Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Genetic Heterogeneity”

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 91 records · Page 5Linked to original sources
PubMedDate not supplied

Screening for mutations in a genetically heterogeneous disorder: DHPLC versus DNA sequence for mutation detection in multiple genes causing Charcot-Marie-Tooth neuropathy.

PURPOSE: To determine the efficacy of denaturing high-performance liquid chromatography (DHPLC) for mutation detection in genetically heterogeneous diseases using Charcot-Marie-Tooth neuropathy as a model. METHODS: (1) Identification of the optimal conditions for mutation scanning by DHPLC using 50 known variants of PMP22, MPZ, GJB1 and EGR2. (2) Comparison of DHPLC with DNA sequencing for mutation detection in 168 patient DNA samples. RESULTS: We established the optimal conditions for screening PMP22, MPZ, GJB1, and EGR2 for mutations. Under optimized conditions, DHPLC was as sensitive as DNA sequencing and detected two mutations that were not identified by automated DNA sequence. CONCLUSIONS: DHPLC increases the efficiency and sensitivity of mutation screening in genetically heterogeneous diseases.

Adult↗
PubMedDate not supplied

Genes as gerontological variables: genetically heterogeneous stocks and complex systems.

In gerontological research utilizing animal models, a major general strategy has been the use of uniform genotypes of inbred strains or their F1 hybrids. These animal models provide standard reference groups that are of major importance in establishing a reliable data base on aging phenomena. There are limitations to their usage, however, particularly in respect to descriptions or evaluations of variances or of covariance relationships. For these purposes, genetically heterogeneous stocks have the advantage that phenotypic variance (and covariance) has a genetic as well as an environmental component. The advantages of genetic heterogeneity are best realized when the stock has been systematically derived (usually by intercrossing of inbred strains) and maintained by a mating scheme of sufficient size to minimize inbreeding. Genetically heterogeneous stocks are of particularly high potential value in the study of complex systems. Some examples of their use in a gerontological context are provided.

Aging↗
PubMed1998

Genetic heterogeneity for familial hypertrophic cardiomyopathy in Chinese: analysis of six Chinese kindreds.

OBJECTIVE: Familial hypertrophic cardiomyopathy (FHCM) is a primary myocardial disease characterized by unexplained ventricular hypertrophy. The application of the techniques of reverse genetics has identified at least five chromosomal loci as the major causes for FHCM in diverse ethnic populations, suggesting substantial genetic heterogeneity for FHCM. Recently, the defective gene loci of two Chinese families with FHCM have been mapped to chromosome 11 and 14q1, respectively. For further understanding of the molecular basis of FHCM in Chinese, we analyzed the linkage between four other Chinese kindreds and DNA markers from chromosome 14q1. METHODS: Six unrelated Chinese families with FHCM, including two previously reported, were studied. Totally 90 family members were included for analysis. DNA from 80 individuals was extracted and polymerase chain reactions were performed using the primers designed according to the sequences derived from the alpha and beta myosin heavy chain gene. Totally four polymorphisms were studied, including three polymorphic microsatellite sequences and one single strand conformation polymorphism. Genetic linkage analysis were performed using the Linkage program. RESULTS: In the six studied families, 39 of the 90 family members were found to be affected diagnosed either by echocardiography or by clinical evaluation. The pattern of inheritance in all six studied families was most consistent with an autosomal dominant trait with a high degree of penetrance. Genetic linkage analysis using polymorphisms on the alpha and beta MHC genes showed a combined maximal lod score of 6.2 for trinucleotide repeat polymorphism AMHC-I 15 at theta = 0.00 for three studied families without recombination. Exclusion of linkage to the chromosome 14q1 location was noted in two of three other families with the maximal lod score of -2 or less. CONCLUSIONS: These results provide further evidence that FHCM in Chinese is genetically heterogeneous. Chromosome 14q1 locus, probably the beta myosin heavy chain gene, is important as the molecular basis for FHCM in Chinese.

Adolescent↗
PubMed1982

[Migration as a factor in the genetic heterogeneity of the population of large cities].

The report deals with the influence of migration on genetic heterogeneity of population of big cities. The study of AB0 blood groups frequency distribution in population of Moscow during the period of 50 years shows that the observed genetic heterogeneity is associated with demographic structure of the groups compared. Besides, the evaluation of genetic identity of Moscow population and that of different Russian regions population is related to the migrants part having come to Moscow from these regions.

ABO Blood-Group System↗
PubMedDate not supplied

Genetic heterogeneity of combined gastric and duodenal ulcers detected by pepsinogen C gene polymorphism.

It has been reported recently that there was genetic heterogeneity in gastric ulcer disease depending upon the location of the ulcer, and that there was a significant association between the restriction fragment length polymorphism (RFLP) for pepsinogen C (PGC) gene and gastric body ulcer. In the present study, the association of the RFLP for PGC gene with combined gastric and duodenal ulcers was investigated to analyse genetic factors in its aetiology. Eighty unrelated controls and 47 patients with combined gastric and duodenal ulcers were studied. The allele frequencies of the large (3.6 kilobase EcoRI fragment) and the small fragment (3.5 kilobase EcoRI fragment) were, respectively 80.6 and 19.4% in controls, 60.0 and 40.0% in patients with combined gastric body and duodenal ulcers, 69.0 and 31.0% in patients with combined gastric angular and duodenal ulcers, and 81.8 and 18.2% in patients with combined gastric antral and duodenal ulcers. The allele frequency of the small fragment was significantly higher in patients with combined gastric body and duodenal ulcers than in controls. The genotypes that possessed the small fragment were significantly more frequent in patients with combined gastric body and duodenal ulcers (66.7%) than in controls (33.8%) and combined gastric antral and duodenal ulcers (27.3%). These results suggest that there is genetic heterogeneity in combined gastric and duodenal ulcers depending upon the location of gastric ulcer, and that combined gastric body and duodenal ulcers are associated with the small fragment allele of the PGC RFLP in the same way as solitary gastric body ulcers.

Blotting, Southern↗
PubMed1982

Genetic heterogeneity of I-cell disease is demonstrated by complementation of lysosomal enzyme processing mutants.

I-cell disease (mucolipidosis II) is a fatal childhood disorder affecting the expression of multiple lysosomal acid hydrolases. The disorder is characterized by clinical and biochemical heterogeneity which may reflect different mutants with a similar phenotype. Genetic complementation studies demonstrating genetic heterogeneity within this disorder are described utilizing cultured fibroblasts from 11 different patients. Fibroblasts from I-cell disease (ICD) and from five different lysosomal storage diseases with single structural gene enzyme deficiencies were fused in different combinations, and fractions enriched for multinucleated heterokaryons were isolated and tested for acid hydrolase activity and electrophoretic mobility. In fusions of ICD fibroblasts and various single lysosomal enzyme-deficient fibroblasts, the activity of the deficient enzyme and of the other ICD hydrolases were restored, demonstrating that ICD is not a lysosomal enzyme structural gene defect and that the ICD defect, and not just the single enzyme deficiency, is corrected. In fusions involving only I-cell fibroblasts, at least two complementation groups were identified by the recovery of activities of all lysosomal enzymes tested in heterokaryons. These results demonstrate the existence of genetic heterogeneity within the disorder and suggest that different mutations can result in the I-cell clinical and biochemical phenotype. The data support an altered post-translational processing of lysosomal enzymes as the cause of ICD and suggest that at least two genes participate in this pathway.

Cell Fusion↗
PubMed1989

Molecular evidence of genetic heterogeneity in Wistar-Kyoto rats: implications for research with the spontaneously hypertensive rat.

Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto ("WKY") rats are frequently employed in experimental studies of hypertension. Although both SHR and WKY rat strains have been presumed to be fully inbred, recent studies have revealed important biologic variability in WKY rats from different commercial sources. Genealogic evidence suggests that, in the United States, breeding stocks of WKY rats may have been distributed to major commercial suppliers as early as the F10 generation. To test the hypothesis that commercially available WKY rats are genetically heterogeneous, we performed deoxyribonucleic acid (DNA) "fingerprint" analysis on genomic DNA of WKY rats from two of the largest vendors in the United States, Taconic Farms and Charles River Laboratories. We found molecular evidence of genetic variability not only among WKY rats from two different breeding facilities, but also among WKY rats within a single breeding facility (Taconic Farms). Although some studies have suggested the possibility of biologic variability in SHR from different sources, preliminary studies have not revealed molecular evidence of genetic heterogeneity in SHR from these vendors. In demonstrating genetic variability in WKY rats from different sources, the current study provides compelling evidence that rats designated WKY do not constitute an inbred strain. Accordingly, the results of studies in which SHR and WKY rats are compared might vary because of genetic heterogeneity in "the WKY rat control strain."

Animals↗
PubMed2000

Calculation of recurrence risks for heterogeneous genetic disorders.

We present general formulae for several common situations in the genetic counseling of heterogeneous disorders. The occurrence or not of parental consanguinity is taken into account, since it distorts significantly the prior probabilities favoring the different mechanisms. Nonsyndromic deafness is used as a numerical application, since it can be produced by any type of monogenic inheritance and can be mixed with variable proportions of environmental cases. Recurrence risks are calculated including or not including environmental factors in the origin of the defect. In underdeveloped countries the proportion of environmentally determined cases of deafness is significantly higher than in first-world countries. Therefore, when environmental causes cannot be excluded, recurrence risks are always higher in developed than in developing countries. On average, when parental consanguinity is present there is a significant increase in recurrence risks for deafness, whether environmental factors are included or not.

Consanguinity↗
PubMed2005

Clonal divergence and genetic heterogeneity in clear cell renal cell carcinomas with sarcomatoid transformation.

BACKGROUND: Approximately 5% of clear cell renal cell carcinomas contain components with sarcomatoid differentiation. It has been suggested that the sarcomatoid elements arise from the clear cell tumors as a consequence of clonal expansions of neoplastic cells with progressively more genetic alterations. Analysis of the pattern of allelic loss and X-chromosome inactivation in both the clear cell and sarcomatoid components of the same tumor allows assessment of the genetic relationship of these tumor elements. METHODS: The authors of the current study examined the pattern of allelic loss in clear cell and sarcomatoid components of renal cell carcinomas from 22 patients who had tumors with both components. DNA samples were prepared from formalin-fixed, paraffin-embedded renal tissue sections using laser-capture microdissection. Five microsatellite polymorphic markers for putative tumor suppressor genes on 5 different chromosomes were analyzed. These included D3S1300 (3p14), D7S522 (7q31), D8S261 (8p21), D9S171 (9p21), and TP53 (17p13). In addition, X-chromosome inactivation analysis was performed in 14 tumors from female patients. RESULTS: The clear cell components showed loss of heterozygosity (LOH) at the D3S1300, D7S522, D8S261, D9S171, and TP53 loci in 18% (4/22), 18% (4/22), 50% (10/20), 15% (3/20), and 20% (4/20) of informative cases, respectively. LOH in the sarcomatoid components was seen at the D3S1300, D7S522, D8S261, D9S171, and TP53 loci in 18% (4/22), 41% (9/22), 70% (14/20), 35% (7/20), and 20% (4/20) of informative cases, respectively. Six cases demonstrated an LOH pattern in the clear cell component that was not seen in the sarcomatoid component. Different patterns of allelic loss were seen in the clear cell and sarcomatoid components in 15 cases. Clonality analysis showed the same pattern of nonrandom X-chromosome inactivation in both clear cell and sarcomatoid components in 13 of the 14 cases studied. One case showed a random pattern of X-chromosome inactivation. CONCLUSION: X-chromosome inactivation analysis data suggest that both clear cell and sarcomatoid components of renal cell carcinomas are derived from the same progenitor cell. Different patterns of allelic loss in multiple chromosomal regions were observed in clear cell and sarcomatoid components from the same patient. This genetic heterogeneity indicates genetic divergence during the clonal evolution of renal cell carcinoma.

Adult↗
PubMed1999

Clinical and genetic heterogeneity in familial focal segmental glomerulosclerosis. International Collaborative Group for the Study of Familial Focal Segmental Glomerulosclerosis.

BACKGROUND: Familial forms of focal segmental glomerulosclerosis (FFSGS) that exhibit autosomal dominant or recessive patterns of inheritance have been described. The genetic basis of these hereditary forms of FSGS is unknown. One recent study of a kindred from Oklahoma with an autosomal dominant form of FSGS linked this disease to a region of chromosome 19q. In addition, polymorphisms in a gene in this region on chromosome 19q13 have been linked to congenital nephrotic syndrome of the Finnish type. We have ascertained and characterized a large family with autosomal dominant FFSGS (Duke 6530). METHODS: Families were compared for clinical and genetic heterogeneity. To test for linkage of our family to this portion of chromosome 19, genomic DNA was isolated from 102 family members, and polymerase chain reaction was performed using eight microsatellite markers that spanned the area of interest on chromosome 19. Data were evaluated using two-point linkage analysis, multipoint analysis, and an admixture test. RESULTS: Linkage was excluded at a distance of +/- 5 to 10 CM for all markers tested with two-point log10 of the odds of linkage (LOD) scores and from an approximate 60 CM interval in this area of chromosome 19q via multipoint analysis. CONCLUSIONS: FSGS has been called the "final common pathway" of glomerular injury, as it is a frequent pathological manifestation with diverse etiologies. This diversity likely correlates with the genetic heterogeneity that we have established. Thus, our data demonstrate that there are at least two genes responsible for this disease, and there is genetic as well as clinical heterogeneity in autosomal dominant FSGS.

Adolescent↗
PubMed1999

Clinical and genetic heterogeneity in autosomal recessive nemaline myopathy.

Autosomal recessive nemaline (rod) myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive nemaline myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of nemaline myopathy. In four families with more severe forms of nemaline myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive nemaline myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.

Child↗
PubMed2002

Evaluating genetic heterogeneity in complex disorders.

OBJECTIVES: The Admixture test is routinely used in linkage analysis to take account of genetic heterogeneity, and yields an estimate of the proportion of families (alpha) segregating the linked disease gene. In complex disorders, the assumptions of the Admixture test are violated. We therefore explore how the estimate of alpha relates to the true proportion of linked families with a complex disorder in a population or dataset. METHODS: We simulated a two-locus heterogeneity model and varied genetic parameters, ascertainment scheme and phenocopy frequency. RESULTS: In this model, alpha is almost always overestimated, by as little as 5% to as much as 60%. The bias is largely attributable to (1). intrafamilial heterogeneity arising from ascertainment of families with many affected members or from analysis of dense pedigrees; (2). low informativeness, which occurs in the presence of reduced penetrance; and (3). differences in the evidence for linkage in linked and unlinked families. This bias is also affected by the analysis phenocopy frequency, but only if the linked locus is dominant and the unlinked locus is recessive. CONCLUSIONS: We conclude that, in complex diseases, the Admixture test has greater value in detecting linkage than in estimating the proportion of linked families in a dataset.

Family↗
PubMedDate not supplied

Genetic heterogeneity in northeastern India: reflection of Tribe-Caste continuum in the genetic structure.

We critically examined the gene frequency data for 11 genetic markers commonly available in the literature for 22 populations of northeastern India in the light of their geographic, linguistic, and ethnic affiliations. The markers investigated were three blood groups (A1A2BO, MNS, and Rh), four serum proteins (KM, Gc, Hp, and Tf), and four enzyme systems (AP, AK, EsD, and Hb). The neighbor-joining tree and multidimensional scaling of the distance matrix suggest relatively high genetic differentiation among the Mongoloid groups, with probably diverse origins when compared to the Caucasoid Indo-European populations, which had probably come from relatively more homogeneous backgrounds. Broadly speaking, the pattern of population affinities conforms to the ethno-historic, linguistic, and geographic backgrounds. An interesting and important feature that emerges from this analysis is the reflection of the effect of the sociological process of a Tribe-Caste continuum on genetic structure. While on one end we have the cluster of Caucasoid caste populations, the other end consists of Mongoloid tribal groups. In between are the populations which were originally tribes but now have become semi-Hinduized caste groups, viz., Rajbanshi, Chutiya, and Ahom. These groups have currently assumed caste status and speak Indo-European languages. Therefore, one may infer that what appears to be a purely sociological phenomenon of a Tribe-Caste continuum may well reflect in their genetic structure.

Blood Group Antigens↗
PubMed1999

Homozygosity mapping in families with Joubert syndrome identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity.

Joubert syndrome is a rare developmental defect of the cerebellar vermis, with autosomal recessive inheritance. The phenotype is highly variable and may include episodic hyperpnea, abnormal eye movements, hypotonia, ataxia, developmental delay, and mental retardation. Even within sibships the phenotype may vary, making it difficult to establish the exact clinical diagnostic boundaries of Joubert syndrome. To genetically localize the gene region, we have performed a whole-genome scan in two consanguineous families of Arabian/Iranian origins, with multiple affected probands. In one family, we detected linkage to the telomeric region of chromosome 9q, close to the marker D9S158, with a multipoint LOD score of Z=+3.7. The second family did not show linkage to this region, giving a first indication of genetic heterogeneity underlying Joubert syndrome. These findings were supported by subsequent analysis of two smaller families-one compatible with linkage to 9q; the other, unlinked. We conclude that Joubert syndrome is clinically and genetically heterogeneous and that one locus maps to chromosome 9q.

Abnormalities, Multiple↗
PubMed2006

The costs and benefits of genetic heterogeneity in resistance against parasites in social insects.

The occurrence of polygyny and polyandry in social insects has long puzzled evolutionary biologists. If cooperation requires genetic relatedness, how do we explain the occurrence and maintenance of mechanisms that reduce the degree of relatedness among colony members? A much-discussed hypothesis states that genetically diverse colonies are more resistant to parasitism than homogenous colonies because genetic diversity reduces the spread of a disease within a colony. However, as we will argue in this note, a necessary condition for the parasite hypothesis is that genetically heterogeneous colonies have a larger suite of parasites that are capable of infecting them. This implicit relationship is important because it implies that even if the cost per infection is reduced, this may not be sufficient to offset the increased rate of acquiring infections. The advantages of genetic heterogeneity as a defense against parasites thus may not be as big as commonly thought.

Animals↗
PubMed1976

[Genetic heterogeneity of congenital metabolic disorders. A bridge between the physician and the basic science researcher].

Earlier diagnosis of genetic diseases was based on clinical symptoms. Today, molecular biology and biochemistry have led to a better understanding of genetic principles. The exact diagnosis of more than 100 metabolic diseases rests on biochemical investigations which in general are carried out by specialized groups outside the sphere of direct patient care. The study of genetic heterogeneity of inherited metabolic disorders may be a bridge between the doctor and the basic researcher. The doctor will principally concentrate on the relation between gene mutation, enzyme deficiency and the resulting clinical peculiarities. The investigation of the genetic heterogeneity may provide important information on the various aspects of molecular genetics and cell metabolism.

Amniotic Fluid↗
PubMed2006

Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome.

Autosomal dominant hyperuricemia, gout, renal cysts, and progressive renal insufficiency are hallmarks of a disease complex comprising familial juvenile hyperuricemic nephropathy and medullary cystic kidney diseases type 1 and type 2. In some families the disease is associated with mutations of the gene coding for uromodulin, but the link between the genetic heterogeneity and mechanism(s) leading to the common phenotype symptoms is not clear. In 19 families, we investigated relevant biochemical parameters, performed linkage analysis to known disease loci, sequenced uromodulin gene, expressed and characterized mutant uromodulin proteins, and performed immunohistochemical and electronoptical investigation in kidney tissues. We proved genetic heterogeneity of the disease. Uromodulin mutations were identified in six families. Expressed, mutant proteins showed distinct glycosylation patterns, impaired intracellular trafficking, and decreased ability to be exposed on the plasma membrane, which corresponded with the observations in the patient's kidney tissue. We found a reduction in urinary uromodulin excretion as a common feature shared by almost all of the families. This was associated with case-specific differences in the uromodulin immunohistochemical staining patterns in kidney. Our results suggest that various genetic defects interfere with uromodulin biology, which could lead to the development of the common disease phenotype. 'Uromodulin-associated kidney diseases' may be thus a more appropriate term for this syndrome.

Adolescent↗