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Results for “Multifactorial Inheritance”

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PubMed2005

Thrombosis and bleeding: when opposites are not so far apart.

Thrombotic events in patients with inherited bleeding disorders occur only rarely. However, in some cases, the co-existence of acquired or inherited prothrombotic risk factors may overcome the hypocoagulative state, modulating the clinical phenotype to a decrease in bleeding symptoms or even to an increase in the likelihood of developing thrombotic complications. This review summarizes the cases of thrombosis reported in the literature and analyzes the most important risk factors for thrombosis in patients with a congenital bleeding tendency. Data were identified by searches of the published literature, including PubMed, references from reviews and abstracts from the most important meetings on this topic. There is increasing evidence that thrombotic complications in patients with hereditary bleeding disorders have a multifactorial pathogenesis, depending on acquired (coagulation factor replacement therapy, central venous catheters, surgery, viral infections) and/or inherited (thrombophilic gene mutations) prothrombotic risk factors.

Blood Coagulation Disorders, Inherited↗

PubMed1992

New familial syndrome of unilateral upper eyelid coloboma, aberrant anterior hairline pattern, and anal anomalies in Manitoba Indians.

We report on 6 (3 male, 3 female) Manitoba Indian children with hypertelorism and variable combinations of unilateral eye malformations, aberrant anterolateral scalp hairline, and nasal and anal anomalies. These children belong to 4 related families. The parents and 7 other sibs are clinically unaffected. The family histories are otherwise unremarkable. The presence of 2 major malformations in sibs and related individuals (with unaffected parents) suggests that this is a newly described pleiotropic autosomal recessive syndrome. The differential diagnosis includes cryptophthalmos syndrome and several other related malformation syndromes. Although multifactorial determination cannot be excluded, the inbred, isolated population and distribution make autosomal recessive inheritance more likely.

Anal Canal↗

PubMed1999

Clinical genetics: an overview.

It is imperative that clinicians understand basic human genetic concepts. In this article, the patterns of inheritance for single gene disorders are described and include the traditional Mendelian, nontraditional, and multifactorial patterns. Next, chromosomal and structural abnormalities are described, followed by a description of the current measures by which genes are detected, including gene mapping and polymorphisms, and concluding with cytogenetic, molecular, and biochemical testing.

Chromosome Aberrations↗

PubMed1977

The distribution of ancestral secondary cases in Parkinson's disease.

Recent evidence suggests a genetic mode of transmission of Parkinson's disease. A multifactorial mechanism is likely, but autosomal dominance with reduced penetrance has not been excluded. The distribution of ancestral second-degree relatives with Parkinson's disease was evaluated in 12 families. Affected relatives were bilaterally distributed more often than would be expected for autosomal dominance. The distribution of ancestral secondary cases suggests a multifactorial etiology for most cases of Parkinson's disease. The possibility of dominant gene inheritance in some families is not entirely ruled out.

Female↗

PubMed1979

On the use of multiple thresholds for the determination of the mode of inheritance of semi-continuous traits.

In this article we reconsider the analysis proposed by Reich et al. (1972) for determining the mode of inheritance for semi-continuous traits from intrafamilial data. We consider both the (general) multifactorial and the single-locus model formulation. We show (numerically), by using a much improved numerical analysis technique for the parameter estimation, that there may be many single-locus models that could have given rise to a particular data set, dependent on its size and nature. Finally we question whether the use of monozygotic twins data, or data obtained from defining further levels of severity of the disease, would improve the discrimination between these two types of models.

Alleles↗

PubMed1983

Genetic analysis of multiple sclerosis in Shetland.

In a family study of all patients with multiple sclerosis in Shetland the number of inbred patients, although high for Britain and higher than in Orkney, is not higher than the number among controls, and the inbreeding coefficients suggest that there is no recessive involvement of rare genes in the aetiology. The kinship coefficients show close interweaving of ancestries of patients and controls and eliminate from the aetiology any involvement of recently introduced single genes dominant or codominant in effect. Family histories show that single locus inheritance is unlikely. Any genetic involvement is likely to be polygenic, but on a multifactorial hypothesis the estimates of heritability are very low. The findings suggest that the genetic contribution to the aetiology of the disease in Shetland is slight.

Consanguinity↗

PubMed2005

Ménière's disease is associated with single nucleotide polymorphisms in the human potassium channel genes, KCNE1 and KCNE3.

Although the bases for both the sporadic and inherited forms of Ménière's disease (MD) remain undefined, it is likely to be multifactorial, one of the factors being a genetic predisposition. Recently, genetic association studies on complex diseases have become very popular and most of them are case-control studies using single nucleotide polymorphisms (SNPs) as markers. Mutations/polymorphisms in KCNE potassium channel genes might play a causative role in MD, because KCNE potassium channels have been suggested to be present and active in transmembrane ion and water transports in the inner ear. In the present study, to identify MD susceptibility genes, we have conducted a genetic association study with optimized sampling, optimized phenotyping/genotyping, and a selection of KCNE genes as the candidate genes. The SNPs analyses identified 112G/A SNP in the KCNE1 gene and 198T/C SNP in the KCNE3 gene in 63 definite MD cases as well as 205 and 237 non-MD control subjects. For both KCNE1 and KCNE3 genes, a significant difference in frequency of each SNP was confirmed between MD cases and non-MD control subjects. The result indicates that 112G/A SNP in the KCNE1 gene and 198T/C SNP in the KCNE3 gene could determine an increased susceptibility to develop MD.

Adult↗

PubMed1989

[Clinico-genetic analysis of the incidence of neoplasms].

The authors sum up the results of clinical and genealogic examinations of 2460 patients with most prevalent tumors, i.e. gastric and mammary carcinomas, melanomas. The obtained values of segregation frequencies for these tumors have proved to be lower than the theoretically expected values for monogenic types of inheritance. A genetic and epidemiologic approach, employed in the tumors analysis, has demonstrated the multifactorial nature of these tumors: the contribution of the genetic factors in mammary carcinoma has made up 52%, in gastric carcinoma 22% for male and 41.1% for female subjects, with the X-chromosome-linked genetic components making up 19%. The studies have shown the possibility of genetic heterogeneity of the tumor forms, identically localized. Basing on these data, the authors have plotted 'repeated risk tables' to assess the potentiality of new cases of the disease in the patients' families; such tables may be useful for practical medicogenetic counselling.

Adult↗

PubMed1994

[Diffuse connective tissue diseases (DCTD)--a review].

The diffuse connective tissue diseases constitute a group of inflammatory diseases with the potential of involvement of many organ systems. The etiopathogenesis is thought to be multifactorial, involving the interaction between particular genetic background and exogenous agents. Recently theories regarding inherited defects in the clearing of immune complexes have been put forward. Serological markers are important diagnostic tools in many of these diseases and emphasize the role of autoimmunity. Epidemiological studies have demonstrated an increase in incidence in some of these diseases and because of selection bias many epidemiological studies may overestimate the severity of these diseases. Therapy aims at modulating and suppressing inflammation. A step towards more directed immune modulation is the use of cyclosporin A and monoclonal antibodies against various surface antigens and mediators in inflammation.

Antigen-Antibody Complex↗

PubMed1993

Segregation analysis of speech and language disorders.

Complex segregation analysis was performed on pedigrees ascertained through 45 probands (26 males, 19 females) with a history of preschool speech and language disorders. Hypotheses concerning mode of inheritance were tested using the POINTER segregation analysis program. Although there is strong evidence for familial transmission of this trait, we were unable to distinguish between a major gene and multifactorial transmission model using likelihood-ratio chi-square tests. Future studies with quantitative measures of speech and language disorders are needed to resolve the issue of mode of inheritance for this trait.

Adolescent↗

PubMed2007

A seventh locus for otosclerosis, OTSC7, maps to chromosome 6q13-16.1.

Otosclerosis is a common form of hearing impairment among white adults with a prevalence of 0.3-0.4%. It is caused by abnormal bone homeostasis of the otic capsule that compromises free motion of the stapes in the oval window. Otosclerosis is in most patients a multifactorial disease, caused by both genetic and environmental factors. In some cases, the disease is inherited as a monogenic autosomal dominant trait, sometimes with reduced penetrance. However, families large enough for genetic linkage studies are extremely rare. To date, five loci (OTSC1-5) have been reported, but none of the responsible genes have been cloned yet. An additional locus, OTSC6, has been reported to the HUGO nomenclature committee but the relevant linkage study has not been published. In this study, a genome-wide linkage study was performed in a large Greek pedigree segregating autosomal dominant otosclerosis. A seventh locus, OTSC7, was localized on chromosome 6q13-16.1 with a multipoint LOD score of 7.5 in the 13.47 cM region defined by markers D6S1036 (centromeric) and D6S300 (telomeric). Linkage analysis of this new locus in 13 smaller Belgian and Dutch families has identified one family from The Netherlands in which allele segregation suggests linkage to this region. The overlap between the critical regions of these two families is a 1.06 Mb interval between the genetic markers D6S1036 (centromeric) and D6S406 (telomeric) on chromosome 6q13.

Chromosome Mapping↗

PubMed2006

Thromboembolism in women.

Venous thromboembolism (VTE) occurs in one of every 1,000 individuals per year. The incidence is much lower in young persons. In persons younger than age 45, the incidence is one of every 10,000 individuals per year. VTE is a multifactorial disease due to the interaction of various risk factors that can be genetic (e.g., inherited thrombophilia), acquired (e.g., age, neoplastic or autoimmune diseases, antiphospholipid antibodies), or transient (e.g., surgical interventions, fractures, trauma, prolonged immobilization). VTE is found equally in the two sexes. There are other transient risk factors for VTE that are typical for females, and these render women more exposed than men to the risk of the disease during their lifetime. Such risk factors are encountered frequently in a woman's life; they are oral contraceptive (OC) use, hormone replacement therapy, and pregnancy/puerperium. Moreover, various obstetric complications have attributed at least in part to an impaired placental circulation, suggesting a thrombosis theory as their common basis. In this review, the relationship between VTE and risk factors specifically of women is discussed, also in relation to coagulation abnormalities causing inherited thrombophilia.

Contraceptives, Oral↗

PubMed1999

The therapeutic potential of targeting drugs at transcription factors.

The pivotal role of gene transcription in a plethora of biological processes indicates that transcription represents a suitable target for potential therapeutic intervention. Ultimately, the pathophysiology of numerous human disease processes must be understood in terms of changes in gene expression within relevant body cell types. There is mounting evidence that genetic variation in transcription factors and/or their binding-site sequences, as well as environmentally induced malfunctioning of these proteins, contribute to common multifactorial disorders including cancer, diabetes, ischaemic heart disease and neural disorders. Even in 'non-inheritable' infectious diseases, alterations of host-cell transcriptional regulation play an important role in pathogenesis. The enormous progress in understanding the mechanisms of transcriptional control offers hope for the development of a new generation of drugs. Such compounds could be specifically designed to modulate either the synthesis of transcription factors, the regulation of their activity by small-molecule bioligands or phosphorylation events, their interactions with activator/repressor proteins or their binding to DNA. Given the remarkable specificity of this approach, it is anticipated that these agents will provide superior tools for the prevention and treatment of a diverse panel of clinical disorders in the not too distant future.

Journal Article↗

PubMed1999

[Specific disorders in the language development: neurobiological basis].

Studies of twins, familial aggregates and particular phenotypic conditions have shown an inherited basis for some dysphasias or specific developmental language impairments (SLI). This predisposition is usually multifactorial but the analysis of some families allows to postulate an autosomal dominant transmission of deficits in specific modular aspects of linguistic competences. Moreover, neuroimaging studies have shown modifications of normal volumetric interhemispheric asymmetries, and in group of SLI with receptive prominent disorder coexist epileptiform activity in wakefulness and non-REM sleep EEG; in some of these cases, antiepileptic drugs, specially steroids, can significantly ameliorate the language processing. As many patients with SLI have a difficulty for discrimination of subtle temporal indices, a hypothesis can also be made of a dysfunction in various subcortical structures (thalamus, basal ganglia, cerebellum) modulating the cerebral cortex in phonological processing.

Aphasia↗

PubMed2000

Porphyrins, porphyrin metabolism, porphyrias. III. Diagnosis, care and monitoring in porphyria cutanea tarda--suggestions for a handling programme.

Deficiency of the fifth enzyme in haem synthesis, uroporphyrinogen decarboxylase (UPGD), may give rise to accumulation and excretion of poly-carboxylated porphyrins, as well as to clinical manifestations in the form of a phototoxic skin reaction and liver engagement leading to cirrhosis and hepatocellular cancer. The cutaneous reaction, presenting as skin fragility and blisters on areas exposed to sun--porphyria cutanea tarda (PCT)--develops only in individuals with a remaining hepatic UPGD activity less than 20% of normal. Experimental results and clinical observation give evidence that PCT is a multifactorial disease. In some individuals a 50%, decrease in UPGD activity is a consequence of inheritance of an allele with a mutation in the gene programming for the enzyme, but in these gene carriers, as well as in the other patients with overt PCT, the activity of the hepatic enzyme is reduced below the critical level by the action of specific inhibitors. In the generation of the enzyme inhibitors, iron plays a central role by promoting the formation of reactive oxygen species, a process where a specific class of cytochrome enzymes; cytochrome P450 1A (CYP4501A), participates. The varying individual susceptibility to development of the disease can be discussed in terms of differences in a spectrum of factors that affect the availability of the free form of this element in the liver, or its pathogenic action. In the article the roles of chronic viral infection, alcohol abuse and exposition to polyhalogenated cyclic hydrocarbons are considered in the light of effects on the availability of iron in the liver. Some genetic prerequisites for susceptibility to PCT-inducing agents are included in a tentative model for the disease, i.e. mutations in the UPGD gene and in the HFE gene affected in haemochromatosis, as well as genetically steered inducibilities of the genes programming for CYP4501A and the rate-limiting enzyme in haem synthesis, 5-aminolevulinate synthase. With the pathogenic model as a basis the different therapeutic strategies that can be applied are discussed, and suggestions for a handling programme for the patient presenting with PCT put forward.

Humans↗

PubMed1991

Complex segregation analysis of nonsyndromic cleft lip and palate.

This study was undertaken to examine the inheritance pattern of nonsyndromic cleft lip with or without cleft palate (CL/P). Complex segregation analysis using the unified model as in POINTER and the regressive model as in REGD programs were applied to analyze a midwestern U.S. Caucasian population of 79 families ascertained through a proband with CL/F. In REGD, the dominant or codominant Mendelian major locus models of inheritance were the most parsimonious fit. In POINTER, besides the Mendelian major locus model, the multifactorial threshold (MF/T) model and the mixed model were also consistent with the observed data. However, the high heritability parameter of .93 (SD .063) in the MF/T model suggests that any random exogenous factors are unlikely to be the underlying mechanisms, and the mixed model indicates that this high heritability is accounted for by a major dominant locus component. These findings indicate that the best explanation for the etiology of CL/P in this study population is a putative major locus associated with markedly decreased penetrance. Molecular studies may provide further insight into the genetic mechanism underlying CL/P.

Cleft Lip↗

PubMed1998

Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations.

BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.

Adult↗

PubMed2001

Genetic epidemiology of glioma.

The present study performed a segregation analysis of a cohort of first-degree relatives (FDR) of glioma patients. The families with two or more gliomas were also expanded to determine if any more gliomas could be detected, and if any other types of cancers were associated. These glioma-prone families (n = 24/432) were extended to include first-, second- and third-degree relatives (n = 807) and a cohort was assembled, the standardized incidence risk for other types of cancer calculated and the pedigrees investigated for a possible mode of inheritance. A segregation analysis of the 2141 FDR in 297 families, performed using the Pointer software, did not clearly reject a multifactorial model chi(2)(3) = 6.13, P< 0.2. However, when letting all parameters be free, the recessive model provided the best fit. In the extended families, no increased risk of other types of cancer was found. This population-based study proposes that familial glioma occurs in about 5% of all glioma cases and that 1% have a possible autosomal dominant inheritance. This first segregation analysis performed in familial glioma must be cautiously interpreted, but an autosomal recessive gene provided the best fit, which could possibly explain 2% of all glioma cases.

Adolescent↗