, mainly from studies including small numbers of selected and motivated patients. PATIENTS AND METHODS: From January till December 1997, we studied the psychometric and quality of life parameters of 77 subjects followed in two French specialized centers. These subjects had been treated for either sporadic or familial or were at risk for medullary thyroid carcinoma. All patients had previously attended genetic counselling with detection of germline Ret-mutations, were informed on their own genetic risk, had good short-term prognosis and performance status and did not receive recent cancer treatment. Each patient was invited to answer two questionnaires, the hospital anxiety and depression scale (HADS) and the subjective quality of life profile (SQLP). RESULTS: We report herein the descriptive results of this study (HADS and SQLP scores and distributions) and describe the individual clinical covariates that might explain the observed differences between subgroups of individuals. Although psychometric scores appeared similar in these subgroups, quality of life scores were lower in Ret-mutation carriers. Genetically-predisposed patients were less satisfied and expressed more expectations for favourable change in their quality of life. CONCLUSION: This finding suggests a high level of frustration and latent unsatisfaction related either to the management of the genetic information given by the clinicians and its psychosocial consequences or simply to the knowledge of the genetic risk of cancer. Further studies on the individual consequences of genetic testing, information delivery and when necessary psychotherapeutic interventions, are needed to insure the quality of presymptomatic genetic testing in this field of oncology.

Adult↗
PubMed2003

Actor-network theory: a tool to support ethical analysis of commercial genetic testing.

Social, ethical and policy analysis of the issues arising from gene patenting and commercial genetic testing is enhanced by the application of science and technology studies, and Actor-Network Theory (ANT) in particular. We suggest the potential for transferring ANT's flexible nature to an applied heuristic methodology for gathering empirical information and for analysing the complex networks involved in the development of genetic technologies. Three concepts are explored in this paper--actor-networks, translation, and drift--and applied to the case of Myriad Genetics and their commercial BRACAnalysis genetic susceptibility test for hereditary breast cancer. Treating this test as an active participant in socio-technical networks clarifies the extent to which it interacts with, shapes and is shaped by people, other technologies, and institutions. Such an understanding enables more sophisticated and nuanced technology assessment, academic analysis, as well as public debate about the social, ethical and policy implications of the commercialization of new genetic technologies.

Breast Neoplasms↗
PubMed1994

Genetic testing: an economic and contractarian analysis.

Medical researchers are rapidly identifying the genetic causes of many diseases. Genes that increase the risk of contracting Alzheimer's, colon and breast cancer, Huntington's, cystic fibrosis and numerous other diseases have been identified. Genetic tests can reveal an individual's probable health status many years in advance of sickness. Many fear that this will lead to 'genetic discrimination' in the employment and health insurance markets. Solutions such as consent laws are impractical and create adverse selection problems. A new form of insurance, genetic insurance, can eliminate these problems and allow everyone to be insured.

Actuarial Analysis↗
PubMed2002

Practical application of molecular genetic testing as an aid to the surgical pathologic diagnosis of sarcomas: a prospective study.

The strong correlation of specific reciprocal translocations with individual tumor types and the demonstration that polymerase chain reaction (PCR)-based methods can detect translocations in tissue samples have stimulated interest in the role of molecular genetic testing in diagnostic surgical pathology. To evaluate the clinical utility of PCR-based molecular analysis of soft tissue neoplasms in routine surgical pathology, 131 consecutive soft tissue tumors submitted for molecular genetic testing at a tertiary care teaching hospital were prospectively analyzed over a 36-month period. RT-PCR was used to test tumor RNA for fusion transcripts characteristic of malignant round cell tumors (including Ewing sarcoma/primitive neuroectodermal tumor, desmoplastic small round cell tumor, and alveolar rhabdomyosarcoma), spindle cell tumors (including synovial sarcoma and congenital fibrosarcoma), and fatty tumors (myxoid liposarcoma). DNA sequence analysis was used to confirm the identity of all PCR products, and the PCR results were compared with the histopathologic diagnosis. We found that sufficient RNA for RT-PCR-based testing was recovered from 96% of the 131 cases and the percentage of tumors that tested positive for the associated characteristic fusion transcript was in general agreement with those reported in the literature. DNA sequence analysis of PCR products identified both variant transcripts and spurious PCR products, underscoring the value of product confirmation steps when testing formalin-fixed, paraffin-embedded tissue. Only in rare cases did testing yield a genetic result that was discordant with the histopathologic diagnosis. We conclude that PCR-based testing is a useful adjunct for the diagnosis of malignant small round cell tumors, spindle cell tumors, and other miscellaneous neoplasms in routine surgical pathology practice.

Base Sequence↗
PubMed1999

The role of Food and Drug Administration regulation of in vitro diagnostic devices--applications to genetics testing.

The Food and Drug Administration (FDA) has been involved in the regulation of in vitro diagnostic devices (IVDs or laboratory tests) since the introduction of the Medical Device Amendments of 1976. IVDs developed as kits or systems intended for use in multiple laboratories require review by the FDA before being marketed to ensure appropriate performance and labeling. IVDs developed as in-house, or so-called "home-brew", tests or laboratory test services are considered medical devices, but historically have not been subject to premarket review as a matter of enforcement discretion. FDA recently established a new regulatory paradigm for in-house tests based on classification of the active ingredients or building blocks of these tests as analyte-specific reagents (ASRs). ASRs are exempt from premarket review but subject to both manufacturing and labeling controls. Currently, genetic tests are received and reviewed by the FDA in the same manner as other in vitro diagnostic tests. The FDA currently is in the process of chartering a new genetics advisory panel to provide the agency with outside expertise to deal with genetic testing issues. We are also continuing to work with other agencies within the Department of Health and Human Services to determine how we can cooperatively help foster this important new area of testing.

Clinical Laboratory Techniques↗
PubMed2002

Review article: genetic testing and counselling for hereditary colorectal cancer.

Colorectal cancer is the second leading cause of cancer death, after lung cancer, in the USA. The great majority (80%) of patients with colorectal cancer have sporadic disease with no evidence of having inherited the disorder. In the remaining 20%, a potentially definable genetic component exists. With the discovery of gene mutations related to hereditary colorectal cancer, risk assessment based on genetic test results is now feasible. The following review focuses on the two well-described colorectal cancer genetic syndromes-familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, the process of genetic counselling, currently available genetic tests, and indications for their use.

Adenomatous Polyposis Coli↗
PubMedDate not supplied

Deficiency of knowledge of genetics and genetic tests among general practitioners, gynecologists, and pediatricians: a global problem.

PURPOSE: The objective of this study was to assess knowledge of genetics and awareness of genetic tests among Dutch general practitioners (GPs), gynecologists (GYNs), and pediatricians (PEDs), as well as factors influencing their knowledge and awareness. METHODS: An anonymous questionnaire inquiry was used, validated with a sample of 52 clinical geneticists (CGs). The study was carried out in primary care (general practice) and secondary care (general and university hospitals) in The Netherlands. A random sample of 200 GPs, 300 GYNs, and 265 PEDs received a questionnaire. In addition, all registered CGs (58) received a questionnaire for validation. In total, 122 GPs, 187 GYNs, 164 PEDs, and 52 CGs returned a completed questionnaire. The main outcome measures were differences in knowledge scores between physicians working in different disciplines and factors influencing these scores. RESULTS: Knowledge scores of GPs (mean 64% correct answers, 61%-66% [95% confidence interval]), GYNs (mean 75% correct answers, 73%-76% [95% confidence interval]), and PEDs (mean 81% correct answers, 79%-82% [95% confidence interval]) were lower than those in the CG validation group (mean 95% correct answers, 94%-96% [95% confidence interval]). The 5th percentile of GPs, GYNs, and PEDs was at approximately 40%, 52% and 62% correct answers, respectively. There was a specific lack of knowledge about DNA testing. In addition to specialty, important factors positively associated with the knowledge scores of nongeneticists are more recent graduation, having taken an elective course in genetics, and providing genetic counseling in their own practice. CONCLUSION: The overall knowledge levels of genetics in many nongeneticist health care providers show clear deficiencies. This is in line with reports from other countries, showing that these deficiencies are a global problem.

Genetic Testing↗
PubMedDate not supplied

Issues in genetic testing of children.

Commentary about the ethical issues involved in the genetic testing in children (GTIC) has centered around beliefs that early testing of children when no medical benefits are anticipated should be discouraged. This article discusses the types of GTIC and the contexts of possible testing scenarios, and provides a review of the current research into the effects of such testing on children and their families. As data cannot support either substantive benefits or harms accrued after GTIC, it is recommended that the traditional ethical analysis based on principled theory be augmented by theories that reflect a family-centered ethic.

Child↗
PubMedDate not supplied

Genetic testing and counseling: selected ethical issues.

As science and technology in genetics continue to expand, complex ethical questions arise that require difficult decisions for all concerned. Rather than having ready-made answers, there may be only more challenging questions for patients, families, and healthcare professionals. These complicated questions may have no straightforward, correct answers, thus creating an ethical quandary. This article discusses some selected ethical issues that occur when patients are considering undergoing genetic testing and counseling, including respecting autonomy and the patient's right to decide, establishing patient-healthcare provider trust, and disclosing private information to others. Several strategies are presented that nurses can use as they assist patients and their families who are facing these challenging ethical dilemmas.

Communication↗
PubMed2004

Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis.

BACKGROUND & AIMS: An attenuated form of familial adenomatous polyposis has been described, but the phenotype remains poorly understood. METHODS: We performed genetic testing on 810 individuals from 2 attenuated familial adenomatous polyposis kindreds harboring an identical germline adenomatous polyposis coli gene mutation. Colonoscopy was performed on mutation-positive persons. RESULTS: The disease-causing mutation was present in 184 individuals. Adenomatous polyps were present in 111 of 120 gene carriers who had colonoscopy at an average age of 41 years. The median number of adenomas was 25 (range, 0-470), with striking variability of polyp numbers and a proximal colonic predominance of polyps. Colorectal cancer occurred in 27 mutation carriers (average age, 58 years; range, 29-81 years), with 75% in the proximal colon. The cumulative risk of colorectal cancer by age 80 was estimated to be 69%. An average of 3.4 recurrent polyps (range, 0-29) were found in the postcolectomy rectal remnant over a mean of 7.8 years (range, 1-34 years), with 1 rectal cancer. CONCLUSIONS: This investigation shows that attenuated familial adenomatous polyposis in the kindreds examined shows a much smaller median number of polyps than typical familial adenomatous polyposis, a wide variability in polyp number even at older ages, and a more proximal colonic location of polyps and cancer, yet it is associated with an extremely high risk of colon cancer. The phenotype of attenuated familial adenomatous polyposis mimics typical familial adenomatous polyposis in some cases but in others is difficult to distinguish from sporadic adenomas and colorectal cancer, thus making genetic testing particularly important.

Adenoma↗
PubMed2026

Role and relevance of genetic testing in patients with kidney stones: a review from EAU Section of Endourology.

PURPOSE OF REVIEW: Kidney stones have a high heritability. More than 40 genes have been identified causing monogenic forms of kidney stone disease (KSD). Kidney stone formers with genetic variants implicated in monogenic forms of KSD often suffer from early onset, high recurrence rates, and chronic kidney disease. Some patients may also exhibit extrarenal disease requiring attention. RECENT FINDINGS: Recent analysis of KSD patients identified a likely monogenic cause in pediatric populations in 17-30% of participants while in adult unselected populations 2.7-8% had a positive finding. More patients carry single genetic variants in monogenic forms that are classically considered as autosomal recessive but may cause an intermediate genetic risk for the development of KSD possibly in interaction with environmental or lifestyle factors. Genome-wide association studies have identified additional risk loci associating with KSD. Their clinical relevance are currently investigated. Patients with recurrent kidney stone episodes may be at elevated risk of progressive chronic kidney disease. SUMMARY: Monogenic causes of KSD are prevalent in patients less than 25 years of age and in some patients with high-risk metabolic profiles. These patients should undergo genetic testing to enable a precise molecular genetic diagnosis and personalized therapy as well as family counseling and screening.

Humans↗
PubMed1994

Molecular medicine: a primer for clinicians--Part VI: Introduction to genetic testing.

Application of the tools of molecular biology to clinical medicine is most apparent than in the development of DNA-based diagnostic and predictive tests. Such tests allow direct examination of the DNA of individuals for the presence or absence of the causative or predisposing molecular defect for a disease or condition. In this and the next two papers, in our series, we will discuss various aspects of genetic testing. We will consider the different types of testing, their current and potential clinical applications and discuss some of the major ethical and legal issues that genetic testing poses.

Alleles↗
PubMed2001

Genetic testing in spinocerebellar ataxias: defining a clinical role.

Although genetic tests for known spinocerebellar ataxia (SCA) genes are increasingly available, their exact clinical role has received much less attention. Currently available DNA tests can define the genotypes of up to two thirds of patients with dominantly inherited SCAs. Certain characteristic clinical features and ethnic predilection of some of the SCA subtypes may help prioritize specific SCA gene testing. Available data on genotype-phenotype correlation suggest that currently available DNA tests cannot accurately predict age of onset or prognosis. Because of the mostly adult-onset symptoms and the absence of effective treatment, genetic counseling is essential for addressing ethical, social, legal, and psychological issues associated with SCA DNA testing.

Animals↗
PubMed1997

Genetic testing for breast cancer susceptibility: frequency of BRCA1 and BRCA2 mutations.

Genetic testing for breast cancer susceptibility became a reality after two cancer predisposition genes, BRCA1 and BRCA2, were identified. Mutations in these two genes were predicted to account for 85% to 90% of hereditary breast and ovarian cancer syndromes. We present results of mutation analysis of the coding sequence of these two genes in 110 consecutive non-Jewish breast cancer patients with a positive family history of breast and/or ovarian cancer. The individuals were identified in various cancer risk evaluation centers in the country. Twenty-two (20%) mutations in the BRCA1 gene and 8 mutations (7%) in the BRCA2 gene were detected. We also analyzed 52 Ashkenazi Jewish breast cancer patients for mutations in the BRCA1 and BRCA2 genes. Eleven Jewish individuals (21%) carried either one of the two common mutations, 185delAG and 5382InsC, in the BRCA1 gene and 4 individuals (8%) had the 6174delT mutation in the BRCA2 gene. The frequency of mutations in BRCA genes in affected people in this ethnic group was not significantly different from the non-Jewish population. On further analysis, the data demonstrate that neither age of onset nor phenotype of the disease had any significant predictive value for the frequency of mutations in these genes. These data confirm the lower prevalence of mutations in either of the BRCA genes in clinical families when compared to high-risk families used for obtaining linkage data in a research setting.

Adult↗
PubMed2006

Medullary thyroid cancer and the impact of genetic testing.

Medullary thyroid cancer (MTC) consists of a rare, undifferentiated tumor and often is described as having a chronic and indolent disease process. Approximately 5%-10% of all thyroid malignancies are MTC, and about 25% of patients diagnosed with the disease have a genetic form that was inherited through a mutation of the RET proto-oncogene. The mutation is expressed by an autosomal dominant allele and, if inherited, has almost a 100% chance of developing into a malignancy. Detection of the germline mutation identifies individuals at risk and enables prophylactic treatment for the prevention of MTC. As a result, patients and family members commonly undergo genetic testing during the diagnostic phase and experience certain psychosocial stressors. The purpose of this article is to provide an overview of MTC and its symptoms, treatment, prognosis, and genetics. The psychosocial effects of genetic testing on the quality of life of patients with MTC also will be described. By learning more about the pathophysiology and psychosocial stressors, nurses can facilitate proper counseling and increase the likelihood of positive outcomes for their patients.

Carcinoma, Medullary↗