Trinucleotide repeat contraction: a pitfall in prenatal diagnosis of myotonic dystrophy.
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Adult↗
Biomedical subjects
J Feingold
Publications and source records attributed to J Feingold.
The mannose binding lectin gene influences the severity of chronic liver disease in cystic fibrosis.
Chronic liver disease is a major complication of cystic fibrosis. Its incidence and severity show marked heterogeneity, even among the homogeneous group of homozygous DeltaF508 patients, suggesting that environmental or genetic factors other than the deletion DeltaF508 may influence the development of cystic fibrosis related liver disease. We investigated whether the allelic variants of mannose binding lectin, an important protein of the immune system, could be associated with the presence of cirrhosis in a population of 216 homogeneous homozygous DeltaF508 patients. Analysis of the data shows that the presence of cirrhosis in cystic fibrosis patients is significantly associated with a mutated mannose binding lectin genotype (homozygous or compound heterozygous for mannose binding lectin variants). The modulating role of mannose binding lectin in the occurrence of cirrhosis in cystic fibrosis could be explained by the fact that hepatotoxic damage from viruses or bacteria might be increased by the immunodeficiency associated with mannose binding lectin variants and might facilitate the degradation of liver status. These data highlight the crucial role of mannose binding lectin in the clinical outcome of cystic fibrosis, as it has recently been shown that the mannose binding lectin gene is a modulating gene of the respiratory involvement in cystic fibrosis patients.
Alleles↗
Genetic predisposition to severe myoclonic epilepsy in infancy.
PURPOSE: To address genetic predisposition to febrile convulsions (FCs) and epilepsy as an etiologic background of severe myoclonic epilepsy in infancy (SMEI). METHODS: Familial antecedents of epilepsy and FCs were analyzed in four groups of patients with SMEI (65 cases), FCs (57 cases), childhood absences (67 cases), and a control group of patients with no neurologic problems (64 cases). RESULTS: Patients with SMEI and those with FCs had significantly increased incidence of FCs in their relatives compared with those with absence epilepsy and with the control group. The incidence of epilepsy in relatives of patients with SMEI and absence epilepsy was increased compared with that in the control group and reached statistical significance. Epilepsy in relatives with SMEI had the characteristics of idiopathic generalized epilepsy. CONCLUSIONS: A genetic predisposition could determine three types of epileptic syndromes: FCs, idiopathic generalized epilepsy, and SMEI.
Adolescent↗
[Li-Fraumeni syndrome: update, new data and guidelines for clinical management].
The Li-Fraumeni syndrome (LFS) is an inherited form of cancer, affecting children and young adults, and characterized by a wide spectrum of tumors, including soft-tissue and bone sarcomas, brain tumours, adenocortical tumours and premenopausal breast cancers. In most of the families, LFS results from germline mutations of the tumor suppressor TP53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. Recently, germline mutations of hCHK2 encoding a kinase, regulating cell cycle via Cdc25C and TP53, were identified in affected families. The LFS working group recommendations are the following: (i) positive testing (screening for a germline TP53 mutation in a patient with a tumor) can be offered both to children and adults in the context of genetic counseling associated to psychological support, to confirm the diagnosis of LFS on a molecular basis. This will allow to offer to the patient a regular clinical review in order to avoid a delay to the diagnosis of another tumor; (ii) the 3 indications for positive testing are: a proband with a tumor belonging to the narrow LFS spectrum and developed before age 36 and, at least, first- or second-degree relative with a LFS spectrum tumor, before age 46, or a patient with multiple primary tumors, 2 of which belonging to the narrow LFS spectrum, the first being developed before 36 or a child with an adenocortical tumour; (iii) presymptomatic testing must be restricted to adults; (iv) the young age of onset of the LFS tumors the prognosis of some tumors, the impossibility to ensure an efficient early detection and the risk for mutation carriers to develop multiple primary tumors justify that prenatal diagnosis might be considered in affected families.
Adult↗
[Epidemiological study of genetic and environmental factors in asthma, bronchial hyperresponsiveness and atopy. Protocol and potential selection bias].
BACKGROUND: The EGEA study combines a case-control study and a family study to assess genetic and environmental risk factors and their interactions for asthma, bronchial hyperresponsiveness and atopy. Information is scanty regarding potential selection biases, in particular regarding familial ressemblance in epidemiological surveys of this kind. METHODS: Asthmatic probands (adult and paediatric) were recruited in chest clinics of six clinical centres. Controls were mostly population-based (electoral rolls) for adults and recruited in surgery departments for children. RESULTS: The population examined includes 348 nuclear families ascertained by one asthmatic and 416 controls, totalling 1847 subjects (EGEA I) and an additional sample of 40 families ascertained by two asthmatic siblings (EGEA II). Potential biases for the various types of analyses have been studied. Quantification of the consequences of the greater participation of probands with a parental history of asthma shows it does not introduce a major bias in the estimates of familial resemblance. Cases and controls showed a good comparability regarding sex, age, area of residence and familial geographical origin, allowing proper associations studies for environmental and candidate genetic factors. CONCLUSIONS: The case-control component of the study will allow to perform studies on environmental factors and association studies for various genetic polymorphisms. Using the family base collected, segregation and genetic linkage/association analyses with DNA markers may be performed.
Adult↗
A new locus for autosomal dominant dilated cardiomyopathy identified on chromosome 6q12-q16.
Dilated cardiomyopathy (DCM) is a heart-muscle disease characterized by ventricular dilatation and impaired heart contraction and is heterogeneous both clinically and genetically. To date, 12 candidate disease loci have been described for autosomal dominant DCM. We report the identification of a new locus on chromosome 6q12-16 in a French family with 9 individuals affected by the pure form of autosomal dominant DCM. This locus was found by using a genomewide search after exclusion of all reported disease loci and genes for DCM. The maximum pairwise LOD score was 3.52 at recombination fraction 0.0 for markers D6S1644 and D6S1694. Haplotype construction delineated a region of 16.4 cM between markers D6S1627 and D6S1716. This locus does not overlap with two other disease loci that have been described in nonpure forms of DCM and have been mapped on 6q23-24 and 6q23. The phospholamban, malic enzyme 1-soluble, and laminin-alpha4 genes were excluded as candidate genes, using single-strand conformation polymorphism or linkage analysis.
Adolescent↗
Segregation analysis of IgE levels in 335 French families (EGEA) using different strategies to correct for the ascertainment through a correlated trait (asthma).
The main objective of this study was to search for a major gene controlling total serum immunoglobulin E (IgE) levels, an intermediate phenotype for asthma and allergy. We studied 335 French nuclear families of the EGEA study (Epidemiological study of the Genetics and Environment of Asthma), ascertained through asthmatic probands (123 are parents in the family, 212 children). Segregation analyses were performed by regressive models, which can take into account a major gene effect, various sources of familial covariation (genetic and/or environmental) as well as measured risk factors (i.e. , age, sex, smoking habits). Different strategies were considered to account for the mode of ascertainment of the families through a correlated trait (asthma): the ascertainment mode was either ignored (strategy A) or taken into account by adjusting IgE levels for the position in the family, i.e., probands, blood relatives, spouses (strategy B) or excluding the asthmatic children-probands and computing the likelihood of each family conditionally on parents' IgE levels (strategy C). Whereas a major gene effect could not be detected with strategy A, strategies B and C showed evidence for the transmission of a dominant major gene for high IgE levels, which was more significant with strategy B. This gene does not interact with any of the covariates and is responsible for approximately 15% of IgE variation (the allele frequency is 0.65).
Adolescent↗
Reappraisal of the association between the DRD2 gene, alcoholism and addiction.
We analysed the impact of the TaqI A1 allele of the D2 dopamine receptor gene on the risk for alcoholism, trying to depict three explanations frequently proposed to explain discrepancies in association and linkage studies: that the A1 allele may act as a marker rather than as a vulnerability factor, that stratification biases and unevaluated controls may explain positive results, and that the A1 allele is modifying the phenotype rather than increasing the risk for alcoholism. We thus tested another (dinucleotide STRP) marker within the DRD2 gene, selected a new homogenous sample of 113 alcoholic patients and 49 unaffected controls strictly matched for ethnic origins, and systematically assessed both samples with a semi-structured interview to detect (in both samples) alcohol dependence, but also such related traits as specificities of complications. The frequency of the A1 allele was not significantly different between alcoholics and controls but when comparing different subgroups of alcoholics, the A1 allele was significantly more frequent in alcoholic patients with somatic complications (OR = 3.00, CI[1.37-6.62]), social and professional complications (OR = 2. 72, CI[1.25-5.90]), or with co-morbid dependence (OR = 2.88, 95% IC [1.16-7.15]). The association for co-morbid dependence and somatic complications was also positive when taking into consideration both STRP and TaqIA polymorphisms. The A1 allele does not increase the risk for alcoholism per se in our sample, but may be involved in a related trait which is partially dependent on the diagnosis of alcoholism, through a disequilibrium with another close mutation.
Adult↗
Acute clinical events in 299 homozygous sickle cell patients living in France. French Study Group on Sickle Cell Disease.
A subset of 299 patients with homozygous sickle cell anaemia, enrolled in the cohort of the French Study Group on sickle cell disease (SCD), was investigated in this study. The majority of patients were children (mean age 10.1 +/- 5.8 yr) of first generation immigrants from Western and Central Africa, the others originated from the French West Indies (20.2%). We report the frequency of the main clinical events (mean follow-up 4.2 +/- 2.2 yr). The prevalence of meningitis-septicaemia and osteomyelitis was, respectively, 11.4% and 12% acute chest syndrome was observed in 134 patients (44.8%). Twenty patients (6.7%) developed stroke with peak prevalence at 10-15 yr of age. One hundred and seventy-two patients (58%) suffered from one or more painful sickle cell crises, while the others (42.5%) never suffered from pain. The overall frequency of acute anaemic episodes was 50.5%, (acute aplastic anaemia 46%; acute splenic sequestration 26%). A group of 27 patients were asymptomatic (follow-up > 3 yr). Epistatic mechanisms influencing SCD were studied. Coinherited alpha-thalassemia strongly reduced the risk of stroke (p <0.001) and increased that of painful crises (p < 0.02). There was a low prevalence of Senegal and Bantu (CAR) betas-chromosomes in patients with meningitis (p <0.04) and osteomyelitis (p < 0.03). Prevalence of Senegal betas-chromosomes was lower in the asymptomatic group of 27 patients (p < 0.02). The patients come from a population of unmixed immigrants in whom the beta-globin gene haplotype strongly reflects the geographic origin and identifies subgroups with a homogenous genetic background. Thus the observed effects might result more from differences in as yet unidentified determinants in the genetic background than from the direct linkage with differences in the beta-globin gene locus.
Acute Disease↗
Estimating prevalence in single-gene kidney diseases progressing to renal failure.
Incidence and prevalence, the measures of "frequency, " are often confused. While in a nonhereditary situation, the useful parameter is the incidence rate, evaluating the impact of an etiologic factor, it is prevalence that is considered useful in a hereditary disease. Prevalence may concern either the whole population or a fraction of this population, that is, males or females or individuals at a given age, for example, at birth. Pathologic phenotype and morbid genotype prevalences have to be clearly differentiated. In this article, we review the epidemiologic surveys allowing an estimation of the distribution of major single-gene kidney diseases progressing to renal failure in different populations. In order to compare their results, the geographic/ethnic composition of the population, the determination of its size, the choice and mode of calculation of the epidemiologic measure, the definition of the disease and modes of diagnosis, the inclusion of cases, the sources of ascertainment and the possible causes of underascertainment, and the period of time during which events were counted should be analyzed accurately. Although their impact in terms of morbidity, hospitalizations, mortality, and cost to society is high, this review shows that information on the prevalence of single-gene kidney diseases is far from complete. To date, the data essentially apply to large populations of European origin. A part of the variation among prevalence data may be due to methodological differences. Not representative are the small populations in which some rare diseases, especially recessive, are found with a high prevalence.
Genetic Predisposition to Disease↗
Genome screen for asthma and related phenotypes in the French EGEA study.
A genome-wide search was conducted in 107 nuclear families with at least two siblings with asthma, as part of the French EGEA study. A two-stage analysis strategy was applied to the 107 families divided into two independent subsets of 46 and 61 families, where all regions detected in the first set of families were tested for replication in the second set. In addition, all regions reported by published genome scans in different populations were examined in the total sample. A total of 254 markers were typed in the first set of families and 70% of them in the second set. Linkage was investigated by model-free methods for asthma and four asthma-related phenotypes: bronchial responsiveness (BR), skin test response, total immunoglobulin E (IgE) levels, and eosinophil count. The two-stage analysis led to the detection of three regions: 11p13 for IgE, 12q24 for eosinophils, and 17q12-21 for asthma and skin tests. Among the regions reported by published genome screens, seven were found in the 107 French EGEA families: three being already detected by the two-stage analysis, 11p13 (p = 0.005), 12q24 (p = 0.0008), and 17q12-21 (p = 0.001), and four additional ones, 1p31 (p = 0.005) for asthma, 11q13 (p = 0.006) for IgE, 13q31 (p = 0.001) for eosinophils, and 19q13 (p = 0.02) for BR.
Adolescent↗
Beta-globin gene haplotypes and alpha-thalassemia analysis in Babinga pygmies from Congo-Brazzaville.
We analyzed beta-globin gene cluster haplotypes and deletional alpha+-thalassemia (-alpha3.7kb) in 54 Babinga pygmy subjects from Congo-Brazzaville. The beta(S)-globin gene frequency was 0.065 and that of the deletional alpha-globin gene (-alpha3.7kb) was 0.29. Eighty-five percent of the beta(S) chromosomes and 13% of the beta(A) chromosomes were associated with the Bantu haplotype, 10% of beta(A) chromosomes with the Senegal haplotype, and the remaining beta chromosomes with atypical haplotypes. None of the chromosomes were of the Benin haplotype. These results are clearly of anthropological and evolutionary interest. They also support earlier observations that alpha+-thalassemia is prevalent at a high frequency in African populations.
Cluster Analysis↗
[Genetic prediction in medicine].
Presymptomatic or predictive genetic testing concerns healthy people. Its aim is to determine individuals at risk for a disease. Presymptomatic testing concerns mainly Mendelian diseases; an abnormal test result will lead to development of the disease in most cases in later life. Predictive testing concerns multifactorial or low penetrating Mendelian diseases; the test result will modify the risk of disorder occurring but with a much smaller degree of certainty.
Chromosome Aberrations↗
[Genes and environment].
Many quantitative characters depend on the action of a large number of genes and environmental factors. The mode of inheritance of these characters is polygenic. The phenotypic variance of the character is the sum of the components, thus the genetic and the environmental variances (VP = VG + VE). The degree of genetic determination VG/VP and VE/VP are difficult to estimate in man. The heritability a related coefficient to VG/VP can be estimated from the degree of ressemblance between relatives. The heritability is the additive genetique variance as a proportion of the phenotypic variance. Polygenic threshold inheritance can account for the familial non mendelian distribution of multifactorial diseases.
Birth Weight↗
Association of variant alleles of mannose binding lectin with severity of pulmonary disease in cystic fibrosis: cohort study.
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Adult↗
Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-degree relatives.
BACKGROUND: Whole blood serotonin (5-HT) and C-terminally directed beta-endorphin protein immunoreactivity (C-ter-beta-EP-ir) are known to be elevated in autistic subjects and might be possible markers of genetic liability to autism. This study thus investigates the familial aggregation of 5-HT and of C-ter-beta-EP-ir levels in first degree relatives of autistic probands. METHODS: In a sample of 62 autistic subjects and 122 of their first-degree relatives, compared to age and sex-matched controls, we measured 5-HT by radioenzymology and C-ter-beta-EP-ir by radioimmunoassay. RESULTS: We confirm the previously reported familiality of hyperserotoninemia in autism as mothers (51%), fathers (45%) and siblings (87%) have elevated levels of 5-HT, and we reveal presence of elevated levels of C-ter-beta-EP-ir in mothers (53%) of autistic subjects. CONCLUSIONS: Familial aggregation of quantitative variables, such as concentration of neurotransmitters, within unaffected relative could serve as an intermediate phenotype and might thus help the search of genetic susceptibility factors in autism.
Adolescent↗
Genetic polymorphism of the mannose-binding protein gene in children with sickle cell disease: identification of three new variant alleles and relationship to infections.
Mannose-binding protein (MBP) is a serum lectin that participates in the innate immune response. MBP deficiency may constitute a risk factor in the development of infections. Three MBP structural variants have been identified with a dominant effect on MBP serum concentration. Similarly, polymorphisms in the promoter of the corresponding gene (HSMBP1B) have been related to variations of MBP concentration in serum. Children with sickle cell disease (SCD) have an increased susceptibility to infections with encapsulated organisms resulting in meningitis, septicaemia, and osteomyelitis. We have investigated the HSMBP1B genotype in 242 children with SCD living in Paris. Apart from the known variant alleles, we identified three novel ones and report their distribution in our sample population. In addition, we found rather unexpectedly an increased frequency of the variant alleles in patients who had not suffered severe infections.
Adolescent↗