PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Heterogeneity Mapping”

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 631 records · Page 35Linked to original sources
PubMed2000

A novel form of distal hereditary motor neuronopathy maps to chromosome 9p21.1-p12.

Distal hereditary motor neuronopathies (dHMNs) form a heterogeneous group of rare disorders characterized by distal weakness and wasting in the limbs with no significant sensory involvement. Harding has classified dHMNs into seven categories based on clinical and genetic criteria. We report a novel form of autosomal recessive dHMN in 7 consanguineous families located in the Jerash region of Jordan. Onset of the disease is between 6 and 10 years of age and is characterized by weakness and atrophy of the lower limbs associated with pyramidal features. Within 2 years, symptoms progress to the upper limbs. Neurophysiological studies typically show normal conduction velocities, reduced compound motor action potential amplitudes, normal sensory nerve action potentials, and chronic neurogenic changes on needle electromyography. No significant abnormalities are seen on sural nerve biopsy. We call this novel form of dHMN Jerash hereditary motor neuronopathy. We studied the families at the molecular genetic level and mapped the Jerash hereditary motor neuronopathy gene to an approximately 0.54-cM region on chromosome 9p21.1-p12, flanked by microsatellite polymorphic marker loci D9S1845 and D9S1791. A maximum LOD score of 19.80 at theta = 0.001 was obtained between the disease and locus D9S1878.

Adolescent↗
PubMed1995

Evidence for a major gene (RP10) for autosomal dominant retinitis pigmentosa on chromosome 7q: linkage mapping in a second, unrelated family.

Retinitis pigmentosa is a genetically heterogeneous form of retinal degeneration, which has X-linked, autosomal recessive and autosomal dominant forms. The disease genes in families with autosomal dominant retinitis pigmentosa (adRP) have been linked to six loci, on 3q, 6p, 7p, 7q, 8q and 19q. In a large American family with late-onset adRP, microsatellite markers were used to test for linkage to the loci on 3q, 6p, 7p, and 8q. Linkage was found to 7q using the marker D7S480. Additional microsatellite markers from 7q were then tested. In total, five markers, D7S480, D7S514, D7S633, D7S650 and D7S677, show statistically significant evidence for linkage in this family, with a maximum two-point lod score of 5.3 at 0% recombination from D7S514. These results confirm an earlier report of linkage to an adRP locus (RP10) in an unrelated family of Spanish origin and indicate that RP10 may be a significant gene for inherited retinal degeneration. In addition, we used recently reported microsatellite markers from 7q to refine the linkage map of the RP10 locus.

Chromosome Mapping↗
PubMed1997

Genetic heterogeneity of primary open angle glaucoma and ocular hypertension: linkage to GLC1A associated with an increased risk of severe glaucomatous optic neuropathy.

The GLC1A locus for autosomal dominant juvenile and middle age onset primary open angle glaucoma (OAG) has been mapped to chromosome 1q21-q31. OAG, however, is a heterogeneous disease. We tested linkage of OAG and ocular hypertension (OHT), a major risk factor for OAG, to GLC1A in eight French families with multiple cases of juvenile and middle age onset OAG. There was strong evidence of genetic heterogeneity, four families being linked to GLC1A and two or three others being unlinked, depending on whether the complete OAG phenotype was analysed alone or jointly with OHT. Peak intraocular pressure (IOP) did not differ significantly between the two groups of families, while linkage to GLC1A conferred a highly increased risk of developing OAG and of having severe glaucomatous optic neuropathy. Testing linkage of familial OAG to GLC1A may therefore have prognostic value too.

Adult↗
PubMed2001

Comparison of 'model-free' and 'model-based' linkage statistics in the presence of locus heterogeneity: single data set and multiple data set applications.

Earlier work [Knapp et al.: Hum Hered 1994;44:44-51] focusing on affected sib pair (ASP) data established the equivalence between the mean test and a test based on a simple recessive lod score, as well as equivalences between certain forms of the maximum likelihood score (MLS) statistic [Risch: Am J Hum Genet 1990;46:242-253] and particular forms of the lod score. Here we extend the results of Knapp et al. [1994] by reconsidering these equivalences for ASP data, but in the presence of locus heterogeneity. We show that Risch's MLS statistic under the possible triangle constraints [Holmans: Am J Hum Genet 1993;52:362-374] is locally equivalent to the ordinary heterogeneity lod score assuming a simple recessive model (HLOD/R); while the one-parameter MLS assuming no dominance variance is locally equivalent to the (homogeneity) recessive lod. The companion paper (this issue, pp 199-208) showed that when considering multiple data sets in the presence of locus heterogeneity, the HLOD can suffer appreciable losses in power. We show here that in ASP data, these equivalences ensure that this same loss in power is incurred by both forms of the MLS statistic as well. The companion paper also introduced an adaptation of the lod, the compound lod score (HLOD/C). We confirm that the HLOD/C maintains higher power than these 'model-free' methods when applied to multiple heterogeneous data sets, even when it is calculated assuming the wrong genetic model.

Chromosome Mapping↗
PubMed2005

The "Kriging" model of spatial genetic structure in human population genetics.

This paper presents the application of Kriging technique in the field of human population genetics for quantifying the spatial genetic heterogeneity of HLA-A locus in the area of China,and for mapping its spatial genetic structure using the measurement of synthetic genetic structure (SPC) and the principal components (PC). Both principles of the method and the basic equations are given. The Kriging model has several advantages over other interpolation and smoothing methods. Firstly, it relies on the structure of the spatial genetic semivariogram model, which can be used to quantify the spatial genetic heterogeneity of the locus (loci) before mapping its spatial genetic structure. Secondly, it is virtually unbiased in the interpolation situation,where the location to be estimated is surrounded by data on all sides and is influenced within the range of these data. Thirdly, it allows of estimative error of interpolation, which can be used to appraise the predicting effect for the spatial estimation,and the error maps can be used to decide where to introduce new sampling population genetic data. However, the "Kriging" model also has some disadvantages. Firstly,when the theoretical spatial genetic semivariogram can not be fitted by any models, the "Kriging" model can not be set up. Secondly, if the Kriging model was built by a poor spatial genetic semivariogram,the Kriging estimation standard deviation is remarkably high in the whole area, hence the Kriging model can not be suitable to estimating the distribution of spatial genetic structure. In these situations,the interpolation algorithm, whose assumption is spatial random rather than spatial autocorrelation,such as the Cavalli-Sforza method in Genography, inverse distance-weighted methods, splines, should be used to estimate or map the distribution of spatial genetic structure.

Genetics, Population↗
PubMed2001

Mapping of Charcot-Marie-Tooth disease type 1C to chromosome 16p identifies a novel locus for demyelinating neuropathies.

Charcot-Marie-Tooth (CMT) neuropathy represents a genetically heterogeneous group of diseases affecting the peripheral nervous system. We report genetic mapping of the disease to chromosome 16p13.1-p12.3, in two families with autosomal dominant CMT type 1C (CMT1C). Affected individuals in these families manifest characteristic CMT symptoms, including high-arched feet, distal muscle weakness and atrophy, depressed deep-tendon reflexes, sensory impairment, slow nerve conduction velocities, and nerve demyelination. A maximal combined LOD score of 14.25 was obtained with marker D16S500. The combined haplotype analysis in these two families localizes the CMT1C gene within a 9-cM interval flanked by markers D16S519 and D16S764. The disease-linked haplotypes in these two pedigrees are not conserved, suggesting that the gene mutation underlying the disease in each family arose independently. The epithelial membrane protein 2 gene (EMP2), which maps to chromosome 16p13.2, was evaluated as a candidate gene for CMT1C.

Charcot-Marie-Tooth Disease↗
PubMed1999

Exclusion of the JRK/JH8 gene as a candidate for human childhood absence epilepsy mapped on 8q24.

Childhood absence epilepsy (CAE), one of the most common epilepsies in children, is genetically and phenotypically heterogeneous. One of the genes responsible for human CAE associated with tonic-clonic seizures has been mapped to chromosome band 8q24 by genetic linkage analysis and is termed ECA1. Recently, we isolated and mapped the JRK/JH8 gene, a human homologue of the mouse epilepsy gene, jerky, on 8q24. The epilepsy phenotype of the mice with inactivated jerky gene as well as its chromosomal localization proposed JRK/JH8 as a prominent candidate for the CAE gene. To confirm whether the JRK/JH8 gene is responsible for ECA1, we performed mutational analyses in the coding region of JRK/JH8 in two CAE families mapped on 8q24, using heteroduplex and direct sequencing methods. We identified seven nucleotide changes, two of which lead to amino acid substitutions. However, these changes did not co-segregate with the disease phenotype. In addition, we redefined the location of JRK/JH8 to be more than 4 Mb distant from D8S502 and ECA1. Thus, negative results of mutation analyses and detailed physical mapping exclude JRK/JH8 as the ECA1 gene.

Animals↗
PubMed2004

Tests for covariate-associated heterogeneity in IBD allele sharing of affected relatives.

Linkage studies that aim to map susceptibility genes for complex diseases commonly test for excess allele sharing among affected relatives. Conventional methods based on identical-by-descent IBD allele sharing do not allow for possible differences among families, such as arise in the case of locus heterogeneity, and thus have reduced ability to detect linkage in the presence of such heterogeneity. We investigated two approaches to test for heterogeneity in allele sharing, using a family-level covariate that may be associated with different disease mechanisms leading to differences in allele sharing. Likelihood ratio tests for heterogeneity were formulated based on an extension of the linear and exponential likelihood models developed by Kong and Cox. Alternatively, we examined the asymptotic and permutation distributions of T-tests for differences between mean allele-sharing linkage scores from two covariate-defined family subgroups, assuming exchangeability. The size and power of heterogeneity tests were evaluated for S(all) and S(pairs) allele-sharing scoring functions using data sets of families with affected sibling and cousin pairs, generated under a model of locus heterogeneity. In certain simulation scenarios, the likelihood ratio test statistics did not follow the expected asymptotic distributions. The type I error estimates for the T-statistics conformed to nominal 5 and 1% levels in all scenarios considered, and corresponding power was comparable to that of the likelihood ratio tests. Application of these tests for heterogeneity detected significant differences in allele sharing between subgroups of families with inflammatory bowel disease.

Algorithms↗
PubMed1997

A meta-analysis of chromosome 18 linkage data for bipolar illness.

We find a meta-data set (715 families, up to 1,124 sib pairs) for bipolar illness to have a strong signal in a 10 cM region around D18S40, and excess paternal sharing on the q arm near marker D18S64. We describe a method for meta-analysis of microsatellite marker data using affected sib-pair (ASP) methodology. Inherent difficulties in such analysis include heterogeneity of allele frequencies and protocol design, measurement errors in genotyping, and map construction. Using identity-by-descent (IBD) allele sharing as the dependent variable, a logistic regression to test for heterogeneity finds only mild heterogeneity, and a limited parent-of-origin effect.

Alleles↗
PubMed2001

Familial (idiopathic) paroxysmal dyskinesias: an update.

The clinical, pathophysiological and genetic features of some of the familial (idiopathic) paroxysmal movement disorders are reviewed. The paroxysmal dyskinesias share features and therefore may have the same pathophysiological mechanisms as other episodic neurological disorders which are known to be channelopathies. Paroxysmal kinesigenic choreoathetosis/dyskinesias (PKC/PKD) is a condition in which brief and frequent dyskinetic attacks are provoked by sudden movement. Antiepileptics particularly carbamazepine are very helpful for this condition. PKC has similarities to episodic ataxia type 1 which is caused by mutations of the KCNA1 gene. PKC and a related disorder in which infantile convulsions are associated (ICCA syndrome) have recently been linked to the pericentromic region of chromososme 16 in the vicinity of some ion channel genes. Paroxysmal exercise-induced dystonia (PED) is a rare disorder manifesting as episodes of dystonia mostly affecting the feet induced by continuous exercise like walking or running. The pathophysiology of PED is unknown and antiepileptic drugs are generally unhelpful. In paroxysmal dystonic choreoathetosis/nonkinesigenic dyskinesias (PDC/PNKD) the attacks are of long duration and induced by a variety of factors including coffee, tea, alcohol and fatigue but not by sudden movement. The gene for familial PDC has been linked to chromosome 2q close to a cluster of ion channel genes. Paroxysmal nocturnal dyskinesia is now known to be a form of frontal lobe epilepsy in some cases which may be familial with an autosomal dominant inheritance and has been given the eponym ADNFLE. ADNFLE is a genetically heterogenous condition. Mutations of the neuronal nicotinic acetylcholine receptor gene that have chromosome 20q have been reported in some families with ADNFLE. However, another family with ADNFLE has been linked to chromosome 15 in the area of another nicotinic acetylcholine receptor gene. Thus the familial paroxysmal dyskinesias appear to be clinically and genetically heterogeneous.

Chromosome Mapping↗
PubMed2001

Molecular genetics of human microcephaly.

Human microcephaly comprises a heterogeneous group of conditions that are characterized by a failure of normal brain growth. Microcephaly can be caused by many injurious or degenerative conditions, or by developmental malformations in which the growth of the brain is impaired as a result of defects in pattern formation, cell proliferation, cell survival, cell differentiation, or cell growth. These latter forms of congenital microcephaly are frequently inherited, usually as recessive traits, and are associated with mental retardation and sometimes epilepsy. Some of the genes that cause congenital microcephaly are likely to control crucial aspects of neural development, and may also be involved in the evolutionary explosion of cortical size that characterizes primates. There has recently been a rapid advance in the use of genetic mapping techniques to identify genetic loci responsible for microcephaly. Although several loci have been mapped, the condition is clearly genetically and clinically heterogeneous.

Brain↗
PubMed2004

Inference on recombination and block structure using unphased data.

In this study compatibility with a tree for unphased genotype data is discussed. If the data are compatible with a tree, the data are consistent with an assumption of no recombination in its evolutionary history. Further, it is said that there is a solution to the perfect phylogeny problem; i.e., for each individual a pair of haplotypes can be defined and the set of all haplotypes can be explained without invoking recombination. A new algorithm to decide whether or not a sample is compatible with a tree is derived. The new algorithm relies on an equivalence relation between sites that mutually determine the phase of each other. (The previous algorithm was based on advanced graph theoretical tools.) The equivalence relation is used to derive the number of solutions to the perfect phylogeny problem. Further, a series of statistics, R ( j ) ( M ), j >or= 2, are defined. These can be used to detect recombination events in the sample's history and to divide the sample into regions that are compatible with a tree. The new statistics are applied to real data from human genes. The results from this application are discussed with reference to recent suggestions that recombination in the human genome is highly heterogeneous.

Biometry↗
PubMed2006

Detecting linkage disequilibrium in the presence of locus heterogeneity.

Locus heterogeneity is a common phenomenon in complex diseases and is one of the most important factors that affect the power of either linkage or linkage disequilibrium (LD) analysis. In linkage analysis, the heterogeneity LOD score (HLOD) rather than LOD itself is often used. However, the existing methods for detecting linkage disequilibrium, such as the TDT and many of its variants, do not take into account locus heterogeneity. We propose two novel likelihood-based methods, an LD-Het likelihood and an LD-multinomial likelihood, to test linkage disequilibrium (LD) that explicitly incorporate locus heterogeneity in the analysis. The LD-Het is applicable to general nuclear family data but requires a working penetrance model. The LD-multinomial is only applicable to affected sib-pair data but does not require specification of a trait model. For affected sib-pair data, both methods have similar power to detect LD under the recessive model, but the LD-multinomial model has greater power when the underlying model is dominant or additive.

Chromosome Mapping↗
PubMed1998

Molecular characterization of jumping translocations reveals spatial and temporal breakpoint heterogeneity.

Jumping translocations (JT) are characterized by the relocalization of the same part of a donor to several recipient chromosomes. Although JT occasionally are constitutional, most are associated with hematologic malignancies. In such cases, JT usually arise during disease progression and are associated with poor prognosis. Despite its clinical importance, this cytogenetic phenomenon has not been characterized at the molecular level. We have analyzed JT in a juvenile chronic myelomonocytic leukemia that subsequently transformed to an acute myeloid leukemia. Detailed fluorescence in situ hybridization (FISH) analyses showed that the cytogenetically identical donor breakpoint at 3q21 was highly heterogeneous. In fact, more than 10 distinct breakpoints, four of which mapped within YACs, were identified. Analyses of samples during disease progression showed that the breakpoint complexity decreased, indicating clonal selection. Hence, the 3q21 breakpoints displayed a spatial as well as a temporal heterogeneity, revealing that JT are highly unstable, showing great variation in the size of donor segment. The breaks at the recipient chromosomes were mapped within the subtelomeric regions. The general telomere length was not affected and an underlying replication error resulting in microsatellite instability was excluded. We conclude that the emergence of JT is unlikely to cause fusion genes or to affect the expression of genes located in the breakpoint regions. The identification of YACs spanning the breakpoints, ie, YACs 913c7, 937g5, 948c2 and 955g1, may facilitate the isolation of DNA sequences leading to a genetic instability associated with the origin of multiple translocations.

Child, Preschool↗
PubMed1988

Localization of the genetic defect in familial adenomatous polyposis within a small region of chromosome 5.

Familial adenomatous polyposis (FAP), a Mendelian disorder that includes familial polyposis coli (FPC) and Gardner syndrome (GS), has an autosomal dominant mode of inheritance. It is characterized by hundreds to thousands of adenomatous polyps that can progress to carcinoma of the colon, suggesting that the gene that harbors the FAP germ-line mutation may play an important role in the somatic genetic pathway to colon cancer. The defect responsible for FAP was recently mapped to the long arm of chromosome 5 by linkage between the FPC phenotype and a locus defined by DNA probe pC11p11 (D5S71), located at 5q21-22. Because an important next step in the paradigm for identification of a disease gene is to obtain a more precise localization, we isolated and mapped by linkage six additional polymorphic DNA markers in the FAP region. Subsequent linkage analysis in six pedigrees, three having the FPC phenotype and three segregating GS, placed the FAP locus very close to a new marker, YN5.48 (D5S81), that is approximately 17 centimorgans distal to C11p11 on the genetic map. The analysis revealed no evidence of genetic heterogeneity between the two phenotypes, a question that had not been clearly resolved by the earlier studies. The new set of markers in the near vicinity of the FAP locus represents a further step toward isolation of the genetic defect and provides the opportunity for preclinical diagnosis of risk status for colon cancer among individuals in families that are segregating adenomatous polyposis.

Adenomatous Polyposis Coli↗
PubMed2005

Oligogenic inheritance in neuroblastoma.

Neuroblastoma (NB), a childhood malignancy affecting neural crest deriving cell lineages, is characterized by great clinical variability and histological heterogeneity. As NB usually occurs as sporadic form, molecular studies were mainly carried out on tumor samples and derived cell lines, leading to the identification of several somatic alterations. Although familial NB is rare, linkage data obtained from different families have provided evidence of linkage to markers mapping to different chromosomal regions, indicating a remarkable genetic heterogeneity of NB. The first evidence of germline mutations in NB pedigrees has been recently reported in the paired-like homeobox 2B (PHOX2B) gene, involved in the development of neural crest deriving cells. Nevertheless, as only a few NB families but not others have been shown to carry PHOX2B mutations, the role of this gene in NB predisposition has still to be clarified. On the basis of the current data, familial NB cannot be modeled as a Mendelian monogenic trait. Instead, an oligogenic mode of inheritance might explain the existence of different NB loci genetically interacting to cause and/or modify the disease-phenotype.

Female↗
PubMed2005

Mild early onset axonal Charcot-Marie-Tooth disease not linked to other axonal Charcot-Marie-Tooth loci.

Autosomal dominant axonal Charcot-Marie-Tooth disease type 2 (CMT2) is a heterogeneous group of disorders with seven chromosomal loci mapped in the uncomplicated forms of CMT2. The authors report clinical, electrophysiologic, and genetic analysis of a Polish CMT2 family. Nine known CMT2 gene loci and one MPZ gene locus have been excluded. The authors' findings suggest that this family represents a novel form of CMT2 disease.

Action Potentials↗