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PubMed2006

Genetic knowledge and moral responsibility: ambiguity at the interface of genetic research and clinical practice.

Despite a rapidly expanding literature on the issue of duty to warn at-risk relatives in the context of clinical genetic testing, little has been written on parallel issues with regard to the management of genetic research results. Some might view this lack as an indication that there is little to discuss in this regard. That is, standard practice is that data obtained through medical research should not be treated as though they are clinically relevant, and this standard should hold for genetic research as well. This paper challenges this conclusion and its underlying assumptions. We argue that the line between genetic research and clinical practice is often ambiguous. In some cases, research data gathered from a very small number of subjects could have immediate clinical implications. Hence, it is unethical for genetic researchers to absolve themselves of clinical responsibilities for research subjects and/or their families, on the grounds that the data were obtained for research purposes. Indeed, we argue that it could well be unethical to embark on some forms of genetic research unless advance arrangements have been made for genetic counseling and clinical follow-up. Furthermore, in some cases, it might be unethical to enroll subjects in studies if the subjects are unwilling to receive their individual results.

Arrhythmogenic Right Ventricular Dysplasia↗
PubMed1993

Gene therapy, concepts, current trials and future directions.

Since the initial human clinical trials of retroviral-mediated gene transfer in the USA in 1989, numerous additional protocols are in process or have been proposed. In the first therapeutic protocol, to treat the genetic disease ADA deficiency, encouraging signs of clinical benefit have been observed in the first two patients. Gene-marking properties are being extensively used in many protocols, particularly in the area of autologous bone marrow transplantation for various cancers. The drug delivery potential of gene therapy is initially being evaluated through delivery of various lymphokines and cytokines in cancer therapy protocols. Testing has also begun for other genetic diseases, Familial Hypercholesterolemia and Hemophilia B. Vector systems and retroviral vectors are developing rapidly, and a clinical trial using a liposome-based delivery has started. The pace of technical development and clinical application has intensified. Although significant clinical therapies are expected from these initial studies, the full potential of gene therapy for wide applications still requires innovative research programs, directed towards true in vivo vectors.

Animals↗
PubMed2006

[Wilson's disease: forms of presentation in childhood].

Wilson's disease can manifest with symptoms of liver disease or neuropsychiatric disorders in children and adults. This autosomal recessive disorder is caused by a copper metabolism disorder due to a mutation in the ATP7B transporter. Excessive amounts of copper accumulate in the body due to inhibition of the release of copper into bile. Because effective treatment is available, recognizing this disease in presymptomatic or early stages, when it can be reversed, is highly important. Diagnosis is often easy but the available tests (measurement of ceruloplasmin, and blood, urinary and liver copper levels) can be misleading. There is no single test with 100% sensitivity in screening nor do any of the tests, when used alone, provide 100% specificity. Diagnosis is currently based on the combination of clinical findings and the results of laboratory tests. Genetic study, with a finding of mutations in the two alleles of the ATP7B gene, is still not a rapid and easily available alternative and the absence of these mutations does not rule out the possible presence of other mutations not yet described.

Chelating Agents↗
PubMed2006

Introduction to molecular cystic fibrosis testing.

Technology improvements are rapidly bringing molecular diagnostics into routine laboratories. Recent recommendations for cystic fibrosis carrier testing by the American College of Medical Genetics (ACMG) have led to commercial test kit development and increased testing volumes. Molecular testing of genetic diseases presents a variety of challenges and situations that may be unfamiliar to laboratories with limited molecular genetic experience. We will briefly review the disease and discuss mutation testing indications, methodologies, quality assurance, and reporting issues associated with cystic fibrosis testing.

Cystic Fibrosis↗
PubMed2026

Field-isolate recombinant tick-borne encephalitis viruses define reporter-stability guidelines for antiviral testing in flaviviruses.

As arthropod-borne viruses continue to threaten populations globally, there is a pressing need for experimental systems that enable rapid antiviral discovery. Reverse-genetics platforms producing recombinant reporter orthoflaviviruses have been developed to address this gap. Here, we present two new recombinant tick-borne encephalitis viruses (TBEVrec) generated on a European-subtype Haselmühl Tiho1 isolate backbone. A reporter gene, either eGFP or Nluc, was inserted in the capsid-coding region of the genome downstream of the capsid RNA regulatory signal and separated from the complete viral polyprotein by a 2A self-cleaving peptide. TBEVrec was better rescued using the circular polymerase extension reaction (CPER) than with the infectious subgenomic amplicon (ISA) method. TBEVrec replicated efficiently in relevant human cell lines, with comparable replication to wild-type TBEV in a neuronal cell line and moderately reduced titers and RNA levels in immune-derived cell lines. Using either eGFP or Nluc, we illustrate how TBEVrec enabled high-content RNAi screening, highlighting Nucleolin and PRKD1 as potential TBEV host factors, and drug testing on a benchtop plate reader. Nanopore sequencing of the eGFP insert revealed that the reporter is excised without affecting flanking regions. Comparative analysis of eGFP and Nluc further shows that this instability is time- and cell type-dependent, and that Nluc is comparatively more stable. From these observations, we outline safeguards and design principles that are broadly applicable both to the rescue of existing constructs and to the design of future recombinant reporter virus platforms.

CPER↗
PubMed2005

A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C.

BACKGROUND: There is increasing interest in the influence of host genetic factors on hepatic fibrosis, and whether genetic markers can reliably identify subjects at risk of developing severe disease. We hypothesised that hepatitis C virus (HCV) infected subjects with progressive fibrosis, classified using strict criteria based on histology at biopsy in addition to disease duration would be more likely to inherit several genetic polymorphisms associated with disease progression compared with subjects with a low rate of disease progression. METHODS: We examined polymorphisms in eight genes that have been reported to have an association with hepatic fibrosis. RESULTS: Associations between polymorphisms in six genes and more rapidly progressing fibrosis were observed, with individual adjusted odds ratios ranging from 2.1 to 4.5. The relationship between rapidly progressing fibrosis and possession of > or =3, > or =4, or > or =5 progression associated alleles was determined and the adjusted odds ratios increased with increasing number of progression associated alleles (9.1, 15.5, and 24.1, respectively). Using logistic regression analysis, a predictive equation was developed and tested using a second cohort of patients with rapidly progressing fibrosis. The predictive equation correctly classified 80% of patients in this second cohort. CONCLUSIONS: This approach may allow determination of a genetic profile predictive of rapid disease progression in HCV and identify patients warranting more aggressive therapeutic management.

Adult↗
PubMed1996

Differential response to Na+ channel blockade, beta-adrenergic stimulation, and rapid pacing in a cellular model mimicking the SCN5A and HERG defects present in the long-QT syndrome.

The long-QT syndrome (LQTS) is a hereditary disorder characterized by an abnormally prolonged QT interval and by life-threatening arrhythmias. Recently, two of the genes responsible for LQTS have been identified: SCN5A, a voltage-dependent Na+ channel on chromosome 3 (LQT3), and HERG, responsible for the rapid component of the delayed rectifier current (IKr), on chromosome 7 (LQT2). We developed an in vitro model to attempt reproduction of the expected alterations in LQT3 and LQT2 patients. Guinea pig ventricular myocytes were exposed to anthopleura toxin A (anthopleurin), an inhibitor of the inactivation of the Na+ current, and to dofetilide, a selective blocker of IKr. Both interventions significantly prolonged action potential duration (APD), by 54 +/- 13 and 62 +/- 16 ms, respectively. Cells pretreated with anthopleurin significantly shortened APD in response to mexiletine, isoproterenol, and rapid pacing (from 264 +/- 38 to 226 +/- 32 ms after mexiletine, P < .001). On the contrary, cells exposed to dofetilide did not shorten the APD after mexiletine and even prolonged it after initial exposure to isoproterenol (from 280 +/- 25 to 313 +/- 20 ms, P < .001); during rapid pacing, APD was shortened but less (38 +/- 9 versus 60 +/- 11 ms, P < .05) than in anthopleurin-treated cells. This study shows that a cellular model for LQTS, based on the recent advances in molecular genetics, can provide adequate "phenotypes" of prolonged repolarization amenable to the testing of interventions of potential clinical relevance. We found differential responses to Na+ channel blockade, to beta-adrenergic stimulation, and to rapid pacing according to specific pretreatment with either anthopleurin (to mimic LQT3) or dofetilide (to mimic LQT2). These different responses in myocytes bear striking similarities with the differential response to analogous interventions in LQTS patients with mutations on the SCN5A and HERG genes.

Action Potentials↗
PubMed2006

Introducing a fast and simple PCR-RFLP analysis for the detection of mutant thiopurine S-methyltransferase alleles TPMT*3A and TPMT*3C.

BACKGROUND: Azathioprine, in combination with corticosteroids, is the first-line therapy of severe forms of pemphigus vulgaris. Patients with an impaired thiopurine S-methyltransferase (TPMT) activity are at risk of developing severe myelo-suppression upon treatment with thiopurines such as azathioprine. Analysis of the TPMT status prior to drug administration is therefore highly recommended. However, because of the limited availability of TPMT testing outside of specialized centres, pre-emptive TPMT testing is not widespread. To avoid laborious biochemical and sequencing assays, we evaluated a new restriction fragment length polymorphism (RFLP) analysis. METHODS: We designed a rapid genetic polymerase chain reaction (PCR)-RFLP screen for the most prevalent mutant TPMT*3A and TPMT*3C alleles that are known to result in reduced TPMT enzyme activity. RESULTS: Validating our fast system on 871 Caucasian DNA samples, we observed that 8.61% of our probands carried the TPMT*3A allele and 0.23% were heterozygous for the TPMT*3C allele, which is in concordance with previously reported allele frequencies. CONCLUSION: This simple and low-cost PCR-RFLP TPMT polymorphism testing approach can be performed in a standard laboratory. It should be applied to all patients prior to receiving thiopurine drug therapy to avoid the severe, but predictable, haematopoietic side-effects of thiopurine drug administration.

Alleles↗
PubMed1998

Increased repetition blindness in schizophrenia patients and first-degree relatives of schizophrenia patients.

This study investigated the phenomenon of repetition blindness in schizophrenia patients and first-degree relatives of schizophrenia patients. Twelve schizophrenia patients, 13 siblings of schizophrenia patients and 26 normal controls were tested on their ability to detect the repetitions within rapidly presentated visual word lists. Schizophrenics and their relatives showed increased repetition blindness compared with normal controls. This suggests a deficit in rapid information processing in schizophrenia.

Adult↗
PubMed2002

Power of a simplified multivariate test for genetic linkage.

In this paper we compare the power of the multivariate Haseman-Elston (MHE) test proposed earlier by Amos et al. (1990) and a computationally rapid new version of the multivariate Haseman-Elston test (NMHE) (Elston et al. 2000). We show that the power of NMHE was, for different simulation setups, identical or higher than that of MHE. In the bivariate case, the power of the NMHE method was somewhat less than that of the computationally intensive maximum likelihood variance components method (Amos et al. 2001). We present comparisons of the empirical distributions of the NMHE test to its limiting distributions for a range of numbers of traits. The distribution of the NMHE test appeared to conform satisfactorily to its limiting asymptotic distribution in large samples. Otherwise, empirical critical values for NMHE are somewhat higher than predicted, i.e. the test proposed by Elston et al. (2000) is non-conservative. The use of empirical critical values is therefore recommended for limited sample sizes (less than several hundred families). We also present the results of a linkage analysis performed by the NMHE method on a set of 4 body size-related traits. The method identified meaningful combinations of traits that showed significant linkage on chromosome 2 and suggestive linkage to regions on chromosomes 16 and 17.

Body Constitution↗
PubMed2006

Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations.

PURPOSE: Traditional genetic approaches to identify gene mutations in cancer are expensive and laborious. Nonetheless, if we are to avoid rejecting effective molecular targeted therapies, we must test these drugs in patients whose tumors harbor mutations in the drug target. We hypothesized that gene expression profiling might be a more rapid and cost-effective method of identifying tumors that contain specific genetic abnormalities. MATERIALS AND METHODS: Gene expression profiles of 46 samples of medulloblastoma were generated using the U133av2 Affymetrix oligonucleotide array and validated using real-time reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Genetic abnormalities were confirmed using fluorescence in situ hybridization (FISH) and direct sequencing. RESULTS: Unsupervised analysis of gene expression profiles partitioned medulloblastomas into five distinct subgroups (subgroups A to E). Gene expression signatures that distinguished these subgroups predicted the presence of key molecular alterations that we subsequently confirmed by gene sequence analysis and FISH. Subgroup-specific abnormalities included mutations in the Wingless (WNT) pathway and deletion of chromosome 6 (subgroup B) and mutations in the Sonic Hedgehog (SHH) pathway (subgroup D). Real-time RT-PCR analysis of gene expression profiles was then used to predict accurately the presence of mutations in the WNT and SHH pathways in a separate group of 31 medulloblastomas. CONCLUSION: Genome-wide expression profiles can partition large tumor cohorts into subgroups that are enriched for specific genetic alterations. This approach may assist ultimately in the selection of patients for future clinical trials of molecular targeted therapies.

Adolescent↗
PubMed2000

Phenotypic and genetic characterization of Paecilomyces lilacinus strains with biocontrol activity against root-knot nematodes.

Efficient selection of fungi for biological control of nematodes requires a series of screening assays. Assessment of genetic diversity in the candidate species maximizes the variety of the isolates tested and permits the assignment of a particular genotype with high nematophagous potential using a rapid novel assay. Molecular analyses also facilitate separation between isolates, allowing the identification of proprietary strains and trace biocontrol strains in the environment. The resistance of propagules to UV radiation is an important factor in the survival of a biocontrol agent. We have analyzed 15 strains of the nematophagous fungus Paecilomyces lilacinus using these principles. Arbitrarily primed DNA and allozyme assays were applied to place the isolates into genetic clusters, and demonstrated that some genetically related P. lilacinus strains exhibit widespread geographic distributions. When exposed to UV radiation, some weakly nematophagous strains were generally more susceptible than effective isolates. A microtitre tray-based assay used to screen the pathogenic activity of each isolate to Meloidogyne javanica egg masses revealed that the nematophagous ability varied between 37%-100%. However, there was no clear relationship between nematophagous ability and genetic clusters. Molecular characterizations revealed sufficient diversity to allow tracking of strains released into the environment.

Animals↗
PubMed1994

Rapid genetic characterization of HIV type 1 strains from four World Health Organization-sponsored vaccine evaluation sites using a heteroduplex mobility assay. WHO Network for HIV Isolation and Characterization.

To assist in the preparation for the testing of vaccines against human immunodeficiency virus (HIV) we, as part of the World Health Organization Network for HIV Isolation and Characterization (WHO-NHIC), evaluated the genotypic variation of HIV-1 in cohorts from Brazil, Rwanda, Thailand, and Uganda. Here we report the results from a pilot study of 65 HIV-1-infected individuals. In all cases in which viral envelope gene fragments could be amplified by polymerase chain reaction, subtypes could be assigned using a heteroduplex mobility assay (HMA)1 by comparison with HIV-1 strains representing six HIV-1 envelope subtypes. All subtype classifications matched those found by envelope gene sequencing. Phylogenetic relationships were further clarified by heteroduplex formation between samples within each subtype. A relatively homogeneous subtype E virus population predominated over subtype B viruses in the sample set from Thailand. Viruses from the other countries were also limited to one or two subtypes but were more divergent within each subtype. All samples from Rwanda (13/13) and some from Uganda (3/16) were of subtype A; all Brazilian samples were of subtype B, except for one belonging to subtype C; most samples from Uganda (13/16) clustered with the subtype D. Analysis by HMA is therefore applicable for screening of HIV-1 genotypes in countries under consideration for large-scale vaccine trials. It should be generally useful when samples containing at least one variable genetic locus need to be rapidly classified by genotype and/or analyzed for epidemiological clustering.

AIDS Vaccines↗
PubMed2003

Genetic mapping and QTL analysis of fiber-related traits in cotton ( Gossypium).

Cotton, the leading natural fiber crop, is largely produced by two primary cultivated allotetraploid species known as Upland or American cotton ( Gossypium hirsutum L.) and Pima or Egyptian cotton ( G. barbadense L.). The allotetraploid species diverged from each other and from their diploid progenitors (A or D genome) through selection and domestication after polyploidization. To analyze cotton AD genomes and dissect agronomic traits, we have developed a genetic map in an F2 population derived from interspecific hybrids between G. hirsutum L. cv. Acala-44 and G. barbadense L. cv. Pima S-7. A total of 392 genetic loci, including 333 amplified fragment length polymorphisms (AFLPs), 47 simple sequence repeats (SSRs), and 12 restriction fragment length polymorphisms (RFLPs), were mapped in 42 linkage groups, which span 3,287 cM and cover approximately 70% of the genome. Using chromosomal aneuploid interspecific hybrids and a set of 29 RFLP and SSR framework markers, we assigned 19 linkage groups involving 223 loci to 12 chromosomes. Comparing four pairs of homoeologous chromosomes, we found that with one exception linkage distances in the A-subgenome chromosomes were larger than those in their D-subgenome homoeologues, reflecting higher recombination frequencies and/or larger chromosomes in the A subgenome. Segregation distortion was observed in 30 out of 392 loci mapped in cotton. Moreover, approximately 29% of the RFLPs behaved as dominant loci, which may result from rapid genomic changes. The cotton genetic map was used for quantitative trait loci (QTL) analysis using composite interval mapping and permutation tests. We detected seven QTLs for six fiber-related traits; five of these were distributed among A-subgenome chromosomes, the genome donor of fiber traits. The detection of QTLs in both the A subgenome in this study and the D subgenome in a previous study suggests that fiber-related traits are controlled by the genes in homoeologous genomes, which are subjected to selection and domestication. Some chromosomes contain clusters of QTLs and presumably contribute to the large amount of phenotypic variation that is present for fiber-related traits.

Chromosome Mapping↗