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Results for “Genetic Heterogeneity”

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PubMed1993

Further evidence for a locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) on chromosome 1p, and evidence for genetic heterogeneity.

Assignment of a susceptibility locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) to chromosome 1p remains controversial. We examined the relationship between CMM/DN and markers D1S47, PND, and D1S160 on seven new families (set B) plus updated versions of six previously reported families (set A). Three linkage analyses were performed: (1) CMM alone--all individuals without confirmed melanoma or borderline lesions were considered unaffected (model I); (2) CMM/DN with variable age at onset and sporadics (model II); and (3) CMM/DN using the model of Bale et al. (model III). For CMM alone and D1S47, Zmax = 3.12 at theta = .10. For D1S160 and CMM alone, Zmax = 1.76 at theta = .10. PND showed no evidence for linkage to CMM alone. Models II and III showed strong evidence for linkage to D1S47, D1S160, and PND in the set A pedigrees but not in the set B families. We tested for homogeneity of CMM/DN (model II) by splitting families into two groups on the basis of (1) the proportion of CMM/DN cases and (2) the occurrence of immune-related tumors. In group 1 there was significant evidence of heterogeneity with both D1S47 and D1S160, and in group 2 there was significant evidence of heterogeneity with D1S160. Thus, diagnostic, clinical, and genetic heterogeneity are the likely reasons that previous studies have failed to confirm linkage of CMM/DN to chromosome 1p. The results showed significant evidence for a CMM locus linked to D1S47, as well as significant evidence for heterogeneity with only a subset of the families appearing linked to chromosome 1p.

Adult↗
PubMed1998

Familial typical migraine: linkage to chromosome 19p13 and evidence for genetic heterogeneity.

Migraine is a frequent familial disorder that, in common with most multifactorial disorders, has an unknown etiology. The authors identified several families with multiple individuals affected by typical migraine using a single set of diagnostic criteria and studied these families for cosegregation between the disorder and markers on chromosome 19, the location of a mutation that causes a rare form of familial hemiplegic migraine (FHM). One large tested family showed both cosegregation and significant allele sharing for markers situated within or adjacent to the FHM locus. Multipoint GENEHUNTER results indicated significant excess allele sharing across a 12.6-cM region containing the FHM Ca2+ channel gene, CACNL1A4 (maximum nonparametric linkage Z score = 6.64, p = 0.0026), with a maximum parametric lod score of 1.92 obtained for a (CAG)n triplet repeat polymorphism situated in exon 47 of this gene. The CAG expansion did not, however, appear to be the cause of migraine in this pedigree. Other tested families showed neither cosegregation nor excess allele sharing to chromosome 19 markers. HOMOG analysis indicated heterogeneity, generating a maximum HLOD score of 3.6. It was concluded that Chr19 mutations either in the CACNL1A4 gene or a closely linked gene are implicated in some pedigrees with familial typical migraine, and that the disorder is genetically heterogeneous.

Calcium Channels↗
PubMed2006

Genetic heterogeneity and efficiency of two different methods of adenovirus-mediated gene transfer in a rat liver transplantation model.

PURPOSE: We used recombinant adenoviral vectors for gene therapy in liver transplantation, and investigated the efficacy of gene transfer and expression on the grafts and genetic heterogeneity, with two exogenous gene transfer methods in three different syngeneic rat strains. METHODS: We transferred adenoviral vector encoding Escherichia coli beta-galactosidase via a donor tail vein 3 days before transplantation; via a recipient tail vein immediately after grafting; and ex vivo by perfusion and clamping during transplantation. RESULTS: The high efficacy of beta-galactosidase gene transfer and expression was seen in both delivery systems, with 70% positivity for hepatocytes on day 3, which persisted for at least 3 weeks after transplantation. The efficacy of gene transfer and expression was similar in the three strains (DA, Lewis, and PVG). CONCLUSIONS: These data suggest that adenovirus-mediated gene transfer delivers effective gene therapy by tail vein injection of a donor or a recipient, or by ex vivo graft perfusion in rat liver transplantation. It is not necessary to consider the differences in the strains. Furthermore, ex vivo graft perfusion is probably more suitable not only for rat liver transplantation but also possibly for future clinical application.

Adenoviridae↗
PubMed1996

Evidence of genetic heterogeneity of hypertrophic cardiomyopathy in eight Chinese patients.

BACKGROUND: The genetic basis causing hypertrophic cardiomyopathy (HCM) was found due to missense mutations in cardiac beta-myosin heavy chain (beta-MHC), cardiac troponin T and alpha-tropomyosin genes in certain affected families. However, most mutations and majority of the affected families were reported to be related to beta-MHC gene. Till now, 20 different missense mutations of beta-MHC gene identified in more than 40 independent families were distributed in exons 8, 9, 13, 14, 15, 16, 19, 20, 21 and 23. Therefore, we chose these 10 exons for screening. METHODS: Eight probands with HCM and 1 normal control were included for screening. 32P-labeled PCR products of these 10 exons of beta-MHC gene were amplified from genomic DNA obtained from peripheral lymphocytes. PCR-DNA single strand conformation polymorphism (PCR-SSCP) analysis was performed using electrophoresis with polyacrylamide gels with and without 10% glycerol. Large amount copies of these 10 exons were also made from genomic DNA with PCR. Detection of sequencing variation of these exons was determined by the direct sequencing method with dideoxy chain termination method and 35S. RESULTS: No abnormal extra bands were noted on PCR-SSCP analysis. Sequencing analysis showed no missense mutation in these probands. CONCLUSIONS: Genetic heterogeneity of HCM is evident in Chinese patients with HCM.

Aged↗
PubMed1976

Genetic heterogeneity and familial carcinoma of the breast.

The particular patterns of familial aggregations of cancer in the several families reported from our clinical resource suggest that multiple genotypes explain their diversity of cancer susceptibility. This knowledge could be of value in improving cancer control. We postulate that each particular genotype functions in concert with differential carcinogenic interactions, including a possible oncogenic virus, contributing to carcinogenesis in the susceptible patient. This reasoning is consistent with a concept of genetic heterogeneity as an explanation for familial carcinoma of the breast. This phenomenon is not unlike the current explanation for the genetics of the mucopolysaccaridoses, the lipidoses and several other major disorders of man which show genetic heterogeneity.

Adolescent↗
PubMed1992

How genetically heterogeneous are the major psychiatric disorders?

Linking specific chromosomal regions with the abnormal genes responsible for major psychiatric disorders is rendered particularly difficult because of three factors: diagnostic uncertainty; the possibility that some psychiatric disorders are caused by the concerted action of more than one gene; and the possibility that similar disorders may result from alternative genetic abnormalities. The approach proposed here is to concentrate initially on the highly focused problem of resolving the question of genetic heterogeneity of a given disorder. To this end, it is recommended (a) that studies concentrate on pedigrees large enough to contain at least two nuclear families with several affected individuals, and (b) that, within them, work be confined to an intensive examination of such small nuclear families containing an affected parent and at least two affected offspring with a fairly unmistakable phenotype--bipolar disorder, type I. By using molecular and genetic techniques designed to extract maximal information from this relatively small number of affected individuals, it should be possible to determine whether or not bipolar disorder is genetically heterogeneous. This is a limited but very important question, and the technology is presently available to answer it. The answer should, in turn, guide subsequent approaches to identification of the relevant gene or genes.

Bipolar Disorder↗
PubMed2003

Familial severe myoclonic epilepsy of infancy: truncation of Nav1.1 and genetic heterogeneity.

BACKGROUND: Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome has been long suspected of having a genetic origin. Recently, mutations in SCN1A and GABRG2 have been described in SMEI patients. The sporadic nature of the SMEI syndrome and the occurrence of SCN1A and GABRG2 mutations in a mild familial phenotype, termed generalized epilepsy with febrile seizure plus complicates genotype-phenotype correlations. In order to further investigate the role of SCN1A and GABRG2 in the pathogenesis of SMEI we have screened for mutations three families with at least two members affected by Dravet syndrome. METHODS: Clinical criteria followed the international classification of epileptic syndromes. Mutational screening of SCN1A and GABRG2 genes was performed by denaturing high performance liquid chromatography (DHPLC) and direct sequencing of DNA fragments showing a variant chromatogram. RESULTS: Thirty-eight fragments spanning 26 exons of SCN1A and nine exons of GABRG2 were analysed in three probands. Five variant chromatograms were identified; four corresponded to known polymorphisms, one to a novel dinucleotide insertion on exon 26 of SCN1A. The mutation leads to a frameshift and a premature stop codon at amino acid 1 779 of the protein. The mutation was present in the affected sibling and was inherited from the mother who had experienced a single febrile seizure in childhood. CONCLUSIONS: Among three families analysed, a single family was mutant for SCN1A. Our study suggests that the syndrome is genetically heterogeneous. The variable expressivity we observed for the c5240insAA mutation suggests that other factors are needed for the development of the full SMEI phenotype.

Adolescent↗
PubMed1998

Genetic heterogeneity of Phthorimaea operculella granulovirus: restriction analysis of wild-type isolates and clones obtained in vitro.

Genetic heterogeneity of a wild-type granulovirus (Tunisia isolate) of the potato tuber moth Phthorimaea operculella (Phthorimaea operculella granulovirus, Phop GV) has been studied. The heterogeneity was indicated by the presence of several submolar fragments in the profiles obtained by use of several restriction endonucleases. It was also demonstrated by variations in the restriction profile of the wild-type Tunisia isolate that had underwent since 1991 in our laboratory numerous passages in vivo. A comparison of the Tunisia isolate used in Egypt in the biological control programme with other PhopGV isolates indicated that it could not be related to any of the 3 genotypes previously defined. Five clones obtained from the Tunisia isolate in vitro were further grown both in vitro and in vivo. The restriction analysis of these clones demonstrated that none of them was identical to the parental wild type virus and to any other PhopGV geographic isolates. Genotypic differences between the clones were also shown. A 19 kbp BamHI fragment absent in the original Tunisia isolate but present in its passages since 1995 at a submolar concentration, was always present at a molar concentration in its clones. The presence of this fragment reflects probably a selection of one or more variants present in the original isolate and its possible adaptation to the growth in our laboratory conditions.

Animals↗
PubMed2006

[Genetic heterogeneity and phenotypes of autosomal dominant polycystic kidney disease in Chinese Han nationality].

OBJECTIVE: To study the genetic heterogeneity of autosomal dominant polycystic kidney disease by linkage analysis with microsatellite DNA tightly linked to PKD1 and PKD2 in Shanghai Han nationality population and to compare the clinical presentation of ADPKD type 1 and 2. METHODS: 43 unrelated ADPKD families were included in this study after informed consent was obtained. Families were typed by using microsatellites for PKD1 and PKD2. Microsatellite DNA were amplified by polymerase chain reaction and studied by linkage analysis. The clinical history, symptoms, complications and records of ultrasound examination of patients of ADPKD type 1 and 2 were collected. The data were analyzed by medical statistics. RESULTS: In total families, 36 families showed to be linked to PKD1, which accounts to 84% of all families. 7 families linked to PKD2, which accounts to 16%. The diagnosis age of patients of ADPKD type 1 and type 2 is 36.8 year and 46.3 year, the frequency and diagnosis age of hypertension is 62%, 54% and 37.4 year, 49.1 year, and the frequency of hepatic cysts, urinary-tract infection, macrohematuria, urinary-tract calculi, cerebrovascular accident is 59% and 60%, 20% and 26%, 33% and 20%, 24% and 14%, 13% and 7%, respectively, the onset age of ESRD is 51.2 year and 64.7 year. CONCLUSION: The results in this study were similar to the ones of foreign reports. There is no significant difference of frequencies of complications between the patients of two types. But the diagnosis age of ADPKD and hypertension, the onset age of ESRD of patients of type 1 are earlier than that of type 2, which suggests that the prognosis of patients of type 2 is better than that of type 1.

Adult↗
PubMed1998

Viremia, genetic heterogeneity, and immunity to hepatitis G/GB-C virus in multiply transfused patients with thalassemia.

BACKGROUND: Thalassemia patients are at high risk for posttransfusion hepatitis. Hepatitis G virus (HGV) has been suspected of being responsible for acute and chronic hepatitis. STUDY DESIGN AND METHODS: The prevalence of HGV infection, its possible association to liver disease, the genetic heterogeneity among the various HGV isolates, and immunity to HGV were studied in 36 thalassemia patients with reverse transcriptase-polymerase chain reaction assay and sequence analysis. RESULTS: HGV RNA was detected in seven patients (19.4%), only two of whom had evidence of hepatitis C virus infection as well. Sequence analysis of the NS3 gene from isolates of the five patients infected with HGV alone revealed 84.7 to 90.9 percent homology at the nucleotide level. Prolonged HGV viremia was not associated with significant liver enzyme elevation. All five patients were chronically infected with the same viral strain. E2 antibodies were detected in 57 percent of the HGV-nonviremic patients and in only 1 of 7 viremic patients. CONCLUSION: HGV is associated with persistent viremia but not with significant biochemical evidence of liver damage. There is some genetic heterogeneity among HGV isolates from thalassemia patients in Israel.

Amino Acid Sequence↗
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↗
PubMed1987

Genetic heterogeneity in X-linked agammaglobulinemia complicates carrier detection and prenatal diagnosis.

X-linked agammaglobulinemia (XLA) is a severe antibody deficiency disease reflecting an arrest of B lymphocyte differentiation at the level of precursor B cells. The disease is inherited in an X-linked recessive mode. In a single eight-generation pedigree the XLA gene was mapped to the Xq21.3-Xq22 area of the X chromosome. The data establish close linkage of the XLA locus to the DXS17 restriction fragment length polymorphic (RFLP) marker locus (the lod score exceeding 6 at phi = 0). A series of RFLP markers around the DXS17 locus provided an RFLP haplotype of use in genetic counselling within this pedigree. In one other pedigree a phenotypically identical disease was inherited but was accompanied by a high frequency of recombination with the DXS17 locus, which made localisation of the gene at the DXS17 locus highly unlikely (lod score less than -3). This genetic heterogeneity complicates genetic counselling within particular pedigrees, especially when the localization of the XLA gene involved in those pedigrees has not been established.

Agammaglobulinemia↗
PubMed1994

Refined mapping of a gene (NPH1) causing familial juvenile nephronophthisis and evidence for genetic heterogeneity.

Familial juvenile nephronophthisis (NPH) is an autosomal recessive progressive tubulo-interstitial kidney disorder, responsible for 6-10% of end-stage renal failure in children, and is frequently associated with Leber amaurosis (termed Senior-Løken syndrome). The biochemical basis of NPH is unknown. We recently reported linkage of the purely renal form of NPH to three markers on chromosome 2. Our results also suggested the existence of genetic heterogeneity between NPH and SLS. To map this NPH gene more precisely, we have now tested the segregation of six new microsatellite markers and five additional families. Haplotype analyses show unequivocally that four NPH families are not linked to the chromosome 2 markers, although there are no clinical or pathological features discernible in these families that could separate them from the families linked to the chromosome 2 NPH locus (NPH1). This reveals genetic heterogeneity in the purely renal form of NPH. In situ hybridization of YAC clones isolated with two closely linked markers assigned the NPH1 region to 2q13. Furthermore, based on haplotype analysis and specific recombination events, the NPH1 gene has been placed between D2S293/D2S340 and D2S121, a genetic interval of about 5-7 cM.

Chromosomes, Human, Pair 2↗
PubMed1996

The use of allozyme electrophoresis to assess genetic heterogeneity among previously subspeciated isolates of Fusobacterium nucleatum.

Fusobacterium nucleatum has been implicated in the pathogenesis of periodontal diseases. Five subspecies have previously been proposed. The validity of these subdivisions was investigated using allozyme electrophoresis for 21 enzyme mobilities. The 18 F. nucleatum isolates tested had previously been subspeciated and included type strains as well as isolates from both oral and extraoral sites. The results showed 2 distinct genetic groups with fixed differences at 82.5% of the test loci, indicative of a species complex with a number of subspecies within each of the 2 groups. There was also evidence of a correlation between the 2 major groups of isolates and the site from which they were taken. It was concluded that there is a high degree of genetic heterogeneity within the species F. nucleatum and that its current subspeciation is of questionable validity.

Abscess↗
PubMed2000

Linkage and LOH studies in 19 cylindromatosis families show no evidence of genetic heterogeneity and refine the CYLD locus on chromosome 16q12-q13.

Familial cylindromatosis is an autosomal dominant predisposition to multiple neoplasms of the skin appendages. The susceptibility gene has previously been mapped to chromosome 16q12-q13 and has features of a recessive oncogene/tumour suppressor gene. We have now evaluated 19 families with this disease by a combination of genetic linkage analysis and loss of heterozygosity in cylindromas from affected individuals. All 15 informative families show linkage to this locus, providing no evidence for genetic heterogeneity. Recombinant mapping has placed the gene in an interval of approximately 1 Mb. There is no evidence, between families, of haplotype sharing that might be indicative of common founder mutations.

Carcinoma, Adenoid Cystic↗
PubMed2003

Benign adult familial myoclonic epilepsy: genetic heterogeneity and allelism with ADCME.

Benign adult familial myoclonic epilepsy (BAFME) has been mapped to chromosome 8q24; however, genetic heterogeneity has been recently suggested. The authors report a clinical and electrophysiologic study of two Italian BAFME families showing linkage to chromosome 2p11.1-q12.2. Their report supports the evidence of non-Japanese families with BAFME and suggests a possible allelism with the recently described autosomal dominant cortical myoclonus and epilepsy syndrome.

Adolescent↗
PubMed2000

[Analysis of genetic heterogeneity of bronchial asthma in relation with the age at the onset of disease].

Earlier, the distribution of bronchial asthma (BA) morbidity with respect to the age of onset (AO) in the Moscow population was found to be bimodal. The distribution had two peaks (before and after 25 years of age) and a significant (P < 0.001) minimum between them. Based on these data, genetic heterogeneity of BA with respect to AO was hypothesized. The purpose of this study was to test this hypothesis via analysis of BA morbidity in families of probands with different AOs. The BA morbidity at different ages and the total recurrent risk of BA were estimated in 1518 relatives of 815 BA probands registered in several district outpatient clinics of Moscow. Based on the data obtained, phenotypic between relatives and correlation by genotype between early-onset and late-onset BA cases (with AOs under and over 25 years, respectively) were estimated. It was demonstrated for the first time that the age distribution of BA morbidity in families of probands was also bimodal. Moreover, when probands with early and late AOs were analyzed separately, proband relatives in each of the two groups exhibited these two peaks of morbidity. This suggests that BA that begins in adolescence and BA of adults are not genetically independent forms of the disease. This agrees with the data on the correlation by genotype between the "forms" with the early and late AOs, which does not significantly differ from 1. However, the prevalence of BA was higher in relatives of those probands who developed BA under the age of 25 compared to relatives of those who developed BA over the age of 25 (11.28 and 7.31%, respectively; P < 0.05). Therefore, patients with early-onset BA are more "burdened" genetically with respect to this disease. Since the BA genetic heterogeneity connected with AO has not been confirmed in this study, it is assumed that the observed bimodal distribution of BA morbidity with respect to age is accounted for by the effect of age itself. In other words, it is hypothesized that ontogenetic factors affect susceptibility to BA so that the susceptibility threshold varies with age.

Adolescent↗