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PubMed1986

[Clinico-genetical studies of colonic cancer. II. Genetic analysis of predisposition to colonic cancer].

The structure of subjection to different clinical forms of colon cancer and to the morbidity as a whole approximates better the quasi-continued phenotypical model within which the contribution of genetic factors reaches 68-84%, that of incidental medium factors being 16-32%. Genetic study of heterogeneity of colon cancer clinical forms revealed that their pathogenetic community was quite high. However, the origin of colon cancer depends strongly on genetic factors (83.7 +/- 7.3%), in comparison with rectal cancer (67.9 +/- 7.1%). The analysis of colon cancer interrelation with other malignant neoplasms (including specific ones for women--breast and uterus cancer) revealed that the development of another malignant neoplasms was the result of the influence of partially common genes (20-50%) which predetermined the development of colon cancer and other malignant neoplasms. According to the data obtained in this study, the tables of repeated risk have been worked out which may be used for medico-genetic consultation.

Adult↗

PubMed1986

Role of prenatal genetic counseling before amniocentesis. A survey of genetics centers.

Although prenatal genetic amniocentesis is an accepted procedure for certain high-risk pregnancies, there is no standard approach to prenatal counseling, timing of counseling, materials used and location of the procedure. This survey of 126 genetics centers offering prenatal genetic amniocentesis reviewed aspects of 48,502 counseling events and a total of 61,174 samples processed in 1982. Eighty-three percent of the samples were obtained after counseling at the centers. Of the patients counseled, 88.5% chose amniocentesis, but the utilization rates varied widely between the centers. The choice of amniocentesis varied measurably with the educational materials used but not with the center size. Educational materials, written or audiovisual, were used by genetics centers in counseling 82% of the patients. There was a wide variation in center size, counseling methods used, the timing and use of counseling, and patient responses in the survey population.

Amniocentesis↗

PubMed1983

[119 cases of spina bifida treated surgically. Results of genetic investigations and genetic counseling].

After the surgical treatment of 119 cases of spina bifida, the authors present their experience of the genetic approach of the subject. From 1976 to 1978, a resolution not directing attitude towards the parents of the affected children has resulted in a total failure to recognize the recurrence risk, and in an absence of special care for the next pregnancies. The consequence has been recurrence cases of spina bifida in 4 families. Since 1979, a genetic inquiry has been systematically carried out, and all the parents have had a genetic counselling. This permitted the birth of 25 normal infants. In one case, the prenatal diagnosis revealed a fetal meningomyelocele, and motived a therapeutical abortion. Nowadays the fiability of the prenatal diagnosis and the possibility of a prevention through periconceptional vitamin supplementation are strong arguments to give a genetic counselling to all the parents of children with spina bifida.

Acetylcholinesterase↗

PubMed1982

Two-dimensional gel electrophoresis of human brain proteins. III. Genetic and non-genetic variations in 145 brains.

To determine the frequency of genetic mutations, polymorphisms, and non-genetic variation in the major human brain proteins, I examined, by equilibrium two-dimensional gel electrophoresis, 145 brains from patients dying of a wide variety of psychiatric, neurological, and non-neurological disorders. Of 176 polypeptides screened, there was one polymorphism of glial fibrillary acidic protein (GFAP-Duarte). Chi square analysis indicated it was non-randomly distributed among different diseases. A possible mutation associated with Joseph's disease is being further investigated. Three examples of a possible mutation of protein 8c:1 were noted. No other genetic mutations were observed. This low frequency of polymorphisms is consistent with results for two-dimensional gel analysis of other tissue and species. The numerous non-genetic variations are described.

Brain Chemistry↗

PubMed1995

Roles of physicians, genetic counselors, and nurses in the genetic counseling process.

A self-administered questionnaire was mailed to 325 genetic counseling professionals in the southeastern United States and 204 (63%) completed it. Among those responding, 32% held master's degrees in genetic counseling, 30% M.D. degrees, 23% degrees in nursing, and 3% master's degrees in social work. While genetic counseling typically involves team effort, members were generally unclear regarding their roles in the process. Respondents rarely referred their clients to social workers but believe they should. Most did not believe that master's trained genetic counselors should be the only health professional who provide counseling. The respondents strongly supported goals that dealt with the educative aspect of counseling and protection of patient autonomy.

Academic Medical Centers↗

PubMed1976

Genetic counseling. An evaluation of public health genetic clinics.

The geographic distribution of County Health Department clinic facilities in the state of California has made it readily possible to establish a regionalized program for genetic counseling services, using public health nurses as a major source of case-finding. From both consumer and health professional standpoints, regionalized satellite genetic counseling clinics have been successful, and in particular, the effectiveness of public health nurses in identifying clinical genetic problems is readily apparent.Long-term follow-up reinforcement of genetic counseling appears to be an important conclusion from these studies. It is our suggestion that reinforcement of counseling would best be accomplished through the health team member (physician, nurse and so forth) following the patient or family rather than through the consulting geneticist.

Adult↗

PubMed1998

[Genetic susceptibility to multiple sclerosis (MS). INSERM Network of Clinical Research on the Genetic Susceptibility to MS].

The clinical manifestations and neuropathological signs of Multiple Sclerosis (MS) have been known for more than a century, but the cause of MS remains unknown. Epidemiological studies indicate that MS is a multi-factorial disease implicating both environmental factors and genetic susceptibility. The role of HLA in the genetic susceptibility to MS has been known since the seventies. Advances in human genetics now allow a systematic approach to genetic susceptibility in MS: possible strategies are reviewed.

Genetic Predisposition to Disease↗

PubMed1998

[Experimental genetic modifications in the renin-angiotensin and kallikrein-kinin systems: significance for understanding cardiovascular regulation and study of genetic determinism of human diseases].

The precise role of the different proteins that constitute the renin-angiotensin and kallikrein-kinin systems in the development of hypertension and some cardiac and renal diseases remains unclear. Genetic manipulations in animals is a powerful approach that provide the opportunity to explore the role of each of these proteins in vivo. Indeed it is possible in the rat and in the mouse to manipulate a specific gene without modifying the other genetic and environmental factors. A causal link can thus be established between the gene and a physiologic or pathologic alteration. The possibilities are either the overexpression of the gene in all or in specific tissues (transgenesis), or the modification (often the inactivation) of the endogenous gene by homologous recombination. The second technique has the advantage to be more specific but it can be used only in the mouse; it is performed by transfecting totipotent embryonic stem cells with a vector harboring identical sequences to those of the gene to be targeted. The embryonic stem cells are then injected into embryos in which they will participate in the generation of the different organs including the gonads. The resulting chimeric animals can therefore transmit the mutation to their offspring creating a new genetically modified mouse strain. Many strains targeted in the different components of the renin-angiotensin and kallikrein-kinin systems have been generated in this way. These animal models should allow to test many physiopathological hypotheses that have been put forward from the results of human genetics and clinical studies, and also to raise new ones.

Animals↗

PubMed1996

The Japan Society of Human Genetics Award Lecture. Application of DNA markers to clinical genetics.

DNA technology using DNA sequence polymorphisms has brought a new system to the fields of medicine and forensic science, especially for the studies of genetic diseases and tumor suppressor genes, and for identification of individuals for forensic purpose. Linkage analysis based on segregation of polymorphic alleles in affected families has contributed to identification of many genetic disease. We isolated a large number of polymorphic DNA markers, called VNTR (variable number of tandem repeat) markers and identified the APC gene that is responsible for familial adenomatous polyposis (FAP) by means of a so-called "positional cloning" and characterized germline and somatic mutations of the APC gene in colorectal cancer patients. In addition, we have applied genetic information during colorectal carcinogenesis to sensitive diagnosis of lymph-node metastasis of colorectal cancer.

Adenomatous Polyposis Coli↗

PubMed2005

Comparison of three methods to estimate genetic ancestry and control for stratification in genetic association studies among admixed populations.

Population stratification may confound the results of genetic association studies among unrelated individuals from admixed populations. Several methods have been proposed to estimate the ancestral information in admixed populations and used to adjust the population stratification in genetic association tests. We evaluate the performances of three different methods: maximum likelihood estimation, ADMIXMAP and Structure through various simulated data sets and real data from Latino subjects participating in a genetic study of asthma. All three methods provide similar information on the accuracy of ancestral estimates and control type I error rate at an approximately similar rate. The most important factor in determining accuracy of the ancestry estimate and in minimizing type I error rate is the number of markers used to estimate ancestry. We demonstrate that approximately 100 ancestry informative markers (AIMs) are required to obtain estimates of ancestry that correlate with correlation coefficients more than 0.9 with the true individual ancestral proportions. In addition, after accounting for the ancestry information in association tests, the excess of type I error rate is controlled at the 5% level when 100 markers are used to estimate ancestry. However, since the effect of admixture on the type I error rate worsens with sample size, the accuracy of ancestry estimates also needs to increase to make the appropriate correction. Using data from the Latino subjects, we also apply these methods to an association study between body mass index and 44 AIMs. These simulations are meant to provide some practical guidelines for investigators conducting association studies in admixed populations.

Asthma↗

PubMed2004

Genetic screening, health care and the insurance industry. Should genetic information be made available to insurers?

The potential use of genetic tests in insurance has raised concerns about discrimination and individuals losing access to health care either because of refusals to test for treatable diseases, or because test-positives cannot afford premiums. Governments have so far largely sought to restrict the use of genetic information by insurance companies. To date the number of tests available with significant actuarial value is limited. However, this is likely to change, raising more clearly the question as to whether the social costs of adverse selection outweigh the social costs of individuals not accessing health care for fear of the consequences of test information being used in insurance markets. In this contribution we set out the policy context and model the potential trade-offs between the losses faced by insurers from adverse selection by insurees (which will increase premiums reducing consumer welfare) and the detrimental health effects that may result from persons refusing to undergo tests that could identify treatable health conditions. It argues that the optimal public policy on genetic testing should reflect overall societal benefit, taking account of these trade-offs. Based on our model, the factors that influence the outcome include: the size of and value attached to the health gains from treatment; deterrent effects of a disclosure requirement on testing for health reasons; incidence of the disease; propensity of test-positives to adverse select; policy value adverse selectors buy in a non-disclosure environment; and price elasticity of demand for insurance. Our illustrative model can be used as a benchmark for developing other scenarios or incorporating real data in order to address the impact of different policies on disclosure and requirement to test.

Genetic Privacy↗

PubMed2005

Complex phenotypes and complex genetics: an introduction to genetic studies of complex traits.

There is currently intense interest in the genetic factors contributing to many diseases with cardiovascular complications. Diseases like atherosclerosis, diabetes, and hypertension are referred to as complex traits because multiple genes contribute to the phenotype either individually or through interactions with each other or the environment. Enabled and energized by the striking successes over the past 20 years in identifying genes that are responsible for single gene traits, many geneticists have turned to the investigation of methods that will allow for the dissection of complex traits. There have already been some successes, so there is no reason to consider the problem as inherently intractable. However, it is important to reflect on what conditions are necessary for the identification of genes that operate in complex traits. A recurring theme in this research area has been difficulty in repeating and validating research findings, and this most often can be attributed to limitations in study design. It is also important to consider that any particular research strategy can only hope to describe a portion of factors that contribute to variation in the population; therefore, the genetic approach cannot be a panacea. New efficient technologies for genotyping and public databases describing the fine structure of genetic correlations in the genome should aid many aspects of the gene discovery process.

Genetic Predisposition to Disease↗

PubMed2004

Flanking gene and genetic background problems in genetically manipulated mice.

Mice carrying engineered genetic modifications have become an indispensable tool in the study of gene functioning. The interpretation of results obtained with targeted mutants is not completely straightforward, however, because of genetic complications due to linkage and epistasis. Effects of closely linked genes flanking the targeted locus might sometimes be responsible for phenotypic changes ascribed to the null mutation. The effects of the latter might also be modified by the general genetic background. This review presents some examples and discusses some simple strategies to deal with these complications.

5' Flanking Region↗

PubMed2004

Genetic medicine at the RNA level: modifications of the genetic repertoire for therapeutic purposes by pre-mRNA trans-splicing.

Gene therapy is conventionally carried out by transferring genetic material to the target cell where the exogenous gene is expressed using the endogenous transcription and translation machinery in parallel with the target cell genome. This review focuses on a new paradigm of gene therapy, the use of trans-splicing to modify the genetic repertoire at the pre-mRNA level to treat genetic and acquired disorders. Therapeutic trans-splicing can be used to alter coding domains, to create novel fusion proteins, to direct gene products to various cellular compartments, and to overcome some of the limitations to vector-derived gene transfer technology, including gene therapy with large genes or with genes coding for toxic proteins. To demonstrate the potential of therapeutic trans-splicing, eukaryotic cis-splicing and trans-splicing are reviewed, followed by a discussion of strategies of therapeutic pre-mRNA trans-splicing directed by exogenous gene transfer.

Animals↗

PubMed2025

Clinical and genetic variant re-analysis among pediatric probands undergoing genetic testing for arrhythmia syndromes.

BACKGROUND: Despite increases in genetic testing, longitudinal data regarding changes in diagnostic yield and variant reclassification for inherited arrhythmia syndromes are limited. OBJECTIVE: Determine longitudinal changes in diagnostic yield and variant classification. METHODS: Single-center retrospective study of probands <18 years undergoing genetic testing for suspected inherited cardiac conditions associated with arrhythmias, 2007 to 2018. Variants were classified as diagnostic (pathogenic/likely pathogenic), non-diagnostic (benign/likely benign [B/LB]), or variants of uncertain significance (VUS). Variant reclassification was performed in October 2023 using VarSome and American College of Medical Genetics criteria. We evaluated results by era (early 2007-2013 vs. later 2014-2018, coinciding with Sanger and next-generation sequencing, respectively) and by likelihood of disease based on clinical evaluation. RESULTS: Of 306 probands, initial testing was 23.2% diagnostic, 55.6% non-diagnostic (33.7% no variant, 21.9% B/LB), and 21.2% VUS. When comparing eras, diagnostic yield decreased (34.1%-15.3%), VUS increased (9.3%-29.9%), and non-diagnostic remained similar (55% to 57%). Variants for 22.7% (46/203) of probands with ≥1 variant changed: 9.9% of diagnostic variants (7/71) downgraded to VUS or non-diagnostic, and 60.0% of VUS changed (23.1% upgraded, 36.9% downgraded). B/LB variants did not change. Probands with higher disease likelihood had 6-times the odds of diagnostic results compared to lower disease likelihood, regardless of era (odds ratio 6.3, 95% confidence interval 3.2-12.4, P < .0001). CONCLUSION: Variant reclassification led to changes in 23% of probands, both downgrading and upgrading status, even among probands initially thought to be pathogenic. When comparing later to earlier eras, VUS variants increased while diagnostic yield decreased. Findings support the need for variant re-interpretation and periodic reclassification over time.

Humans↗

PubMed1991

The genetic structure of natural populations of Drosophila melanogaster. XXIV. Effects of hybrid dysgenesis on the components of genetic variance of variability.

Eight hundred second chromosomes were extracted from the Ishigakijima population, one of the southernmost populations of Drosophila melanogaster in Japan. Half of them were extracted in Native cytoplasm (P-type), and half in Foreign cytoplasm (M-type). Various population-genetic parameters, including the frequency of lethal-carrying second chromosomes (Q = 0.235 for the Native; 0.218 for the Foreign), the allelism rate of lethal second chromosome (Ic = 0.0217 for the Native; 0.0134 for the Foreign), the homozygous detrimental and lethal loads (D = 0.179 for the Native; 0.270 for the Foreign; L = 0.262 for the Native; 0.240 for the Foreign), the average degree of dominance of mildly deleterious mutations (ĥE = 0.244 for the Native; 0.208 for the Foreign), and the components of genetic variance for viability [additive (sigma A2) and dominance (sigma D2)](ŝigma A2 = 0.0187 for the Native; 0.0172 for the Foreign; ŝigma D2 = 0.0005 for the Native; 0.0009 for the Foreign) were estimated. The data indicate that D was significantly larger and hE was significantly smaller in the Foreign cytoplasm. However, the estimates of additive and dominance variances were not significantly different between the two cytoplasms. The additive genetic variance for viability in the Ishigakijima population was greater than expected on the basis of mutation-selection balance confirming previous studies on papers of D. melanogaster in warm climates.

Animals↗

PubMed1996

Genetic markers and quantitative genetic variation in Medicago truncatula (Leguminosae): a comparative analysis of population structure.

Two populations of the selfing annual Medicago truncatula Gaertn. (Leguminoseae), each subdivided into three subpopulations, were studied for both metric traits (quantitative characters) and genetic markers (random amplified polymorphic DNA and one morphological, single-locus marker). Hierarchical analyses of variance components show that (1) populations are more differentiated for quantitative characters than for marker loci, (2) the contribution of both within and among subpopulations components of variance to overall genetic variance of these characters is reduced as compared to markers, and (3) at the population level, within population structure is slightly but not significantly larger for markers than for quantitative traits. Under the hypothesis that most markers are neutral, such comparisons may be used to make hypotheses about the strength and heterogeneity of natural selection in the face of genetic drift and gene flow. We thus suggest that in these populations, quantitative characters are under strong divergent selection among populations, and that gene flow is restricted among populations and subpopulations.

Biological Evolution↗

PubMed1976

Genetic studies of coliphage P1. III. Extended genetic map.

An extensive genetic map of coliphage P1 has been constructed for 113 amber mutants, using primarily a modification of the conventional complementation spot test. These spot tests failed to classify the mutants into cistrons, but when they were quantitated they permitted assignment of the mutants into 10 linkage clusters. Furthermore, a linear order could be deduced for most of the mutants within each cluster. This strongly suggested that recombination was the predominant event generating plaques and that, for the practical purpose of rapid genetic mapping, such spot tests could be considered as a series of two-factor crosses. Six of the 10 linkage clusters correlated with the P1 genetic map established by Scott (1968). The locations of the remaining four clusters were determined by three-factor crosses and by prophage deletion mapping. The nonrandom occurrence of termini for 14 deletion prophages, which we established previously (Walker and Walker, 1975), and the coincidence of these termini with five out of ten regions demarcating the linkage clusters are discussed. Complementation tests in liquid frequently gave ambiguous results. Therefore, cistron designations were not assigned.

Chromosome Mapping↗