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Results for “Genetic Heterogeneity”

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PubMed2006

Evidence of genetic heterogeneity in MRCS (microcornea, rod-cone dystrophy, cataract, and posterior staphyloma) syndrome.

PURPOSE: To present the detailed phenotype of a subject with MRCS (microcornea, retinal dystrophy, cataract, and posterior staphyloma) syndrome and to investigate the underlying molecular genetic basis. DESIGN: Interventional case report. METHODS: Clinical examination, electrophysiologic assessment, B-scan ultrasonography, and mutation screening of the gene VMD2. The protocol of the study was approved by the local ethics committee and informed consent was obtained. RESULTS: A 12-year-old boy was identified with bilateral microcornea, rod-cone dystrophy, congenital cataracts, and posterior staphylomata associated with high myopia (MRCS). Mutation screening failed to identify disease-causing sequence variants in VMD2, the gene associated with MRCS syndrome. All previous subjects have had pathogenic VMD2 sequence alterations. CONCLUSIONS: We present a further report of the MRCS syndrome and provide evidence in support of genetic heterogeneity in this phenotype.

Bestrophins↗
PubMed2003

Hormone levels and cataract scores as sex-specific, mid-life predictors of longevity in genetically heterogeneous mice.

Serum levels of thyroxine (T4), leptin, and insulin-like growth factor-I (IGF-I), as well as cataract severity, were evaluated as predictors of life span in a population of genetically heterogeneous mice (UM-HET3). Long life span was predicted by low levels of leptin at age 4 months in females, and by low levels of IGF-I at age 15 months and high levels of T4 at age 4 months, in males. Cataract severity at either 18 or 24 months was also a significant predictor of life span in females only, but in contrast to what has been reported in human studies, relatively severe cataract was correlated with longer life span. Additional work is needed to evaluate the role of these hormones as potential modulators of the aging process, and to resolve the conflicting data obtained for cataract severity as a predictor of life span.

Animals↗
PubMed1992

Genetic heterogeneity and population structure of Gond-related tribes in the Vidarbha region of Maharashtra.

Genetic heterogeneity in nine polymorphic loci is observed among Gond-related tribes in the Vidarbha region of Maharashtra. Pardhans, with their high ABO*A2 gene frequency (4.01%), low m gene frequency (57%), high P*1 gene frequency (42.7%), and high HbS trait (31.58%), differ significantly from other tribes. Per locus average heterozygosity among the studied tribes ranged from 36.24% to 40.37%, with Pardhans being more heterozygous. Analysis by FST and the empirical relationship between average allele frequencies and the ratio of within-gene to total gene diversity show that the tribes are isolated and that differentiation among them is at an early stage and approximately in conformity with expected differentiation under genetic drift. However, distances and principal components analysis reveal that Pardhans are far removed from the other tribes and from other central Dravidian tribes. Furthermore, of the various demographic parameters estimated, the high average heterozygosity in Pardhans is significantly correlated with mean marital distance (MMD), regression of MMD on wife's age, and effective population size. There is congruence between genetic and demographic data, showing that Pardhans are distinct. This conforms with Haimendorf's (1979) contention based on cultural traits that Pardhans are Gonds by historical accident and are later migrants to the Gond area from the north. The most significant and practical observation of the present study is that migration from an originally nontribal (Pardhan) to a tribal (Gond) area and admixture lead to severe disease course, differential selection pressure, and hence highly elevated HbS trait frequency.

Blood Group Antigens↗
PubMed2005

Genetic heterogeneity of BCR/ABL+ adult B-cell precursor acute lymphoblastic leukemia: impact on the clinical, biological and immunophenotypical disease characteristics.

Philadelphia-positive (Ph(+)) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a genetically heterogeneous disease with a very poor prognosis. In this study, we analyzed the frequency of supernumerary Ph, trisomy 8, monosomy 7, and del(9p21) by FISH and its relationship with the characteristics of the disease, in 46 BCR/ABL(+) adult BCP-ALL patients. The frequency of supernumerary Ph, trisomy 8, monosomy 7 and del(9p21) was 30%, 20%, 15%, and 24%, respectively. Although all patients displayed a BII/common phenotype, supernumerary Ph and trisomy 8 were associated with higher expression of CD19 and CD22 and of CD19, CD34, CD45, and HLA-DR, respectively; in turn, cases with monosomy 7 showed lower CD19, CD22, CD34, and cCD79a and del(9p21)(+) blasts were CD13(-) and CD33(-). Overall, similar clinical and hematological features were observed at presentation, independently of the underlying genetic abnormalities. However, relapse-free survival (RFS) was significantly shorter in cases with supernumerary Ph, trisomy 8, and del(9p21), the latter being the most powerful independent prognostic factor for RFS.

Adult↗
PubMedDate not supplied

Genetic heterogeneity of prostatic carcinoma-derived cell lines as emphasized by DNA fingerprinting.

To investigate genetic heterogeneity during in vitro cultivation of human prostatic carcinomas following radical prostatectomy we performed DNA fingerprinting using the digoxygenin-labeled probes (GACA)4 and (GTG)5. DNA was isolated from fresh material stemming from different areas within one tumor and from cell cultures of the same material. The patterns which were obtained by the nucleolar organizer region (NOR)-specific probe (GACA)4 exhibit only a few prominent low molecular mass bands and no differences were observed between any of the tumors analyzed so far. Changes in the fingerprint pattern occurred between cell cultures derived from different areas within one tumor when the DNA was cleaved by HaeIII and signals detected with the (GTG)5 probe. The "area-specific" pattern was stable during several subcultivations of these cell lines, indicating genetic stability of these prostatic carcinoma cells in vitro. Thus individual cell lines derived from radical prostatectomy seem to represent a biological system very close to the situation in vivo.

Base Sequence↗
PubMed2005

Genetic heterogeneity, modifier genes, and quantitative phenotypes in psychiatric illness: searching for a framework.

Schizophrenia has long been thought to be clinically heterogeneous. A range of studies suggests that this is due to genetic heterogeneity. Some clinical features, such as negative symptoms, are associated with a greater risk of illness in relatives. Affected sibling pairs are correlated for clinical and course features as well as subforms of illness, and twin studies suggest that this is due to genetic factors. This is further supported by findings that subjects from families linked to some chromosomal regions may differ clinically from those from unlinked families. Moreover, some genes may affect clinical features without altering susceptibility (ie are modifier genes). High-risk genotypes may have quantitative, rather than categorical effects, and may influence milder or subclinical phenotypes. Another recent finding is that nonpsychotic relatives may have personality features that resemble those of their affected relatives. These findings taken together suggest that there may be several classes of gene action in schizophrenia: some genes may influence susceptibility only, others may influence clinical features only, and still others may have a mixed effect. Furthermore, subsets of these classes may affect personality and other traits in nonpsychotic relatives. Understanding these classes of gene action may help guide the design of linkage and association studies that have increased power. We describe five classes of genes and their predictions of the outcomes of family, twin, and several types of linkage studies. We go on to explore how these predictions can in turn be used to aid in the design of linkage studies.

Genetic Linkage↗
PubMed1989

Multiple trait prediction for a type of model with heterogeneous genetic and residual covariance structures.

A restricted set of models is defined that allows for heterogeneous genetic and residual covariance structures. Multiple trait models and models with multiple random factors are included. The restriction on the model is that the correlations among genetic effects in different classes are the same. Equivalently, the genetic covariance matrices are assumed to differ between classes due to scaling. This assumption greatly reduces the number of parameters that must be specified and does not adversely affect the computational burden of a mixed model analysis. An application of the model for genetic evaluation of beef cattle is described and illustrated numerically.

Analysis of Variance↗
PubMed1998

The presence of anti-neutrophil antibodies reflects clinical and genetic heterogeneity within inflammatory bowel disease.

A detailed investigation of the relationship between anti-neutrophil cytoplasmic antibodies (ANCA) status, HLA genotype, and clinical patterns of inflammatory bowel disease was carried out, involving 236 European patients resident in the United Kingdom [120 had ulcerative colitis (UC), 116 had Crohn's disease (CD)]. ANCA status was determined on coded plasma samples in Los Angeles using a two-stage assay [fixed neutrophil enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence], and HLA genotyping was carried out by polymerase chain reaction. The results provide evidence that ANCA reflect clinical and genetic heterogeneity within the inflammatory bowel diseases. In the UC patients, 78.3% were ANCA positive [64.2 perinuclear (pANCA)], but only 46.5% CD patients were ANCA positive (19.3% pANCA). Furthermore, mean ELISA binding was significantly lower in CD (14.5% +/- 18.8% versus 40.5% +/- 41.0% in UC, p = 2.31 x 10(-9)). Only 15 CD samples, all from patients with colonic disease, displayed ELISA > 20%; and the six CD patients with highest ELISA binding had clinical features very similar to ulcerative colitis. Moreover, in UC, significant relationships between ANCA status and genotype were noted. Thus, 92.7% of patients with the DR3 DQ2 TNF2 haplotype were ANCA positive [p = 0.03 versus DR3 DQ2 TNF2-negative patients (73.9%)]. ELISA binding was increased in DR3 DQ2 TNF2-positive patients (56.0 versus 35.7%, p = 0.02). In this population of UC, ANCA was not associated with DR2, DR4, or clinical pattern. These data emphasize the many factors that need to be considered in genetic marker studies in inflammatory bowel disease. Extensive disease heterogeneity, ethnicity, and methodological differences in ANCA detection are all pertinent.

Adult↗
PubMed2005

Phenotypic and genetic heterogeneity in a genome-wide linkage study of asthma families.

BACKGROUND: Asthma is a complex genetic disease with more than 20 genome-wide scans conducted so far. Regions on almost every chromosome have been linked to asthma and several genes have been associated. However, most of these associations are weak and are still awaiting replication. METHODS: In this study, we conducted a second-stage genome-wide scan with 408 microsatellite markers on 201 asthma-affected sib pair families and defined clinical subgroups to identify phenotype-genotype relations. RESULTS: The lowest P value for asthma in the total sample was 0.003 on chromosome 11, while several of the clinical subsets reached lower significance levels than in the overall sample. Suggestive evidence for linkage (p = 0.0007) was found for total IgE on chromosomes 1, 7 and again on chromosome 11, as well as for HDM asthma on chromosome 12. Weaker linkage signals could be found on chromosomes 4 and 5 for early onset and HDM, and, newly described, on chromosome 2 for severe asthma and on chromosome 9 for hay fever. CONCLUSIONS: This phenotypic dissection underlines the importance of detailed clinical characterisations and the extreme genetic heterogeneity of asthma.

Age of Onset↗
PubMed2005

Investigation of genetic heterogeneity in Mycobacterium tuberculosis isolates from tuberculosis patients using DNA fingerprinting.

BACKGROUND: DNA fingerprinting of Mycobacterium tuberculosis (MTB) based on IS6110 has been shown to be a powerful epidemiologic tool. Restriction enzyme analysis (REA) is a fingerprinting technique, which is used for differentiation and investigation of genetic diversity among mycobacterial species. AIMS: To investigating the genetic heterogeneity in MTB isolates in Ahvaz, Iran. SETTINGS AND DESIGN: It was a cross-sectional study conducted in Ahvaz, Iran. METHODS AND MATERIAL: One hundred and eighty clinical isolates of MTB were collected from TB reference unit, PHLS, Ahvaz, Iran. The PCR-REA employed uses a simple DNA extraction followed by a PCR step involving a single primer based on the insertion sequence IS6110. Restriction enzyme analysis was performed on the amplification products using HaeIII enzyme. STATISTICAL ANALYSIS: Data was analyzed using SPSS software and chi-square test/Fishers' exact test was applied wherever applicable. RESULTS: The isolates were divided into four clusters based on their REA patterns. Cluster I contained 71.1% of strains with two fragments of 72 and 118. Cluster II with three fragments of 72, 118, and 194; cluster III with three fragments of 118, 194, and 234; and cluster IV with four fragments of 72, 118, 194, and 234 base pairs. As many as 73.8% of the identical fingerprint patterns were seen in male patients. Accounting the men as the major population in the study, there was no significant difference between REA patterns and sex; similarly, with age, patients' occupation and degree of smear positivity. However, we found significant correlation between REA patterns and patients' origin. As many as 61.6% of identical patterns were found in the patients who were lived in the same suburb. CONCLUSIONS: By PCR-based REA typing, the isolates studied were grouped into four clusters each containing between two and four fragments. However, in order to ascertain the level of heterogeneity of MTB isolates in their sample, further testing with a more discriminatory method is needed.

Adult↗
PubMed2004

Wolcott-Rallison Syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity.

Wolcott-Rallison syndrome (WRS) is a rare autosomal-recessive disorder characterized by the association of permanent neonatal or early-infancy insulin-dependent diabetes, multiple epiphyseal dysplasia and growth retardation, and other variable multisystemic clinical manifestations. Based on genetic studies of two inbred families, we previously identified the gene responsible for this disorder as EIF2AK3, the pancreatic eukaryotic initiation factor 2alpha (eIF2alpha) kinase. Here, we have studied 12 families with WRS, totalling 18 cases. With the exception of one case, all patients carried EIF2AK3 mutations resulting in truncated or missense versions of the protein. Exclusion of EIF2AK3 mutations in the one patient case was confirmed by both linkage and sequence data. The activities of missense versions of EIF2AK3 were characterized in vivo and in vitro and found to have a complete lack of activity in four mutant proteins and residual kinase activity in one. Remarkably, the onset of diabetes was relatively late (30 months) in the patient expressing the partially defective EIF2AK3 mutant and in the patient with no EIF2AK3 involvement (18 months) compared with other patients (<6 months). The patient with no EIF2AK3 involvement did not have any of the other variable clinical manifestations associated with WRS, which supports the idea that the genetic heterogeneity between this variant form of WRS and EIF2AK3 WRS correlates with some clinical heterogeneity.

Adolescent↗
PubMed1996

Further evidence of genetic heterogeneity in hereditary hydronephrosis.

Hereditary hydronephrosis is a rare condition but several families are described in the literature. The inheritance pattern is autosomal dominant (McKusick number 143400) but the exact aetiology of the hydronephrosis is not clear. However, linkage with the HLA region on chromosome six has been shown previously. We report a family not showing linkage to this region, giving further evidence of genetic heterogeneity in this condition.

Adolescent↗
PubMed2006

Genetic heterogeneity and phenotypic anomalies in children with atrioventricular canal defect and tetralogy of Fallot.

Tetralogy of Fallot associated with the atrioventricular canal defect has been usually reported in association with Down syndrome. The aim of the present study was to describe the cardiac aspects and the genetic anomalies in children with this association of heart defects. We identified 64 patients with atrioventricular canal defect tetralogy of Fallot. All children underwent complete cardiovascular, clinical phenotypic and genetic evaluation. A genetic syndrome or extracardiac anomalies were found in 56 patients (87.5%). Down syndrome (43 patients, 67.2%) was the most frequent genetic diagnosis. Other syndromes were 8p deletion, trisomy 13, duplication 5p, cranio-cerebello-cardiac syndrome, Cantrell syndrome, CHARGE association, VACTERL association, and DiGeorge syndrome related to maternal diabetes. No patients in our series had 22q11 deletion. Tetralogy of Fallot with extreme dextroposition of the aorta was found in seven patients (only one with Down syndrome). Additional cardiac malformations were present in 23 patients (only 11 with Down syndrome). The association between atrioventricular canal defect and tetralogy of Fallot represents a cardiac phenotype with strong genetic characteristics. For this reason, a careful genetic examination is required. Our study confirms the high prevalence of Down syndrome, but also reveals a significant genetic heterogeneity. Additional cardiac defects are prevalent in patients without Down syndrome.

Adolescent↗
PubMed2002

Genetic heterogeneity in the foot-and-mouth disease virus Leader and 3C proteinases.

The Leader and 3C proteinases of foot-and-mouth disease virus (FMDV) are responsible for almost all the proteolytic processing events of the viral polyprotein precursor. Investigation into the genetic heterogeneity of the regions encoding these proteins from isolates of six FMDV serotypes revealed the 3C proteinase to be more conserved than the Leader proteinase. Maximum likelihood analysis indicated similar phylogenetic groupings for the non-structural protein coding regions of both the Leader and 3C. These groupings were different from the structural VP1 protein coding region which, as shown previously, grouped according to serotype. Two distinct clades were apparent for both the Leader and 3C coding regions: one comprising of serotypes A, O and C together with SAT (South African Territories) isolates from eastern Africa. The other clade consisted of SAT isolates originating from southern Africa. Only one virus isolate, obtained from a buffalo in Uganda, did not conform to this phylogenetic pattern. This SAT 1 virus grouped with types A, O and C in the Leader analysis, but with the southern African SAT types in the 3C analysis, implicating intertypic recombination. The leader proteinases of southern African SAT type isolates differed from those present in European type isolates, particularly in the self-processing region. A three-dimensional structure was modeled for the Leader proteinase of one of the SAT type viruses, ZIM/7/83/2, and compared with the previously elucidated crystal structure of O(1)Kaufbeuren Leader proteinase. The active sites of the two leaders were found to superimpose closely, despite the observed sequence variation between the two molecules. Comparison of the 3C proteinase P1 cleavage sites suggested that the FMDV 3C proteinase may possess a broader substrate specificity, as observed in hepatitis A virus 3C proteinase.

3C Viral Proteases↗
PubMed2000

Evidence for genetic heterogeneity in families with congenital motor nystagmus (CN).

Congenital motor nystagmus (CN) is a relatively common genetic disorder (approximately 1 in 1500) characterized by bilateral involuntary ocular oscillations, with onset occurring within the first six months of life. To date, three loci associated with CN have been mapped to chromosomes 6p12, Xp11.4-p11.3, and Xq26-q27. We analyzed five pedigrees segregating for CN. Mapping studies using markers in these three regions showed that only one pedigree exhibited suggestive linkage with a lod score of 2.08, straight theta=0.0, at chromosome Xp11. This pedigree had both affected male and female members, with two unaffected obligate female carriers. The remaining four pedigrees did not exhibit evidence of linkage for any of the three chromosome locations. Three of the pedigrees, Pedigrees 2, 4, and 5, exhibited several instances of male-to-male transmission, excluding X-linkage, and exhibited a lod score of -3.82, straight theta=0.0, for marker D6S459 located at 6p12, thus excluding the chromosome 6 locus. This provides evidence for at least a fourth locus associated with CN.

Chromosome Mapping↗
PubMed2004

Genetic heterogeneity in familial idiopathic basal ganglia calcification (Fahr disease).

Familial idiopathic basal ganglia calcification (IBGC, Fahr disease) is an inherited neurologic condition characterized by basal ganglia and extra-basal ganglia brain calcifications, parkinsonism, and neuropsychiatric symptoms. The authors examined six families for linkage to the previously identified genetic locus (IBGC1) located on chromosome 14q. The authors found evidence against linkage to IBGC1 in five of the six families supporting previous preliminary studies demonstrating genetic heterogeneity in familial IBGC.

Basal Ganglia Diseases↗
PubMed2001

Oculopharyngodistal myopathy is genetically heterogeneous and most cases are distinct from oculopharyngeal muscular dystrophy.

The question whether oculopharyngodistal myopathy (MIM 164310) is a distinct disease entity or a variant of oculopharyngeal muscular dystrophy (MIM 164300) persists. To answer this question, we examined five patients with the clinical characteristics of oculopharyngodistal myopathy for GCG expansion in poly(A)-binding protein nuclear 1 gene (previously called poly(A)-binding protein 2), the causative gene defect for oculopharyngeal muscular dystrophy. Only one of our five patients had the significant GCG expansion. Thus, oculopharyngodistal myopathy is a genetically heterogeneous disorder, which includes patients with oculopharyngeal muscular dystrophy but, for the most part, is different genetically from oculopharyngeal muscular dystrophy.

Aged↗