Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Inheritance”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 307 records · Page 17Linked to original sources

Inherited biochemical defects affecting the kidney.

The identification of a disease entity as one that is the result of a heritable defect offers the physician an opportunity to intervene in a variety of ways. As emphasized, knowledge of the heritable pattern of a particular disease allows the physician an opportunity to counsel family members in personal disease risk and the offspring. Such genetic counseling results in a reduction of affected cases for many inherited diseases. There is every expectation that similar approaches would be effective for inherited renal diseases. The heritable diseases are a favored group for investigative purposes since these diseases result from a single gene defect no matter how plieotropic the effects of that defect. Thus the investigator is capable of constant probing with tools available for identifying that one event or component that lies at the basis of the disease. The emphasis of this chapter is on those inherited renal diseases for which we have reached a high level of understanding of this single defect. In many of these diseases a single enzyme is identified as deficient and is the presumed genetic defect. In others (cystinuria, RTA, and cystinosis) the precise biochemical answers appear close at hand. Thus a variety of therapeutic approaches to overcome either the gene defect or ill effects of the gene defect emerge for diseases involving the kidney and are listed in Table 7. For some of these diseases the new diagnostic technique of prenatal diagnosis can be used (Table 8). This genetic option provides couples at risk for bearing affected offspring with reduced risk. For a number of other diseases that are not identified by amniocentesis, this risk can be effectively lowered to acceptable levels by use of artificial insemination. Thus the inherited diseases of the kidney are amenable to medical intervention at a variety of levels. Such intervention can predictably lead to a lowering of both the incidence and consequences of these gene defects.

Acidosis, Renal Tubular↗

Intermediate inheritance of Tourette syndrome, assuming assortative mating.

Segregation analysis incorporating assortative mating was used to test for major locus inheritance of Tourette syndrome in a single large pedigree containing 182 members. The analysis provided evidence of a major locus with an intermediate inheritance pattern for which the penetrance was estimated from the data as 28% in heterozygotes and 98%-99% in homozygotes. A significant assortative mating correlation was estimated from the data as 70%-79%. In contrast, when assortative mating was not included in the model, intermediate inheritance was not inferred. If, in addition, constancy of the allele frequencies across generations was not assumed, Mendelian transmission was rejected. Each subject, affected or unaffected, was assigned a score reflecting the presence and severity of symptoms. Higher means scores in affected homozygotes than in affected heterozygotes suggested greater severity in homozygotes: genotype information was obtained from genotype probabilities computed assuming intermediate inheritance.

Adolescent↗

Mendelian inheritance in man: diagnoses in the UMLS.

Because they deal with many distinct but rare inheritance diseases, geneticists have difficulty translating from their codes to other biomedical coding schemes. The objective of this research was to investigate the potential uses and difficulties of using the UMLS Metathesaurus for genetic diagnoses and to make recommendations to UMLS developers for improvements in UMLS for common genetic disorders. The 110 most common Mendelian Inheritance in Man disorders from the Missouri Genetic Disease Program over the period of one year were translated into MeSH, ICD and SNOMED. The more common diseases are more likely to be mapped than the rarer ones. Diseases with a proven genetic inheritance pattern are more likely to be mapped than those with speculated inheritance patterns. Approximately one third of all diagnoses were not mapped across all three coding schemes in Meta-1.2. The ICD coding scheme was found to be too broad to be meaningful for genetic diagnosis or epidemiological purposes. MeSH and SNOMED need to be made more specific and complete, and all of the new version of SNOMED needs to be included in the Metathesaurus.

Abstracting and Indexing↗

[Inherited eye diseases in the Entlebucher mountain dog].

Ophthalmoscopic examinations of 276 Entlebucher Mountain Dogs between 1987 and 1992 revealed a high incidence of inherited ocular diseases in this particular breed. A posterior polar cataract was seen in 42.4% of dogs examined. This cataract develops between one and two years of age and is in the majority of cases stationary. Development of mature cataracts was noticed in 8% of dogs with polar opacities. A progressive retinal degeneration (rod/cone-abiotrophy) was observed in 24.9% of the dogs examined. The fundus abnormalities are comparable to other forms of retinal degeneration, such as hyperreflectivity of the tapetal fundus, attenuation of the retinal vasculature, depigmentation of the non tapetal fundus, and pallor of the optic disc. Visual deficits were first seen at the age of 3 years, the majority of affected dogs going blind between 6 and 8 years of age. As a third suspected inherited ocular disease glaucoma was seen in 3.3% of the dogs examined. Glaucoma affects older animals. In the nine cases examined by gonioscopy goniodysgenesis was observed. Initially, glaucoma occurs unilaterally, but the opposite eye may also become affected, in which case animals go blind. Pedigree analysis revealed an autosomal recessive mode of inheritance for the cataracts and the PRA, whereas the mode of transmission is unclear for the glaucoma. 11.9% of the dogs examined had more than one inherited eye disease.

Animals↗

Inherited and congenital disorders of the exocrine pancreas.

The spectrum of inherited and congenital disorders of the exocrine pancreas is described. Although functional disturbances of the exocrine pancreas are less frequent in childhood than in adult life, there is a wide spectrum of causes, many of which are genetic or congenital in origin. Rarely, a disturbance of pancreatic function may arise as a result of disordered embryogenesis. More frequently, however, inherited disorders affecting multiple organs give rise to pancreatic dysfunction. Among Caucasian children, cystic fibrosis (CF) is, by far, the most common inherited disorder of disturbed pancreatic function. Examples of rarer, inherited causes of pancreatic dysfunction include Shwachman-Diamond syndrome, Johanson-Blizzard syndrome, Pearson's syndrome, pancreatic agenesis, and isolated enzyme deficiencies. Hereditary pancreatitis and several recently recognized metabolic causes of chronic pancreatitis can also produce severe pancreatic exocrine dysfunction.

Adolescent↗

Busulphan kinetics and limited sampling model in children with leukemia and inherited disorders.

Busulphan pharmacokinetics were investigated in 20 children, who underwent bone marrow transplantation for either leukemia or inherited disorders. Busulphan (1.90-6.02 mg/kg/day) was administered orally as a single dose or twice daily. Busulphan kinetics were found to be linear within the studied range. Children with inherited disorders eliminated busulphan significantly faster after the first and the last dose with half-lives (t1/2) of 1.93 and 1.71 h, respectively compared to children with leukemia (3.16 and 2.70 h, respectively). The area under plasma concentration curves (AUCs, corrected for mg/kg) as an expression for the systemic exposure of busulphan were significantly higher in children with leukemia, 22.4 and 19.04 mumol/l.h (5527 and 4690 ng.h.ml-1) after the first and the last dose, respectively, compared to 11.2 and 8.2 mumol/l.h (2768 and 2029 ng.h.ml-1) found in children with inherited disorders. The present results confirm those reported by others, ie busulphan pharmacokinetics can be influenced by the underlying disease and its status. Our population pharmacokinetic analysis showed a negative correlation between the weight corrected clearance and the age in both groups of children. However, clearance was about 42% higher in children with inherited disorders compared to those with leukemia. To estimate AUC for the first dose, we evaluated a limited sampling model based on three concentrations (1, 3 and 6 h). A high correlation (r = 0.998, P < 0.0001, n = 40) between the estimated and the determined AUC was found. The present model is reliable and adequate for studying more patients, with a long-term follow-up combined with drug monitoring in correlation with drug efficacy and toxicity to define the optimal busulphan dosage required.

Administration, Oral↗

Polygenic inheritance of predisposition to lung cancer.

Inherited predisposition to lung tumor development appears to be a complex genetic trait, in humans as well as in experimental animals. In humans, tobacco smoking represents the main risk factor for lung tumors. Familial clusterings of lung cancer cases are rare, although affected sib pairs are reported. However, several studies have reported an increased risk of lung cancer in first degree relatives of lung cancer patients, as compared with appropriate controls. Inheritence of particular alleles of genes or phenotypes for drug metabolizing enzymes are also associated with an increased lung cancer risk. In experimental models, murine inbred strains with high genetic predisposition to lung cancer are available, as well as resistant strains. A major locus affecting inherited predisposition to lung cancer in mice has been mapped on chromosome 6, near the Kras2 gene. The locus, pulmonary adenoma susceptibility 1 (Pas1) derives from the A/J strain. Additional "minor" loci have also been mapped. Dominant lung tumor resistance loci have also demonstrated in the mouse genome. Therefore, evidence for polygenic inheritance of predisposition to lung cancer is demonstrated in the mouse model, and it is strongly suggested for human lung cancer.

Adenocarcinoma↗

[Problems of molecular genetics of inherited diseases].

The paper reviews the basic achievements in the study of human inherited diseases by applying the guidelines and technology of reversed genetics, outlines the results of genome mapping, positional cloning of disease loci, identification of gene mutations and DNA diagnosis of inherited diseases. It also discusses the problems of molecular heterogeneity of inherited diseases and of the relationships between the genotype and the biochemical and clinical phenotypes of diseases, gives the data on identification of genetic risk factors and polymorphic linked markers for some common diseases, and characterizes the lines in the development of approaches to gene therapy for inherited diseases.

Genetic Diseases, Inborn↗

Inherited susceptibility and acquired allelic imbalance in rat mammary carcinogenesis.

Individual genetically determined susceptibility to cancer as well as acquired epigenetic and genetic organ specific alterations are important considerations in choosing target populations for chemopreventive trials. These individual epigenetic and genetic alterations can also serve as potential biomarkers for chemoprevention clinical trials. In order to model these potential markers for chemoprevention investigations, we are examining a series of interrelated rat models. Inbred rats vary in their susceptibility to mammary cancer induction by environmental agents. For example, the WF strain is highly susceptible to chemically induced mammary cancer while the Cop rat is almost completely resistant. The F344 is intermediate in susceptibility to chemically induced mammary cancer. These differential susceptibilities are inherited in a dominant pattern. For example, resistance is due to the inheritance of Mcs gene(s) which likely act by altering the differentiation lineage of mammary epithelial cells. As tumors form in the mammary glands of these rats, they acquire additional epigenetic and genetic alterations. Epigenetic initiation is a very frequent cellular event following carcinogen exposure which may predispose cells to genetic change including allelic imbalance. For example, following a standard dose of NMU or DMBA over 1% of cells are epigenetically initiated. During the carcinogenesis process, initiated cells may acquire genetic change such as oncogene activation and allelic imbalance. Interestingly, the pattern of allelic imbalance appears to be an inherited trait. For example, a non-random loss of heterozygosity (LOH) in rat chromosome 1 following DMBA only occurs in certain strains, such as Cop rats. Interestingly this change does not occur following initiation by ionizing radiation. It will thus be important to identify these epigenetic and genetic events which underlie mammary carcinogenesis as well as determine their patterns of inherited predisposition and temporal occurrence. Such knowledge is critical if we are to develop new molecular markers for chemoprevention trials.

Alleles↗

Dominant inheritance of isolated hypermethioninemia is associated with a mutation in the human methionine adenosyltransferase 1A gene.

Methionine adenosyltransferase (MAT) I/III deficiency, characterized by isolated persistent hypermethioninemia, is caused by mutations in the MAT1A gene encoding MAT(alpha)1, the subunit of major hepatic enzymes MAT I ([alpha1]4) and III([alpha1]2). We have characterized 10 MAT1A mutations in MAT I/III-deficient individuals and shown that the associated hypermethioninemic phenotype was inherited as an autosomal recessive trait. However, dominant inheritance of hypermethioninemia, also hypothesized to be caused by MAT I/III deficiency, has been reported in two families. Here we show that the only mutation uncovered in one of these families, G, is a G-->A transition at nt 791 in exon VII of one MAT1A allele that converts an arginine at position 264 to a histidine (R264H). This single allelic R264H mutation was subsequently identified in two hypermethioninemic individuals in an additional family, C. Family C members were also found to inherit hypermethioninemia in a dominant fashion, and the available affected members analyzed carried the single allelic R264H mutation. Substitution of R-264 with histidine (R264H, the naturally occurring mutant), leucine (R264L), aspartic acid (R264D), or glutamic acid (R264E) greatly reduced MAT activity and severely impaired the ability of the MAT(alpha)1 subunits to form homodimers essential for optimal catalytic activity. On the other hand, when lysine was substituted for R-264 (R264K), the mutant alpha1 subunit was able to form dimers that retain significant MAT activity, suggesting that amino acid 264 is involved in intersubunit salt-bridge formation. Cotransfection studies show that R264/R264H MAT(alpha)1 heterodimers are enzymatically inactive, thus providing an explanation for the R264H-mediated dominant inheritance of hypermethioninemia.

Adolescent↗

Febrile convulsions in selected large families: a single-major-locus mode of inheritance?

As part of a genetic linkage study of febrile convulsions, families with at least four members with the disorder were identified. By applying known principles of human inheritance, possible modes of transmission of febrile convulsions and factors which might impede progress in understanding their inheritance were analyzed. In eight families, 75 of 333 members had febrile convulsions. Inheritance of the disorder occurred in 43, 51, and 46% of children, siblings and all first-degree relatives of probands respectively. Vertical transmission occurred through three to four generations, including from male to male. In these families with multiple affected members, the findings support an autosomal dominant mode of inheritance of febrile convulsions.

Electroencephalography↗

Application of the a priori methods for genetico-mathematical analysis of the inheritance pattern of ulcer disease.

The a priori methods were used to perform a detailed genetico-mathematical analysis of the pattern ulcer disease is inherited. The study included families of 351 probands. Of these, 267 were with duodenal ulcer, 57 with gastric ulcer type II, and 27 with gastric ulcer type III. The types of gastric ulcer were defined according to the classification proposed by H. Johnson. The cases of duodenal ulcer were also analyzed depending on the type of familial predisposition of the patients. The results from Bernstein's a priori method and Li's a priori correction method exclude autosomal recessive pattern of inheritance of the three types of peptic ulcer, not even in the families with healthy but hereditarily predisposed parents. On the other hand, the difference between the numbers of actually observed and theoretically predicted sick children in all groups studied, including those in the families with one sick parent, found by applying the Hogben modification of Bernstein's a priori method, is not consistent with an autosomal dominant pattern of inheritance. Nor is this inheritance pattern consistent with the finding that there are no essential differences between the quantitative parameters of the families with one or two sick parents. It is, therefore, concluded that this disease is not possible to be passed down in generations in a monogenic mode.

Duodenal Ulcer↗

Inherited dental anomalies and abnormalities.

A considerable body of evidence exists to suggest that genes play a dominant role in the etiology of the dental anomalies reviewed. It has been postulated that some kind of genetically controlled interrelationship may exist for some of these coincidental dental anomalies, as evidenced by their frequency of association. It has also been speculated that a "common genetic defect" may give rise to different phenotypic manifestations, including missing, malformed, and even ectopic and malpositioned teeth. The maxillary teeth that develop in the critical marginal areas of the dental lamina, namely the lateral incisors, canines and second premolars, seem most susceptible. Such dental anomalies may be symptoms of an inheritable developmental disturbance of tooth structures. Knowing that these dental anomalies can be inherited, a familial history and early clinical or radiographic detection of one anomaly, could alert parents and clinicians to the high likelihood of detection of other defects in the same individual and similar defects in other family members. Early diagnosis is important so that interceptive pediatric and orthodontic opportunities in relation to missing, malformed and ectopically erupting teeth are not overlooked. Further family studies are necessary to reveal the mode of inheritance of some of these dental anomalies and twin studies comparing monozygous and dizygous twins would enable an estimation of the extent of their inheritance.

Anodontia↗

Genetico-mathematical analysis of the inheritance pattern of ulcer disease. A posteriori methods. The maximum likelihood method.

Inheritance pattern of ulcer disease was analysed genetico-mathematically using one of the a posteriori methods--the method of maximum likelihood. We studied the families of 351 hereditary predisposed probands of whom 57 with type II gastric ulcer disease, 27 with type III gastric ulcer disease and 267 with duodenal ulcer disease. The types of ulcer disease were determined according to H. Johnson. The analysis of the patients with duodenal ulcer also included the types of familial predisposition of the probands. The results yielded by the maximum likelihood method excluded to a great degree the possibility of monogenic transmission of ulcer disease. None to the three types of peptic ulcer showed autosomal recessive pattern of inheritance; it was not found even in the families with phenotypically healthy but hereditary predisposed parents. No evidence was found of autosomal dominant pattern of inheritance of the disease in all studied groups including the families with one sick parent. This is supported by the different values of the segregation coefficients in the families with one sick father and one sick mother. The absence of evidence for monogenic mode of inheritance of the disease indicated by the detailed genetico-mathematical analysis should be further evaluated by the criteria of polygenicity.

Humans↗

Genetic changes in inherited and sporadic ovarian carcinomas by comparative genomic hybridization: extensive similarity except for a difference at chromosome 2q24-q32.

Germ-line mutations in the BRCA1 and BRCA2 genes confer a predisposition to breast as well as ovarian carcinoma. Except for loss of the respective wild-type allele, somatic genetic changes needed for the progression of inherited ovarian tumors are unknown. A genome-wide search for such alterations was performed by comparative genomic hybridization analysis on BRCA1 and BRCA2 mutation-positive (n = 20) ovarian carcinoma specimens. Comparison with sporadic ovarian carcinomas (n = 20) revealed extensive genetic similarity between the inherited and sporadic carcinomas with the sole exception of a frequent gain of 2q24-q32 in the inherited group, suggesting the presence of an oncogene at 2q24-q32 operating in the absence of BRCA1 function. The overall similarity of gains and losses by comparative genomic hybridization suggests a common main pathway in tumor progression of both inherited and sporadic ovarian carcinomas.

Adolescent↗

Description of a large kindred with autosomal dominant inheritance of branchial arch anomalies, hearing loss, and ear pits, and exclusion of the branchio-oto-renal (BOR) syndrome gene locus (chromosome 8q13.3).

It has been suggested that branchio-oculo-facial (BOF) syndrome, deafness with ear pits, and associated conditions [MIM nos. 125100, 120502], and branchio-oto-renal (BOR) [MIM no. 113650] or Melnick-Fraser syndrome represent phenotypic variants of the BOR syndrome, which is inherited in an autosomal dominant (AD) manner and has variable clinical expression. Recently, the BOR gene was mapped to chromosome region 8q13.3 and its sequence was identified as the human homolog of the Drosophila eyes absent (EYA1) gene. We studied an extended family with AD inheritance of branchial arch anomalies (BAA), hearing loss, and ear pits, whose phenotype differed from that of patients with BOR in that none of the affected members had renal abnormalities or lacrimal duct stenosis. Fifteen affected members were studied; ear pits were present in all of them, whereas hearing loss and other BAA were present in 40 and 20%, respectively. Blood was collected from 31 patients; DNA was extracted by standard methods and amplified using primers from microsatellite sequences flanking the BOR locus on chromosome 8q13.3 (D8S1807, D8S530, and D8S543). Linkage analysis was performed under two models of AD inheritance with different penetrance: 100% and 80%. In both cases, the logarithm of odds (LOD) scores produced were significantly less than -2; exclusion of the 8q13.3 locus was also confirmed by multipoint LOD score analysis. We conclude that, in one large family with AD inheritance of BAA, hearing loss and ear pits, the BOR locus was excluded. This represents the first documentation of heterogeneity in branchio-oto anomalies, syndromes with phenotypes similar to BOR syndrome.

Branchial Region↗

Sex-biased heteroplasmy and mitochondrial DNA inheritance in the mussel Mytilus galloprovincialis Lmk.

An exceptional mode of mtDNA inheritance involving separate maternal and paternal transmission routes has been reported recently in the mussel Mytilus edulis. This mode of inheritance provides an explanation for the high levels of heteroplasmy for two highly diverged genomes observed in males of this species. Here we provide evidence for a similar pattern of heteroplasmy in Atlantic and Mediterranean forms of the related mussel M. galloprovincialis. The results support the hypothesis that this mode of mtDNA inheritance has an ancient origin. In addition, the detection of some heteroplasmic females suggests preferential, rather than exclusive, transmission within male and female lines of descent. We also present evidence that the two highly diverged genomes display a parallel split between the Atlantic and Mediterranean forms, consistent with neutral evolution.

Animals↗

Maternal transmission of congenital heart diseases: new recurrence risk figures and the questions of cytoplasmic inheritance and vulnerability to teratogens.

A review of 8 studies involving 3,996 offspring of parents who have congenital heart disease revealed that the risk for all defects was substantially higher if the affected parent was the mother rather than the father. The risk ratio ranged from a high of 6.39 for aortic stenosis to a low of 1.48 for patent ductus arteriosus, and the ratio was statistically significant in aortic stenosis (p = 0.025) and ventricular septal defect (p less than 0.001). Despite the relatively large number of cases, there were still too few patients to reveal statistical significance for a malformation such as atrioventricular canal, in which there were 5 affected offspring among 36 children of mothers who had atrioventricular canal and no affected children among 16 offspring of affected fathers (p = 0.12). The possible reasons for the preponderance of affected offspring of mothers with a congenital heart disease was studied in the context of various modes of inheritance and maternal physiology. The preliminary conclusion is that although many familial cases of congenital heart disease are compatible with multifactorial inheritance and vulnerability to teratogens, an important subset of cases, particularly in some high-risk families, may be better explained by cytoplasmic inheritance than by multifactorial or mendelian modes. Current genetic counseling should take into account the differences in risk to offspring of affected mothers while confirmation and further investigation proceeds.

Abnormalities, Drug-Induced↗