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PubMed1999

Gene defects in idiopathic epilepsy.

Idiopathic epilepsies are mainly due to genetic factors. In most cases the mode of inheritance is either oligogenic or multifactorial. Only a few rare idiopathic epilepsies are single gene disorders. Monogenic epilepsies offer the chance to identify genes/gene families which might also be involved in the aetiology of common forms of the disease. The genetic basis of two monogenic epilepsies have recently been identified: autosomal dominant nocturnal frontal lobe epilepsy and benign familial neonatal convulsions.

Chromosomes, Human, Pair 20↗

PubMed1992

Contribution to the genetics of rolandic epilepsy: waking and sleep EEGs in siblings.

Waking and sleep EEGs were recorded in 69 siblings of 43 patients with rolandic spikes. 36 suffered from rolandic epilepsy, 7 from other diseases or symptoms (headaches, migraine, learning problems). At least one sibling with epileptic activity was found in 51.16% of the patients. Taking the 69 siblings as a basis, in 26 (37.68%) epileptic activity was recorded. Benign spike foci were recorded in only 4 siblings, generalized spike-wave complexes were seen in 22. Most epileptic activity was recorded in the age group of 5-12 years (54.3%). Nearly one-half (17.4%) was recorded exclusively in sleep, predominantly in sleep stage C (88%). Siblings of patients with (40%) and without seizures (37.5%) showed approximately the same rate, likewise siblings with (40%) and without seizures (34.8%). An autosomal-dominant mode of inheritance is assumed, but a multifactorial mode is also discussed.

Adolescent↗

PubMed1977

Hereditary determination of several hemodynamic indices.

Investigation of the genetic determination of hemodynamic indices (the volume of circulating blood, the time of total blood circuit, the rate of lesser blood flow and the minute heart volume) is carried out in 16 mono- and 15 dizygotic twin pairs. The volume of circulating blood only was found to be highly genetically determined (G = 0.90). The role of heredity and environment was almost the same in genesis of the time of total blood circuit and the rate of lesser blood flow (G = 0.34 and 0.48 respectively), while the effect of environment is prevailed for the minute heart volume. The coefficient of genetic determination G is considered to be the most competent estimate among other indices of heredity, because it makes possible to isolate the additive variance and the variance of determing genetic component of phenotypical dispersion of a character. On the basis of the parameters studied, a multifactorial character of hemodynamics indices inheritance is suggested.

Adult↗

PubMed1984

The genetics of urinary tract malformations.

In this discussion I have excluded consideration of the genetics of purely renal malformations, such as polycystic kidneys, and of functional disorders of the kidney. Systematic family studies are available for renal agenesis, duplication of the ureters, vesico-ureteric reflux (each probably due to maldevelopment of the ureteric bud), bladder exstrophy and hypospadias as isolated malformations. Renal agenesis has a birth frequency of about 1.2 in 10 000 and the proportion affected of sibs is about 3 per cent. Duplication of the ureter has a birth frequency of about 1 per cent and the proportion affected of sibs and parents of probands is about 12 per cent. Vesico-ureteral reflux also has a prevalence in early childhood of about 1 per cent and the proportion of sibs affected is about 10 per cent. Bladder exstrophy has a birth frequency of about 1 in 20 000 and perhaps about 1 per cent of sibs are affected. Hypospadias has a birth frequency in boys of about 1 in 300 and the proportion affected of brothers is about 10 per cent. Further family studies are needed of these malformations when they occur in isolation. Either the multifactorial threshold model or dominant inheritance with reduced penetrance and varied expressivity would fit the data available.

Bladder Exstrophy↗

PubMedDate not supplied

Genetic determinants of type 2 diabetes mellitus: lessons learned from family studies.

Non insulin dependent diabetes mellitus (Type 2) is a multifactorial disease, with a polygenic inheritance and environmental factors contributing to its clinical expression. The search for the genetic determinants of Type 2 diabetes began when several genes involved in the mechanisms of insulin secretion or action were cloned, localized in the human genome, and when informative polymorphisms were described within or in the vicinity of these genes. It then became possible to compare, in groups of patients and normoglycaemic controls from various populations, the frequency of the different alleles of polymorphic markers of various candidate genes (e.g. insulin, insulin receptor, glucose transporters). The conflicting results observed in these studies can be ascribed to the small size of the population samples, to the genetic heterogeneity of Type 2 diabetes mellitus, but also to the methodology used therein. Indeed, these studies searched for a correlation between the frequency of certain alleles or genotypes and the phenotype of diabetes (studies of associations in affected populations compared to healthy controls). However in order to attribute to a gene the responsibility for a disease it is necessary to demonstrate the cotransmission in affected kindreds of a morbid allele of the gene along with the disease (familial or linkage analysis). The aim of this review is to summarize the results of family studies of Type 2 diabetes and Maturity Onset Diabetes of the Young (MODY), particularly with concern to the mutations described in candidate genes, and the implication of glucokinase in these disorders.

Amyloid↗

PubMed1997

[Atopic dermatitis].

Nowadays about 15% of a birth cohort develops atopic dermatitis of varying severity, while only about 3% were affected in the sixties. The pathogenesis of the disease is multifactorial, based on genetic (polygenic inheritance) and environmental factors, the latter presumably accounting for the rising incidence. Several genes of importance for the immune pathogenesis of atopic diseases, including atopic dermatitis, have been identified. Exogenous factors, for instance air humidity and colonization of the skin with Staphylococcus aureus and Pityrosporum ovale are also important in the pathogenesis. Specific allergies, for instance dust mite allergy and food allergy, may be contributory causes. Treatment is directed against the dry skin, the eczematous reaction, skin infections and potential, specific allergies. Information given to patients and parents through "eczema schools" might be an important part of therapy with focus on atopic diseases, treatment strategy and prevention.

Child, Preschool↗

PubMed1999

The rod photoreceptor ATP-binding cassette transporter gene, ABCR, and retinal disease: from monogenic to multifactorial.

The ABCR gene encodes a rod photoreceptor specific ATP-binding cassette transporter. Mutations in ABCR are associated with at least four inherited retinal dystrophies: Stargardt disease, Fundus Flavimaculatus, cone-rod dystrophy, and retinitis pigmentosa. A statistically significant increase in heterozygous ABCR alterations has been identified in patients with age-related macular degeneration (AMD). A pedigree is described which manifests both Stargardt disease and AMD in which an ABCR mutation cosegregates with both disease phenotypes. These data from this case report support the hypothesis that ABCR is a dominant susceptibility locus for AMD. Recent work regarding ABCR is reviewed and a model is presented in which decreased ABCR function correlates with severity of retinal disease.

ATP-Binding Cassette Transporters↗

PubMed1976

The inheritance of affective disorders: a review of data and of hypotheses.

A genetic factor in affective disorders is suggested by twin and family history studies. The form of disorder (BP or UP) is transmitted within families. Early onset of affective disorder is associated with increased morbid risk of the disorder in relatives, but age at onset is not itself a transmitted factor. Female relatives have higher prevalence of illness, but sex of the ill person does not appear to be a factor in transmission. Genetic models of multifactorial or single-gene autosomal inheritance are compatible with some but not all of the family history studies reported. The hypothesis of sex-linked transmission of BP illness has been proposed, and some pedigrees compatible with X-linkage have been reported, but family studies do not suggest that this is generally present. Other possible modes of inheritance remain to be tested. Investigative strategies for identification of the "affective genotype" are discussed on the basis of biochemical, pharmacological, or other characteristics of persons with the disorders and their relatives, and on the basis of studies of known linkage markers.

Age Factors↗

PubMed1982

Family studies in psoriasis. II. Inheritance of HLA genotypes.

The study of HLA genotypes in psoriatic families attempts to probe into the genetic transmission of disease. A strong association of psoriasis with HLA antigens determined by locus B is well known, but its relationships are still unsolved. A group of 39 families, living in southern Poland and containing 19 affected parents and 52 psoriatic children, was studied. To discriminate between dominant and recessive modes of 'disease' genes inheritance, two tests were used. No significant differences were found between the observed and the expected distributions of genotypes with HLA-B 13 or HLA-B 17. The expected and the observed numbers of affected sib pairs sharing two, one or no HLA haplotypes were compatible with the proportions of 1/4, 1/2 and 1/4 in the case of independent segregation of psoriasis and HLA antigens. The results support the hypothesis of multifactorial determination of disease. The hypothetical inheritance of parental HLA haplotypes carrying 'psoriatic' genes in cis or trans positions was considered. Of nine possible combinations, two were shown graphically that resulted in offspring compatible with the observed pyenotypical expression of disease.

Female↗

PubMed2002

Prevalence of inherited thrombophilia in young thrombosis patients from the East Bohemian region.

Venous thromboembolism is a multifactorial disease that is defined by multiple interactions between genetic and environmental components. Inherited thrombophilia may result in a hypercoagulable state that causes an increased tendency to thrombosis. We assessed the prevalence of factor V Leiden, factor II 20210A, antithrombin III, protein C and protein S deficiency, and the presence of antiphospholipid syndrome among 325 thrombosis patients from the East Bohemian region with a first episode of thrombosis under the age of 45 years. The average age of the first thrombotic event was 34 years (age range, 14-45 years). These data are not known yet from this part of the Czech Republic. Factor V Leiden was found in 40%, factor II 20210A in 6%, antithrombin III deficiency in 4%, protein C deficiency in 6%, and protein S deficiency in 11% in this cohort. Lupus anticoagulant was detected in 8% and anticardiolipin antibodies in 6%. Our results confirm the usefulness of thrombophilia work-up in patients with venous thrombosis before the age of 45 years in our region. The diagnosis of inherited thrombophilia is important for further management of these patients.

Adolescent↗

PubMed1999

Oesophageal atresia, related malformations, and medical problems: a family study.

Oesophageal atresia (OA) and tracheo-oesophageal fistula (TOF) are life-threatening malformations of generally undefined cause. Previous reports of familial cases suggest a genetic contribution. The pattern of inheritance appears non-Mendelian, i.e., multifactorial. Individuals with OA/TOF often have other malformations and medical problems. The aim of this study was to determine the association in OA/TOF cases and healthy control subjects of associated malformations, midline defects, and medical conditions. We also investigate the relationships of these conditions in the relatives of the cases and controls. The results show that infants with OA/TOF frequently have VACTERL anomalies (vertebral, 17%; anal, 12%; cardiac, 20%; renal, 16%; limb, 10%) and other midline defects (cleft lip and palate, 2%; sacral dysgenesis, 2%; urogenital anomalies, 5%). The following medical problems were also reported: oesophageal dysmotility, 21%; gastro-oesophageal reflux, 22%; chest infections, 6%; and autonomic dysfunction, 0.5%. The first-degree relatives of children with OA are much more likely to have one of the aforementioned malformations or medical conditions when compared with the control group: one or more VACTERL anomalies (P < 0.01), gastro-oesophageal reflux (P < 0.05), recurrent respiratory infections (P < 0.05), and autonomic dysfunction (P < 0.001). The more distant relatives also show an increased incidence of such problems although in this case the data must be viewed with caution. The results confirm that the associated malformations and related medical problems occur significantly more frequently in the relatives of individuals with OA/TOF. These families may prove valuable for linkage analysis in an attempt to determine the genetics of OA/TOF.

Abnormalities, Multiple↗

PubMed2006

Current perspectives on the genetic causes of neural tube defects.

Neural tube defects (NTDs) are a group of severe congenital abnormalities resulting from the failure of neurulation. The pattern of inheritance of these complex defects is multifactorial, making it difficult to identify the underlying causes. Scientific research has rapidly progressed in experimental embryology and molecular genetics to elucidate the basis of neurulation. Crucial mechanisms of neurulation include the planar cell polarity pathway, which is essential for the initiation of neural tube closure, and the sonic hedgehog signaling pathway, which regulates neural plate bending. Genes influencing neurulation have been investigated for their contribution to human neural tube defects, but only genes with well-established role in convergent extension provide an exciting new set of candidate genes. Biochemical factors such as folic acid appear to be the greatest modifiers of NTDs risk in the human population. Consequently, much research has focused on genes of folate-related metabolic pathways. Variants of several such genes have been found to be significantly associated with the risk of neural tube defects in more studies. In this manuscript, we reviewed the current perspectives on the causes of neural tube defects and highlighted that we are still a long way from understanding the etiology of these complex defects.

Animals↗

PubMed1997

Sensitivity to cerebral ischaemic insult in a rat model of stroke is determined by a single genetic locus.

Ischaemic stroke is a complex disorder caused by a combination of genetic and environmental factors. Clinical and epidemiological studies have provided strong evidence for genetic influences in the development of human stroke and several mendelian traits featuring stroke have been described. The genetic analysis of the non-mendelian, common ischaemic stroke in humans is hindered by the late onset of the disease and the mode of inheritance, which is complex, polygenic and multifactorial. An important approach to the study of such polygenic diseases is the use of appropriate animal models in which individual contributing factors can be recognized and analysed. The spontaneously hypertensive stroke-prone rat (SHRSP) is an experimental model of stroke characterized by a high frequency of spontaneous strokes as well as an increased sensitivity to experimentally induced focal cerebral ischaemia. Rubattu et al. performed a genomewide screen in an F2 cross obtained by mating SHRSP and SHR, in which latency to stroke on Japanese rat diet was used as a phenotype. This study identified three major quantitative trait loci (QTLs), STR-1-3. Of these, STR-2 and 3 conferred a protective effect against stroke in the presence of SHRSP alleles and STR-2 co-localized with the genes encoding for atrial natriuretic and brain natriuretic factors. Our investigation was designed to identify the genetic component responsible for large infarct volumes in the SHRSP in response to a focal ischaemic insult by performance of a genome scan in an F2 cross derived from the SHRSP and the normotensive reference strain, WKY rat. We identified a highly significant QTL on rat chromosome 5 with a lod score of 16.6 which accounts for 67% of the total variance, co-localizes with the genes encoding atrial and brain natriuretic factor and is blood pressure independent.

Animals↗

PubMed1995

An international two-stage genome-wide search for schizophrenia susceptibility genes.

Schizophrenia is thought to be a multifactorial disease with complex mode of inheritance. Using a two-stage strategy for another complex disorder, a number of putative IDDM-susceptibility genes have recently been mapped. We now report the results of a two-stage genome-wide search for genes conferring susceptibility to schizophrenia. In stage I, model-free linkage analyses of large pedigrees from Iceland, a geographical isolate, revealed 26 loci suggestive of linkage. In stage II, ten of these were followed-up in a second international collaborative study comprising families from Austria, Canada, Germany, Italy, Scotland, Sweden, Taiwan and the United States. Potential linkage findings of stage I on chromosomes 6p, 9 and 20 were observed again in the second sample. Furthermore, in a third sample from China, fine mapping of the 6p region by association studies also showed evidence for linkage or linkage disequilibrium. Combining our results with other recent findings revealed significant evidence for linkage to an area distal of the HLA region on chromosome 6p. However, in a fourth sample from Europe, the 6p fine mapping finding observed in the Chinese sample could not be replicated. Finally, evidence suggestive of locus heterogeneity and oligogenic transmission in schizophrenia was obtained.

Chromosomes, Human, Pair 20↗

PubMed1980

General causal models for sex differences in the familial transmission of multifactorial traits: an application to human spatial visualizing ability.

A general multifactorial model is given for the inheritance of traits that exhibit a sexual dimorphism. The model allows for polygenic inheritance, cultural transmission, phenotypic assortative mating, and a common environment of rearing. Several cultural mechanisms are described for which transmission from parent to offspring is sex-dependent and for which many different patterns of sex-specific correlations can result. A special case of the general model is described in which phenotypic differences between males and females are due only to differences in nontransmissible environmental factors and/or genetic factors that do not contribute to variability within a sex. Application of these models to human spatial visualizing ability, using data reported by others, gives an estimate of 45 per cent for the proportion of the variance that is accounted for by transmissible factors. Neither an X-linked hypothesis nor a sex-specific cultural mechanism is required to explain the transmission of spatial ability.

Female↗

PubMed1994

Complex genetic disease: can genetic strategies in Alzheimer's disease and new genetic mechanisms be applied to epilepsy?

Strategies used in molecular genetics have changed modern neurology. The gene or genes responsible for several major neurologic diseases have now been identified using "reverse" or positional genetics. Unexpected new genetic mechanisms have been discovered in human neurologic diseases, including (a) identical mutations of the prion protein gene in Creutzfeldt-Jakob disease and fatal familial insomnia with the phenotypic expression directed by an accompanying polymorphism; (b) stable duplications of chromosome 17 in Charcot-Marie-Tooth disease (type 1A) that involve many genes, only one of which appears to cause neuropathy; and (c) highly variable, dynamic mutations in myotonic dystrophy, fragile X syndrome, and Kennedy's syndrome that modulate variable expressivity in multiple tissues. There is growing recognition that neurologic diseases are often complex genetic diseases with multifactorial rather than simple modes of inheritance. For example, genetic association/linkage strategies have interacted with biochemistry and immunopathology studies to produce new insights into the disease mechanism of late-onset Alzheimer's disease. The role of apolipoprotein E in late-onset Alzheimer's disease is an example of how new analytical techniques of genetic disease can be applied to dissect multiple genes. Similar research strategies are suggested for the study of epilepsy as a complex disease.

Alleles↗

PubMed1985

Genetics of congenital heart malformations: a stochastic model.

A stochastic model is proposed to explain how alterations in the properties of developing endocardial cells could control the outgrowth of endocardial cushions in normal persons, in subjects from families with a predisposition to congenital heart defects, and in subjects with trisomy 21. Normal and abnormal outgrowth of the endocardial cushions of the atrioventricular (AV) canal were modeled by computer simulations. Computer simulations depicted not only the sequence of normal AV valve development, but also illustrated how increased cellular adhesiveness of fibroblasts from the endocardial cushions of the AV canal--which we have observed in vitro among cultured cells from Down syndrome abortuses--may result in AV canal defects. The stochastic model so elaborated demonstrates how single gene changes may result in abnormalities in only a proportion of subjects carrying mutant alleles, yielding inheritance patterns characterized previously as being "multifactorial" in origin.

Cell Adhesion↗

PubMed1993

Linkage analysis of infantile pyloric stenosis and markers from chromosome 9q11-q33: no evidence for a major gene in this candidate region.

A genetic component in the aetiology of infantile pyloric stenosis (PS) is well established. Segregation analysis is compatible with a multifactorial sex modified threshold model of inheritance but a major gene of low penetrance has not been excluded. PS has been reported to occur in 57% (four of seven) of cases with duplication of chromosome 9q11-q33. Twenty families with PS were studied using genetic markers at loci D9S55, D9S111, D9S15, D9S12, D9S56, D9S59, and ASS from this region of chromosome 9. Pairwise lod scores of -2 were obtained with all these markers at recombination fractions greater or equal to 0.04 under both autosomal dominant and autosomal recessive models of inheritance. This provides evidence against the existence of a major locus predisposing to PS within chromosome 9q11-q33.

Chromosomes, Human, Pair 9↗