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PubMed2001

Adult onset neurological disorders. Predictive genetic testing.

BACKGROUND: With the rapid advances in gene discovery and genetic diagnosis, increasing numbers of hereditary adult onset neurological disorders can be diagnosed prior to the onset of symptoms. Such testing is called predictive or presymptomatic testing. OBJECTIVE: To present current practice for predictive testing for adult onset neurological disorders and the rationale behind it. DISCUSSION: Predictive testing should be undertaken in the setting of a formal counselling process both before and after results are given. Counselling incorporates genetic information and social and legal repercussions of taking a predictive genetic test. For predictive genetic testing to be possible, the causative mutation in the family must be known. The majority of those at risk of adult onset incurable neurodegenerative disorders choose not to have predictive testing.

Adult↗

PubMed2005

A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes.

The authors propose a novel approach to evaluate the effects of risk factors on disease risks in carriers of high-penetrance alleles in disease susceptibility genes. Most studies to date have utilised data collected on carriers identified through ongoing genetic testing programs. The advantage of this approach is that it allows relatively large numbers of affected and unaffected carriers to be identified rapidly. However, genetic testing is targeted at individuals with a strong family history of disease, so that the selection of carriers is not random with respect to disease status. Risk factors are often analysed by standard cohort analysis methods, but these can be biased in retrospective studies if subjects are selected on the basis of phenotype. To overcome this problem, a weighted cohort approach is proposed, under which individuals are weighted according to certain sampling probabilities in order to mimic a true cohort. The method is illustrated by analyses of data from the International BRCA1/2 Carrier Cohort Study (IBCCS). Simulations demonstrate that the method gives rate ratio estimates that are close to unbiased provided that the absolute disease risks are well estimated. The power to detect associations is, however, reduced compared with an unweighted approach.

Adult↗

PubMed2006

Policy implications of genetic testing: not just for geneticists anymore.

Genetic testing is expanding rapidly to become part of mainstream medicine. While genetic tests bring with them the promise of improved diagnosis and treatment for patients, they also raise several policy challenges. These challenges include the lack of a coherent oversight system to ensure the quality of tests and testing laboratories, the rise of direct-to-consumer genetic testing, the dearth of professional guidelines to assist the transition of genetic tests from research to medical practice, and the absence of federal legislation to protect the privacy of genetic information and prevent genetic discrimination.

Genetic Techniques↗

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↗

PubMed1994

Application of molecular genetics in public health: improved follow-up in a neonatal hemoglobinopathy screening program.

Newborn screening for the hemoglobinopathies has been shown to reduce morbidity and mortality, particularly for sickle cell anemia, by facilitating initiation of penicillin prophylaxis by 4 months of age. The purpose of the current investigation was to determine whether molecular genetic follow-up testing could be introduced into a neonatal hemoglobinopathy screening program and, if successfully introduced, whether it would reduce time to diagnostic confirmation. Between July 1, 1991, and October 7, 1992, 518 original dried blood specimens were referred from the Texas Department of Health Neonatal Hemoglobinopathy Screening Program for molecular genetic follow-up testing. Allele-specific cleavage (ASC) after amplification with matched and mismatched polymerase chain reaction primers was compared to allele-specific oligonucleotide (ASO) hybridization. By November 2, 1992, molecular genetic analyses were definitive in 506, and agreement was observed between ASC and ASO hybridization in all specimens analyzed. Approximately 13% of those initially screened FS were considered probable S/beta-thal by DNA and RNA testing. Rapid molecular genetic analysis contributed to a substantial reduction of the mean age at confirmation by approximately 50%, to about 2 months of age. ASC is a reliable method for molecular genetic analysis of dried blood specimens, providing methodology which can be readily automated. An automated method is demonstrated that is based on microtiter plate technology and will significantly reduce labor intensity and costs, while increasing sample throughput. Even with current manual testing methods, DNA and RNA analysis of initial newborn screening specimens will reduce the age at confirmation well under 4 months, the age cut-off for effective initiation of penicillin prophylaxis.

Alleles↗

PubMed1998

Genetic test for myophosphorylase deficiency in Charolais cattle.

OBJECTIVE: To develop a simple test for the determination of genetic susceptibility to myophosphorylase deficiency in Charolais cattle. ANIMALS: 48 adult Charolais cattle and 233 calves from one herd and 3 Charolais cattle from 2 other herds. Sixty Piedmontese and 34 Saler cattle provided negative-control samples. PROCEDURE: Cattle were from a Charolais herd in which myophosphorylase deficiency was identified and 2 other herds in which cattle had signs compatible with the disease. Genomic DNA was isolated from heparinized blood samples. A segment of the myophosphorylase gene containing the mutation site was amplified by polymerase chain reaction assays, and the genotype (normal vs affected allele) was determined by using restriction enzyme and agarose gel electrophoretic analysis. RESULTS: The 3 myophosphorylase genotypes (homozygous normal, homozygous affected, and heterozygous) could be readily identified. Segregation of the affected allele could be determined in an extended pedigree, and all clinically affected cattle were homozygous for this allele. Determination of the distribution of normal and affected alleles in a large population did not indicate a strong selective advantage for heterozygous carriers in this herd. Heterozygotes were also identified in Charolais cattle from the 2 other herds. CONCLUSIONS: Breeders of Charolais cattle can use this genetic test to perform marker-assisted selection and remove cattle with the mutant myophosphorylase allele from the breeding population. Alternatively, they could more accurately determine selective advantages and disadvantages for cattle with the affected allele. CLINICAL RELEVANCE: Development of this test enables rapid genetic screening of Charolais and related breeds of cattle for detection of the mutation responsible for myophosphorylase deficiency.

Animals↗

PubMed1999

Hereditary breast cancer. Psychosocial issues and family physicians' role.

OBJECTIVES: To outline the psychosocial issues in hereditary breast cancer (HBC) assessment and discuss the role of family physicians. QUALITY OF EVIDENCE: A literature search using MEDLINE, CINAHL, CancerLit, and HealthStar databases was conducted from January 1990 to April 1998, using the key words breast cancer or neoplasm and familial or hereditary, genetic testing or screening, primary care or family physician or counseling, genetic counseling, psychosocial or psychological. We found only a few studies focusing on a small number of well-studied "research families." MAIN FINDINGS: Women with a family history of breast cancer were likely to be highly interested in genetic testing for cancer risk. The benefit of testing for those with negative results is reassurance. Those found to be carriers of genetic mutations might benefit from increased surveillance and prophylactic therapy. Risks of testing include anxiety, depression, guilt, altered self-image, and insurance and employment discrimination. A family physician's role is to assess risk, to provide information and support so women can make informed choices about referral to familial cancer clinics, to offer cancer surveillance, and to provide support once genetic test results are available. CONCLUSION: Genetic testing is rapidly moving from research to clinical applications. Family physicians play an integral role in educating and managing women at risk for HBC. Physicians must prepare themselves with knowledge and counseling skills to meet the challenges of this new technology.

Adult↗

PubMed1997

Clinical molecular genetic testing.

Recent advances in human molecular genetics are rapidly producing clinical genetic tests for a variety of conditions. In addition to tests for rare genetic disorders, tests for common illnesses with mixed genetic and environmental etiologies are being developed. While practice guidelines for test utilization are being developed, many physicians would benefit from additional knowledge about the design and limitations of these tests. This article reviews the genetic background necessary to understand linkage-based and direct mutations tests and discusses some of the issues physicians must consider when selecting an appropriate test for a given clinical situation.

Genetic Techniques↗

PubMed1994

Genetics, ethics, and Alzheimer disease.

This article considers the emerging research on Alzheimer disease (AD) genetics in relation to ethical questions surrounding presymptomatic and prenatal genetic testing. Given the rapid advance in AD genetics over the past 8 years, it is likely that the attention of clinicians and ethicists will increasingly turn to genetic issues. After a survey of current genetic knowledge, this article addresses 3 areas of likely ethical concern. While AD genetic screening programs are currently rare and restricted to specific pedigrees, they will become more common in the future. It is, therefore, imperative that society and clinicians begin to consider the ethical issues this raises.

Alzheimer Disease↗

PubMed1995

[Hyperaldosteronism sensitive to dexamethasone with adrenal adenoma. Clinical, biological and genetic study].

OBJECTIVES: Dexamethasone-sensitive hyperaldosteronism is associated with early onset hypertension and primary hyperaldosteronism. Diagnosis is difficult but can be improved by genetic testing for the mutant gene. METHODS: We collected the clinical, biological and genetic elements observed in a family with dexamethasone-sensible hyperaldosteronism. Complete data were obtained in 5 adult subjects with the disease. Degree of hypertension varied, more so in the second generations as did hypokaliaemia and hyperaldosteronism. In affected patients, there was a 10 to 50 fold increase in urinary 18-OH components and 18 oxocortisol. RESULTS: Single dose (1.5 mg) dexamethasone led to a greater than 80% drop in aldosterone levels in the blood and urine, confirming the abnormal effect of ACTH on mineralocorticoid secretion. At the dose of 1 mg/d for 10 weeks, dexamethasone lowered mean 24-H ambulatory arterial pressure (11.8/9.6 mmHg) and corrected for the hypokaliaemia (+0.54 mmol/l) and the hyperaldosteronism (mean decrease -36% and -75% in blood and urine respectively). An adrenal tumour was identified in hyperplasic glands in two subjects and a micronodular formation was identified in two others. The specific molecular diagnosis of the disease was done with Southern blotting. Among the 18 families in 3 generations, 8 carried a 11 beta OHase-aldosterone synthetase chimeric gene. This mutation cosegregates with hormonal abnormalities and confirms the autosomal dominant inheritance of the disease. CONCLUSION: The simplicity and rapidity of genetic testing allows early diagnosis of this disease among families with early onset hypertension and associated hyperaldosteronism with or without adrenal hyperplasia and/or a tumoral formation.

Adolescent↗

PubMed2026

Rapid genome sequencing identifies treatable conditions in non-intensive care unit hospitalized children.

PURPOSE: The utility of rapid genome sequencing (RGS) has been evaluated in pediatric intensive care unit (ICU) settings, but few studies have investigated its use in non-critically ill hospitalized children. Our study assesses the impact of RGS use in the non-ICU setting. METHODS: We analyzed RGS results obtained for hospitalized children from 2019 to 2023 and evaluated the impact on non-ICU patient care. Changes in management were determined via chart review of the first 30 days after testing. RESULTS: RGS was performed on 422 individuals: 339 ICU and 83 non-ICU. The diagnostic rate was 39% (32 of 83) in non-ICU and 35% (120 of 339) in ICU patients. Eighty-one percent of diagnostic RGS results in non-ICU patients had a management change within 30 days, and 56% (18 of 32) received a disease-targeted intervention, including medication or diet change, listing for transplant, or connection with a clinical trial. Of the children who received these intervention changes, the most common disease categories were metabolic (61%, 11 of 18) and epilepsy (22%, 4 of 18). CONCLUSION: RGS is effective at identifying treatable diagnoses in the non-ICU setting, with most patients experiencing a change in their care, and over half receiving disease-focused interventions. Our results support the utility of RGS in non-ICU hospitalized children and can impact providers' decision-making and payer coverage.

Genome sequencing↗

PubMed2000

A rapid fluorescent multiplexed-PCR analysis (FMPA) for founder mutations in the BRCA1 and BRCA2 genes.

Mutations of the BRCA1 and BRCA2 genes account for approximately 80% of hereditary breast/ovarian cancer families, but the size of these two genes makes mutation analysis time-consuming and technically challenging. In some populations such as the Ashkenazi Jewish and the French-Canadian, a small number of recurrent founder mutations account for the majority of mutations in cancer families. We have therefore developed two rapid genetic screening tests, which allow us to detect three frequent frameshift mutations in the Ashkenazi Jewish population and five frameshift mutations in the French-Canadian population. These fluorescent non-radioactive methods permit the simultaneous detection of multiple mutations by generating multiplexed PCR-amplified gene fragments, and by discriminating these on the basis of their size in a denaturing polyacrylamide gel. Using these methods, we were able to correctly identify all mutants in a blinded analysis of 276 DNA samples, including 30 derived from paraffin-embedded tumor samples and 10 from buccal-cell brushes, with no false positive or false negative results. These techniques designed for the direct detection of recurrent mutations in the BRCA1 and BRCA2 genes, have the advantages of being efficient, sensitive, cost-effective, and are applicable to large scale screening for epidemiologic studies.

BRCA2 Protein↗

PubMed2000

A guide for diagnosis of patients with arterial and venous thrombosis.

Inasmuch as coagulation laboratories are involved in providing a diagnosis for underlying causes of venous and arterial thrombosis, we present a comprehensive review of the biological properties and functions of the components of the hemostatic system as they relate to the diagnosis of arterial and venous thrombosis. Moreover, as coagulation laboratories are necessary to evaluate the success of initial treatment modalities and to provide guidance for supplemental therapeutic intervention, we include information on antiplatelet and antithrombotic therapy. Included in clinical coagulation testing are assays that evaluate the potential of blood to form clots and tests for platelet numbers and platelet functions. Clot-based assays directly detect the biological activity of procoagulant factors and fibrinogen; chromogenic substrate assays evaluate proteolytic activities of clotting as well as fibrinolysis enzymes; and specific antibodies measure the concentrations of coagulation and fibrinolysis enzymes in plasma. Genetic testing is rapidly becoming incorporated into the clinical routine. The prothrombin time (PT), activated partial prothrombin time (APTT), and thrombin time (TT) are screening assays that measure the clotting times of recalcified whole blood or platelet-poor plasma. In addition to their function as screening assays, PT, APTT, and TT are the backbone of all the specialized clot-based assays for factor activities and for the indirect measurement of inhibitory antithrombin and protein C activities. Molecular markers related to hemostasis and fibrinolysis consist of proteins or peptides that indicate an ongoing physiological or abnormal process related to clot formation, thrombosis, vascular damage, or drug effect. Molecular markers are currently identified by means of specific antibodies prepared against them. The list of hemostatic molecular markers is rapidly growing. Most of the assays developed for molecular marker measurement, with the notable exception of the d-dimer assay, are typically used in clinical research.

Antifibrinolytic Agents↗

PubMed2005

Understanding genetics: a primer for occupational health practice.

Because biologic diversity is essential for life, genes have developed many versions that may be further modified by interaction with other genes and with environmental factors. Polymorphic alterations of genetic material influence drug responses, predisposition or resistance to disease, and susceptibility to environmental toxicity. The occupational health professional should be aware of rapidly changing genetic tests, be able to distinguish between screening and diagnostic modalities, be able to access genetic resources to find the latest protocols, and should consider the ethical, legal, and social implications of genetic testing in the workplace.

DNA↗

PubMed2005

[Ethical guidelines on genetic testing and gene therapy].

According to the recent and rapid advances in molecular genetics research, genetic testing and gene therapy have a potential of giving unexpected influence to the human beings. To prevent and to solve various ethical, legal and social implementations (ELSI) of genetic testing and gene therapy, several guidelines have been established. In Japan, all researchers and all clinicians have to know and keep the following three guidelines on genetic testing and a guideline on gene therapy: 1) "Guidelines for Researches on Human Genome and Gene (2001)" by the three Ministries (Education, Health and Economy), 2) "Guidelines for Genetic Testing (2001)" by the Genetic--medicine--related 10 societies, 3) "Ethical Principles on Entrusted Genetic Testing (2001)" by the Japan Registered Clinical Laboratories Association, and 4) "Guidelines for Clinical Research on Gene Therapy (2002)" by the two Ministries (Health and Education).

Bioethics↗

PubMedDate not supplied

Genetic testing coverage and reimbursement: a provider's dilemma.

The rapid growth of new molecular genetic tests stimulated by the diagnostic potential of DNA/RNA analyses has resulted in the capability of molecular genetic assay technology outpacing the American Medical Association Current Procedural Terminology (CPT) codes and Medicare reimbursement. The AMA CPT Editorial Panel is poised to change the way we report genetic testing, and this change may have the potential to stimulate a governmental review of how Medicare is paying for diagnostic genetic testing. Genetic assays are costly, and those in laboratory management need to be aware of potential changes that may influence the ability of their laboratory to provide access to genetic testing services for their physician clientele. The commercialization of genetic testing has resulted in a proliferation of commercial laboratories and university medical center laboratories, CLIA-certified to perform high complexity testing, offering some level of genetic testing. The genetic tests are offered as home brew (in-house developed) assays, most of which are using analyte-specific reagents. Because these are home brew assays, there is no standardization in how the industry tests for specific mutations. As these genetic assays are billed using the generic molecular diagnostic codes, 83890 through 83912, from the Pathology and Laboratory Chemistry subsection of the CPT, payers are not able to identify the specific mutations being tested and make payment determinations based on the mutations as they relate to the diagnosis code. This article discusses the history of molecular diagnostic coding and related reimbursement, current coverage issues, and the genetic coding proposal under consideration by the AMA CPT Editorial Panel.

Centers for Medicare and Medicaid Services, U.S.↗

PubMed2003

Familial frontotemporal dementia: from gene discovery to clinical molecular diagnostics.

Genetic testing is important for diagnosis and prediction of many diseases. The development of a clinical genetic test can be rapid for common disorders, but for rare genetic disorders this process can take years, if it occurs at all. We review the path from gene discovery to development of a clinical genetic test, using frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) as an example of a complex, rare genetic condition. An Institutional Review Board-approved multidisciplinary research program was developed to identify patients with familial frontotemporal dementia. Genetic counseling is provided and DNA obtained to identify mutations associated with FTDP-17. In some cases it may be appropriate for individuals to be given the opportunity to learn information from the research study to prevent unnecessary diagnostic studies or the utilization of inappropriate therapies, and to make predictive testing possible. Mutations identified in a research laboratory must be confirmed in a clinical laboratory to be used clinically. To facilitate the development of clinical genetic testing for a rare disorder, it is useful for a research laboratory to partner with a clinical laboratory. Most clinical molecular assays are developed in research laboratories and must be properly validated. We conclude that the transition of genetic testing for rare diseases from the research laboratory to the clinical laboratory requires a validation process that maintains the quality-control elements necessary for genetic testing but is flexible enough to permit testing to be developed for the benefit of patients and families.

Chromosomes, Human, Pair 17↗

PubMed1999

Genetic testing and the clinical laboratory improvement amendments of 1988: present and future.

CLIA '88 superseded CLIA '67. CLIA '88 set standards designed to improve quality and expanded federal oversight to virtually all clinical laboratories in the United States. Presumably because genetics testing was then in its infancy, CLIA '88 did not devote a special section to genetics testing. Biochemical and immunochemical tests used to evaluate inborn errors of metabolism and other genetic entities were categorized as analytes in the Clinical Chemistry section, and DNA probes used primarily in infectious disease were included in Microbiology. The legal, social, economic, and ethical implications of genetic testing and the rapid commercialization of these tests led to recommendations that genetic testing be defined as a laboratory specialty with a subsection in CLIA. The advisory committee created under CLIA was assigned to review these recommendations. The committee agreed that genetics testing was sufficiently different from other areas already included in CLIA to warrant a separate section. Two definitions were adopted. The more clear-cut one is for molecular genetic and cytogenic tests. This includes the analysis of human DNA/RNA in evaluating genetic diseases. The second definition is not as clear-cut and is for the analysis of proteins and metabolites used predominantly to detect inborn errors of metabolism. Many of these analytes already are categorized according to their uses for other purposes. The recommendations for genetic testing include detailed and specific proposals concerning personnel, confidentiality and informed consent, quality control, contamination, proficiency testing, validation of tests, special reporting, retention of records, and reuse of tested specimens.

Clinical Laboratory Techniques↗