SEARCH · PubMed Health

Results for “Multifactorial Inheritance”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,261 records · Page 70Linked to original sources

PubMed2006

Perinatal stroke in Saudi children. Clinical features and risk factors.

OBJECTIVES: To describe the clinical features and presentations of perinatal stroke in a prospective and retrospective cohort of Saudi children and ascertain the risk factors. METHODS: Patients with perinatal stroke were identified from within a cohort of 104 Saudi children who were evaluated at the Division of Pediatric Neurology at King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Saudi Arabia from July 1992 to February 2001 (retrospective study) and February 2001 to March 2003 (prospective study). Neuroimaging for suspected cases of stroke consisted of cranial CT, MRI, or both. RESULTS: During the study period, 23 (22%) of 104 children (aged one month to 12 years) were diagnosed to have had perinatal stroke. The male:female ratio was 1.6:1. Ten (67%) of the 15 children who had unilateral ischemic involvement had their lesion in the left hemisphere. The presentation of the ischemic result was within 24-72 hours of life in 13 (57%) patients, and in 6 children (26%), motor impairment was recognized at or after the age of 4 months. Nine children (39%) had seizures at presentation. Pregnancy, labour, and delivery risk factors were ascertained in 18 (78%) cases. The most common of these included emergency cesarean section in 5 cases, and instrumental delivery in another 5. Screening for prothrombotic risk factors detected abnormalities in 6 (26%) patients on at least one test carried out between 2 months and 9 years of age. Four children (17%) had low protein C, which was associated with low protein S and raised anticardiolipin antibodies (ACA) in one patient, and low antithrombin III in another. Low protein S was detected in a 42-month-old boy. The abnormality in the sixth child was confined to raised ACA. CONCLUSIONS: The present study highlights the non-specific features by which stroke presents during the neonatal period. The data are in keeping with the potential role for inherited and acquired thrombophilia as being the underlying cause. However, the high prevalence of additional acquired antenatal and perinatal risk factors support a multifactorial disorder.

Child↗

PubMed1981

On the distribution of nonrighthandedness among twins and their families.

In 773 three-generation families of twins, individual probability of nonrighthandedness (NRH) depends significantly on the handedness of that individual's parents. The parents of twins are much more often NRH than are their nontwinbearing siblings. The twins and their siblings apparently inherit the excess liability for NRH shown by their parents. Monozygotic (MZ) pairs are significantly about twice as often concordant (casewise) for handedness as dizygotic (DZ) pairs. Overall, the best-fitting mode of transmission is autosomal, NRH dominant to RH with penetrance of about 50% in the heterozygote, or multifactorial, with heritability of 60-70%. Under the major-gene approach, heterogeneity seems likely, with about one-third of the families showing no NRH outside of the twin sibships. MZ/DZ concordance ratio is about four in those families, suggestive of recessive inheritance. A 1.16-fold excess of NRH in twins compared to their siblings, and a 1.8-fold excess in the second-born members of same-sex discordant paris, leaves open the possibility that a minor portion of NRH in twins may be secondary to transient hypoxia and/or acidosis.

Adolescent↗

PubMedDate not supplied

The genetics of schizophrenia. Current knowledge and future directions.

Multiple research paradigms have provided evidence for a substantial genetic component in the etiology of schizophrenic disorders. This article reviews the major research strategies which have been employed in the examination of the genetic hypothesis in schizophrenia. Family studies have provided overwhelming support regarding familial transmission but cannot clearly resolve issues related to genetic-versus-environmental mechanisms. Twin and adoption studies, however, offer consistent evidence for a substantial genetic component and indicate environmental familial factors to be much less important. Quantitative modeling studies represent more specific attempts to identify the genetic mechanism and mode of inheritance responsible for the familial distribution of schizophrenia. To date, however, these quantitative models have not unequivocally supported a specific mode of genetic transmission. For instance, relevant studies provide little support for the mechanism of single major locus inheritance. Furthermore, although a mechanism involving two, three, or four loci cannot be ruled out, there is no compelling support for such models. The multifactorial polygenic model has received the most support and indicates that genetic factors play a greater role than environmental factors in familial transmission. A mixed genetic model including both a multifactorial component and a single major locus cannot be ruled out. Finally, studies of linkage analysis offer a more powerful technique used for testing the hypothesis of a single pathogenic gene, but the results of linkage analysis in schizophrenia are still preliminary and inconsistent. Evidence for a chromosome 5 gene locus has been provided in some studies but not replicated in others. The important implications of genetic-phenotypic heterogeneity and methodological deficiencies are discussed with respect to limitations on the interpretability of these studies and directions for future research.

Adoption↗

PubMed2005

The genetics of euthyroid familial goiter.

In endemic goiters, thyroidal enlargement reflects an increase in cell proliferation triggered by low dietary iodine. However, not all individuals in the same iodine-deficient regions develop a goiter, and iodine supplementation does not prevent goiter development in all treated subjects. Familial clustering of goiters, usually with an autosomal-dominant pattern of inheritance, has repeatedly been reported. Moreover, other environmental and etiological factors are likely to be involved in the development of euthyroid goiter. Therefore, a multifactorial etiology based on complex interactions of an individual's genetic makeup and environment is likely. Family and twin studies suggest a considerable influence by a strong genetic component in euthyroid familial goiter.

Family Health↗

PubMed2001

Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration.

Mutations in ABCR (ABCA4) have been reported to cause a spectrum of autosomal recessively inherited retinopathies, including Stargardt disease (STGD), cone-rod dystrophy and retinitis pigmentosa. Individuals heterozygous for ABCR mutations may be predisposed to develop the multifactorial disorder age-related macular degeneration (AMD). We hypothesized that some carriers of STGD alleles have an increased risk to develop AMD. We tested this hypothesis in a cohort of families that manifest both STGD and AMD. With a direct-sequencing mutation detection strategy, we found that AMD-affected relatives of STGD patients are more likely to be carriers of pathogenic STGD alleles than predicted based on chance alone. We further investigated the role of AMD-associated ABCR mutations by testing for expression and ATP-binding defects in an in vitro biochemical assay. We found that mutations associated with AMD have a range of assayable defects ranging from no detectable defect to apparent null alleles. Of the 21 missense ABCR mutations reported in patients with AMD, 16 (76%) show abnormalities in protein expression, ATP-binding or ATPase activity. We infer that carrier relatives of STGD patients are predisposed to develop AMD.

ATP-Binding Cassette Transporters↗

PubMed1999

Disease taxonomy--monogenic muscular dystrophy.

The field of the autosomal recessive progressive muscular dystrophies has clarified significantly following the recent elucidation of the genetic and molecular etiology of a number of these entities. These studies illustrate how genetics provides a rationale and objective basis for a new, refined nosology. Furthermore, whereas most of these studies point towards the pivotal role played by a number of structural proteins--all directly or indirectly associated with dystrophin--a calpain protease was shown to be involved in the Réunion-type limb girdle muscular dystrophy. This discovery raises the issue of whether these mechanisms are all part of one and the same pathway or of distinct pathophysiological pathways (structuropathy versus enzymopathy) leading to similar phenotypes. Finally, all of these diseases are considered as classical monogenic traits. Some findings suggest, however, that epistatic interactions have been overlooked and that the inheritance models could be slightly more complex. These results are discussed in light of the coming challenges of the identification of genes underlying complex multifactorial traits.

Humans↗

PubMedDate not supplied

Familial IgA nephropathy.

To date, more than 90 families with multiple members with IgA nephropathy have been reported. The case for genetic predisposition as a cause of familial clustering of IgA nephropathy is supported by several factors, including variable time points in the onset of the disease in relatives with IgA nephropathy; the presence of abnormalities of IgA production in both affected and unaffected family members; the clustering of the birthplaces of ancestors of large pedigrees containing multiple affected members with IgA nephropathy, which suggests the existence of a "founder effect". Immunogenetic studies does not conclusively indicate that HLA is involved in the pathogenesis of IgA nephropathy. The specific mode of inheritance of familial IgA nephropathy is difficult to establish with certainty. IgA nephropathy may be a single gene trait with incomplete penetrance. Alternatively, a multifactorial genetic disease could account for the increased prevalence of the disorder among relatives of affected individuals. Clinicians must become aware that IgA nephropathy may aggregate within families in a substantial number of cases. The availability of multiplex families offers an ideal opportunity to design a molecular genetics approach to map the gene(s) or pathway(s) responsible for the development of IgA nephropathy.

Genetic Predisposition to Disease↗

PubMed2000

[The genome and neurology. The example of Parkinson's disease].

In the recent years, many genes involved in inherited neurological disorders have been identified, and the achievement of the human genome project should accelerate their discovery. For common disorders which are of multifactorial origin, the identification of genetic susceptibility factors is still difficult. However, the study of rare monogenic forms of these disorders has proven to be fruitful. An example is Parkinson's disease, in which mutations in the alpha synculein gene are responsible for an autosomal dominant form. The study of alpha-synculein led to the conclusion that this protein is a major component of Lewy bodies, which constitute the pathological hallmark of the disease. The study of autosomal recessive forms allowed to demonstrate the relative frequency and the large variety of mutations in the Parkin gene. Parkin is probably involved in ubiquitination of proteins before their degradation by the proteasome and the identification of its cellular targets should allow the understanding of the specificity of neurodegenerative process in the human disease.

Genes, Dominant↗

PubMedDate not supplied

[Heredity and environment in the genesis, epigenesis and evolution of the orofacial area].

Genetic and evolutionary aspects of the dento-facial complex are described according to the concept of heredity as a force of preservation for the human species, though ruled by natural selection and by mutational changes. Ontogenesis and growth of the oral structures reflect mutual regulations between genes and environmental factors. Therefore, the authors carry out an analysis of environmental and constitutional factors affecting dental and facial development. Three levels are identified: individual morphogenesis and growth; actual heredity of parietal dento-facial traits; role and meaning of teeth, jaws and temporo-mandibular joint during evolution leading to Homo sapiens sapiens. As far as individual development is concerned, genes provide only the input for initial cell proliferation and/or differentiation. Further on, growth and morphogenesis of oro-facial structures takes place by means of cell-to-cell and cell-to-substrate interactions. The final, structural result is due to reciprocal interactions among developing structures: muscles modify bone, teeth alignment influences bony bases alignment, ecc. Each structure is genetically determined (teeth, bones, muscles) and each structure carries out epigenetic regulations on other structures: no structure is secluded from biological function of the organism. The inheritance of oro-facial "traits", then, is hardly valuable. First of all, "traits" actually do not exist: they are the product of complex, multifactorial biological mechanisms. Moreover, facial characteristics are affected by polygenic regulation, each gene often showing pleiotropic effects. It has been calculated that 85-90% of facial dimensions in due to epigenetic modifications. Evolution and phylogenesis give evidence about the deep environmental influence on oro-facial morphology. Apart from certain molecular features regarding tooth structure (several dental proteins are today the same as those of the first Vertebrates who lived 500 millions of years ago), tooth number, form, and size depend upon environmental factors. Therefore, dentistry has the important task to preserve fundamental characteristics of dentition, and to intercept environmental pathogenetic factors, as dentition represents a precious instrument for the survival of the human species.

Biological Evolution↗

PubMed1979

Inheritance of childhood diabetes.

In the parents of 250 diabetic children the occurrence of juvenile and maturity onset diabetes was found to be more frequent than in the parents of 230 medical students. Assuming a multifactorial poligeneic heredity, the role of common genes predisposing to diabetes cannot be neglected in the manifestation of the two types of the disease. In the families where juvenile diabetes had occurred, the probability of occurrence of juvenile diabetes is considerably higher than that of maturity onset diabetes. This might be in connection with the fact that the provocative factors are different in juvenile and maturity onset diabetes.

Adolescent↗

PubMed1984

Genetic analysis of cleft lip with or without cleft palate in Danish kindreds.

The present study population consists of 2,532 families ascertained through non-syndromic cleft lip with or without cleft palate (CL +/- P) surgical probands born in Denmark between 1941 and 1971. Three samples were derived for analyses of the trait "clefted (CL +/- P) or not." Sample 1 consists of the 26 largest multigenerational families with four or more affected members. Both samples 2-MG and 2-N consist of nuclear families with at least two children and at least one proband among the children. Sample 2-MG contains 846 nuclear families derived from the kindreds with three or more generations. Sample 2-N contains a further 1,181 kindreds with only two generations, nuclear family information available. Four methods of analysis were used: 1) Pedigree analysis was performed on each of the multigenerational kindreds of Sample 1. Results were consistent with autosomal recessive inheritance in eight families and codominant inheritance in three families. These simple genetic hypotheses could not be distinguished in the remaining 15 families. 2) The goodness-of-fit of the multifactorial threshold (MF/T) model was tested in Samples 2-MG and 2-N. The MF/T model was rejected in both samples. 3) Classical segregation analysis was performed on Samples 2-MG and 2-N. Results were consistent with a possible recessive major gene for CL +/- P in Sample 2-MG, but not in Sample 2-N, and with significant admixture of sporadic cases in both samples. 4) Complex segregation analysis under the mixed model was performed on Samples 2-MG and 2-N. In Sample 2-MG, results were consistent with either the general mixed model or with an hypothesis of no major gene. In Sample 2-N, four hypotheses were equally likely: the mixed model with no polygenic component, the mixed model with the major gene component, the mixed model with no sib environmental correlation, and major gene alone. Three conclusions may be drawn: 1) The data provide no support for the MF/T model. 2) The data are consistent with the possibility of a major gene in a portion of the kindreds. 3) The data provide evidence for genetic heterogeneity for CL +/- P.

Child↗

PubMed1997

A search for environmental and genetic background for neural tube defects: twenty-five years of experience.

The present paper illustrates the author's 25-year experience in a step by step approach to the definition of environmental and genetic background of neural tube defects. Based on the birth defects registry, a complete ascertainment of all deliveries was performed in Southern Poland during two periods: 1970-1972, and 1979-1981. The birth prevalence of neural tube defects (NTD), as well as other CNS malformations was determined. The empiric recurrence risk was calculated as 3.2% +/- 1.6. Based on this figure, the relative risk (RR = 37.6 p < 0.001) and heritability (h2 = 74.7 +/- 6.7) were estimated. Our own modification of Morton's complex segregation analysis was applied. Three Mendelian (dominant, additive and recessive) and one multifactorial model were tested. The results did not provide a clear cut discrimination between different models; however the lowest x2 value was obtained for additive inheritance with 61% of penetrance and the frequency of sporadic cases equaled 55%. A search for genetic markers did not support the hypothesis that HLA-A,B,C loci are equivalents of T/t like locus in mice. The results of the study on transcobalamine levels in amniotic fluid may suggests that different transcobalamine metabolism reflects phenotypic expression of genetic susceptibility to NTD development. Current research status and future perspectives on genetic and environmental background of NTD are also presented.

Abnormalities, Drug-Induced↗

PubMed1998

[Neural tube defects (NTD)--assessment from the perspective of 25 years of studies].

The present paper illustrates the authors 25-year experience in step by step approach to the definition of environmental and genetic background of neural tube defects. Based on the birth defects registry, a complete ascertainment of all deliveries was performed in Southern Poland during two period: 1970-1972, and 1979-1981. The birth prevalence of neural tube defects (NTD), as well as other CNS malformations was determined. The empiric recurrence risk was calculated as 3.2% +/- 1.6. Based on this figure, the relative risk (RR = 37.6 p < 0.001) and heritability (h2 = 74.7 +/- 6.7) were estimated. Our own modification of Morton's complex segregation analysis was applied. Three Mendelian (dominant, additive and recessive) and one multifactorial model were tested. The results did not provide a clear cut discrimination between different models; however the lowest 2 value was obtained for additive inheritance with 61% of penetrance and the frequency of sporadic cases equaled 55%. A search for genetic markers did not support the hypothesis that HLA-A,B,C loci are equivalents of T/t like locus in mice. The results of the study on transcobalamine levels in amniotic fluid may suggests that different transcobalamine metabolism reflects phenotypic expression of genetic susceptibility to NTD development. Current research and future perspectives on genetic and environmental background of NTD are also presented.

Amniotic Fluid↗

PubMed1990

X chromosome genes involved in the regulation of facial clefting and spina bifida.

Congenital malformations such as cleft palate and spina bifida may be multifactorial in etiology. They occur as a result of both environmental agents and defective genes. Consequently it is both practically and intellectually difficult to study their effects experimentally. The advent of molecular biology technology has enabled many genes on the human chromosome to be mapped and some to be cloned. Using these techniques and families that display common congenital malformations inherited in a purely genetic manner, the genetic defects can be separated from the environmental components. This report documents our studies of several families that have cleft palate or spina bifida as X-linked disorders. Their phenotype is similar to the more common multifactorial cases but segregates as a single gene in an X-linked fashion. Localization of these genes using different X chromosome DNA probes and linkage analysis is the first step towards our understanding of the genetic contribution to the etiology of congenital malformations.

Anencephaly↗

PubMedDate not supplied

Possible factors in the etiology of Alzheimer's disease.

Inherited cases of Alzheimer's disease (AD) comprise only a very small proportion of the total. The remainder are of unknown etiopathogenesis, but they are very probably multifactorial in origin. This article describes studies on four possible factors: aluminum; viruses--in particular, herpes simplex type I virus (HSV1); defective DNA repair; and head trauma. Specific problems associated with aluminum, such as inadvertent contamination and its insolubility, have led to some controversy over its usage. Nonetheless, the effects of aluminum on animals and neuronal cells in culture have been studied intensively. Changes in protein structure and location in the cell are described, including the finding in this laboratory of a change in tau resembling that in AD neurofibrillary tangles, and also the lack of appreciable binding of aluminum to DNA. As for HSV1, there has previously been uncertainty about whether HSV1 DNA is present in human brain. Work in this laboratory using polymerase chain reaction has shown that HSV1 DNA is present in many normal aged brains and AD brains, but is absent in brains from younger people. Studies on DNA damage and repair in AD and normal cells are described, and finally, the possible involvement of head trauma is discussed.

Aluminum↗

PubMed2002

Pathology, diagnosis and pathogenesis of AA amyloidosis.

Amyloid is defined as a proteinaceous tissue deposit that shows a typical green birefringence in polarised light after staining with Congo red, the presence of non-branching linear fibrils of indefinite length with an approximate diameter of 10-12 nm and a distinct X-ray diffraction pattern consistent with Pauling's model of a cross-beta fibril. Approximately 45% of generalised amyloidoses are secondary or reactive (AA) amyloidosis. Among the causes of AA amyloidosis are rheumatic diseases, idiopathic diseases, inherited diseases, infectious diseases and malignant tumours. Recent decades have provided significant advances in our understanding of the pathology and pathogenesis of AA amyloidosis. Its pathogenesis is multifactorial involving many variables such as primary structure of the precursor protein, acute phase response, the presence of non-fibril proteins (e.g. amyloid P component, apolipoprotein E, glycosaminoglycans, proteoglycans and basement membrane proteins), receptors, lipid metabolism and proteases. Study of the pathogenesis of AA amyloidosis has provided many insights into the nature of conformational diseases, which may help in the understanding of other members of this particularly heterogeneous group of diseases, such as Alzheimer's disease and transmissible spongiform encephalopathies.

Amyloidosis↗

PubMedDate not supplied

Cardiovascular genomics.

The ongoing explosion of genomic information is revolutionizing cardiovascular science. More complete genomic maps allow easier identification of genes that cause monogenic inherited diseases. In addition, analyses of variations in gene expression in cardiovascular diseases are revealing new potential candidate genes as well as novel biomarkers for many common, multifactorial diseases. While experiments are revealing new pathophysiologic pathways, these genomic studies are also generating enormous amounts of data. Even as we learn how to sift through mountains of genomic information, new technologies in proteomics are rapidly advancing and promise to provide additional critical tools for diagnosis and for identifying new therapies.

Biomarkers↗

PubMed2002

Cancer causation: the Darwinian downside of past success?

Causal mechanisms in all diseases are diverse and multifactorial, but medical scientists, as pragmatists, inevitably focus on limited or circumscribed components of pathogenetic puzzles. In cancer, epidemiologists have traditionally sought to incriminate exposures; geneticists uncover inherited susceptibility; and molecular biologists deconstruct the proximal mechanisms of cell transformation. Molecular epidemiology promises to deliver new insights in terms of gene-environment interactions. Each of these endeavours has undeniably provided rich dividends and insights into cancer causation, but are these likely to be sufficient as a coherent explanation of our vulnerability to cancer? I suggest that the biological plausibility of causal mechanisms would benefit from a historical, evolutionary perspective. The essential argument is that genes or gene variants and phenotypic traits that were adaptively selected in the past as advantageous now contribute crucially to cancer because of their mismatch with current environmental and social circumstances. The risk attributes of skin pigmentation and some dietary factors in cancer can be plausibly interpreted within this context. A case is made here for a Darwinian perspective on breast and prostate cancers, for which current understanding of causation is limited and contentious.

Causality↗