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Familial atrial myxomas may present as a component of the Carney complex, an autosomal dominant multiple neoplasia and lentiginosis syndrome. Although a gene defect for the Carney complex in some families maps to chromosome 2p, this syndrome is genetically heterogeneous, and other genetic loci also produce familial atrial myxomas.
Myxoma is the most common type of primary cardiac tumor, accounting for 1/3 to 1/2 of all cases. Although a majority are sporadic, about 7% are familial, with autosomal dominant inheritance. The Carney complex refers to the association of atrial myxomas with extracardiac myxomas or Cushing syndrome or both, with or without multiple lentigines and pigmented nevi. The disorder is genetically heterogeneous, with multiple families being linked to 2p16 and a single report of one family not linked. We investigated two multigenerational kindreds, with 10 members affected by the Carney complex. By using microsatellite markers that span the candidate region, we established haplotypes for affected and unaffected family members. Our two kindreds do not show linkage to the chromosome 2p16 region. This study provides further evidence for genetic heterogeneity of the gene(s) involved in producing the Carney complex.
Hereditary Gingival Fibromatosis (HGF) is the most common genetic form of gingival fibromatosis. The condition is most frequently reported to be transmitted as an autosomal-dominant trait, but autosomal-recessive inheritance has also been reported. The clinical presentation of HGF is variable, both in the distribution (number of teeth involved) and in the degree (severity) of expression. It is unknown if the variable clinical expression of HGF in different families is due to variable expression of a common gene mutation, allelic mutations, or non-allelic mutations. The apparently different modes of Mendelian inheritance of HGF suggest genetic heterogeneity. A gene locus for HGF has been localized to a 37-cM genetic interval on chromosome 2p21-p22 (D2S1352, Zmax = 5.10, theta = 0.00) flanked by D2S1788 and D2S441. To evaluate the generality of this linkage, we tested linkage with 9 markers from this candidate region in another large family, segregating for an autosomal-dominant form of generalized HGF, and found no support for linkage with any of these markers. Furthermore, statistical tests of this apparent heterogeneity were highly significant. Analysis of these data provides direct evidence that at least two genetically distinct loci are responsible for autosomal-dominant hereditary gingival fibromatosis.
Discovering molecular heterogeneities in phenotypically defined disease is of critical importance both for understanding pathogenic mechanisms of complex diseases and for finding efficient treatments. Recently, it has been recognized that cellular phenotypes are determined by the concerted actions of many functionally related genes in modular fashions. The underlying modular mechanisms should help the understanding of hidden genetic heterogeneities of complex diseases. We defined a putative disease module to be the functional gene groups in terms of both biological process and cellular localization, which are significantly enriched with genes highly variably expressed across the disease samples. As a validation, we used two large cancer datasets to evaluate the ability of the modules for correctly partitioning samples. Then, we sought the subtypes of complex diffuse large B-cell lymphoma (DLBCL) using a public dataset. Finally, the clinical significance of the identified subtypes was verified by survival analysis. In two validation datasets, we achieved highly accurate partitions that best fit the clinical cancer phenotypes. Then, for the notoriously heterogeneous DLBCL, we demonstrated that two partitioned subtypes using an identified module ("cellular response to stress") had very different 5-year overall rates (65% vs. 14%) and were highly significantly (P < 0.007) correlated with the clinical survival rate. Finally, we built a multivariate Cox proportional-hazard prediction model that included 4 genes as risk predictors for survival over DLBCL. The proposed modular approach is a promising computational strategy for peeling off genetic heterogeneities and understanding the modular mechanisms of human diseases such as cancers.
Primary congenital glaucoma (GLC3) is an inherited eye disorder that accounts for 0.01-0.04% of total blindness. Although a large number of chromosomal abnormalities have already been reported in patients with congenital glaucoma, the precise location and pathogenesis of this condition remain elusive. By using a group of 17 GLC3 families and a combination of both candidate regional and general positional mapping strategies, we have mapped a locus for GLC3 to the short arm of chromosome 2. Eleven families showed no recombination with 3 tightly linked markers of D2S177 (Z = 9.40), D2S1346 (Z = 8.83), and D2S1348 (Z = 8.90) with a combined haplotype lod score of 11.50. Haplotype and multipoint linkage analyses of 14 DNA markers from 2p indicated that the disease gene is located in the 2p21 region and is flanked by DNA markers D2S1788/D2S1325 (theta = 0.03; Z = 5.42) and D2S1356 (theta = 0.05; Z = 4.69). Inspection of haplotype and heterogeneity analysis confirmed that 6 families are not linked to the 2p21 region, thus providing the first proof of genetic heterogeneity for this phenotype. We therefore designated the locus on 2p21 GLC3A and positioned it in the overall linkage map of Tel-D2S405-D2S367-(D2S1788/D2S1325)-[(GLC3A++ +, D2S177)/(D2S1346/D2S1348)]-D2S1356-D2S119- D2S1761-D2S1248-D2S1352-D2S406- D2S441-Cen. Of the seven genes mapping to the 2p21 region, CAD, CALM2, and LHCGR are centromeric to D2S119 and can be excluded as a candidate for GLC3A, but mutations in PRKR, TIK, SOS1, or SPTBN1 may still be accountable for this phenotype. As human 2p21 shows homology with mouse chromosomes 11 and 17, the homolog of GLC3A is expected to reside on one of these two chromosomes.
The gene for autosomal dominant "benign" familial neonatal convulsions, a transient, primary epilepsy of infancy, has recently been assigned to chromosome 20q. To determine whether this disorder is genetically heterogeneous, we performed linkage analysis in two previously unreported pedigrees with benign familial neonatal convulsions in which clinical heterogeneity was evident. There were 14 affected persons in the first family, and none had seizures (febrile or afebrile) after the age of 2 months. The second family had 13 affected individuals and 2 obligate carriers; seizures frequently did not remit until 6 to 24 months, febrile convulsions occurred in at least 2 patients, apparent audiogenic seizures occurred in 4 patients, and 1 individual had refractory epilepsy until late adolescence. Linkage studies with the chromosome 20 markers D20S19 and D20S20 were performed in both families. The resulting data favored linkage of the disease and marker loci in Family 2 by a maximum odds ratio of 45:1 at 6% recombination. In Family 1, however, the odds were greater than 20,000:1 against linkage at 10% recombination or less. We conclude that the syndrome of benign familial neonatal convulsions is clinically and genetically heterogeneous. Further study will be necessary to clarify the relationship between phenotype and genotype in this disorder.
OBJECTIVE: To explore genetic patterns of non-specific mental retardation (NSMR). METHODS: Using segregation analysis, Finney method and Falconer method, the authors studied 157 pedigrees with NSMR selected in a population survey in Shandong province. RESULTS: Ux U multiplex families may accept the autosomal recessive inheritance, Ux U total families is the autosomal recessive inheritance while it may be the multifactorial inheritance with major-gene effect, the frequency of sporadic cases is approximately 46%; Ux A mating families may keep the incomplete penetrance in autosomal dominant inheritance. CONCLUSION: The genetic pattern of NSMR has the genetic heterogeneity.
We studied 20 Mediterranean families (40 patients) with autosomal recessive hereditary spastic paraplegia and thin corpus callosum (ARHSP-TCC, MIM 604360) to characterize their clinical and genetic features. In six families (17 patients) of Algerian Italian, Moroccan, and Portuguese ancestry, we found data consistent with linkage to the SPG11 locus on chromosome 15q13-15, whereas, in four families (nine patients of Italian, French, and Portuguese ancestry) linkage to the SPG11 locus could firmly be excluded, reinforcing the notion that ARHSP-TCC is genetically heterogeneous. Patients from linked and unlinked families could not be distinguished on the basis of clinical features alone. In SPG11-linked kindred, haplotype reconstruction allowed significant refinement to 6 cM, of the minimal chromosomal interval, but analysis of two genes (MAP1A and SEMA6D) in this region did not identify causative mutations. Our findings suggest that ARHSP-TCC is the most frequent form of ARHSP in Mediterranean countries and that it is particularly frequent in Italy.
Weill-Marchesani syndrome (WMS) is a rare condition characterized by short stature, brachydactyly, joint stiffness, and characteristic eye abnormalities including microspherophakia, ectopia of lens, severe myopia, and glaucoma. Both autosomal recessive (AR) and autosomal dominant (AD) modes of inheritance have been described for WMS. A locus for AR WMS has recently been mapped to chromosome 19p13.3-p13.2 while mutation within the fibrillin-1 gene (15q21.1) was found in one AD WMS family. In order to answer the question of whether or not genetic heterogeneity could be related to a clinical heterogeneity, we reviewed 128 WMS patients from the literature (including 57 AR, 50 AD, and 21 sporadic cases), with a particular attention to clinical features. Statistical analyses using Fischer exact test were used to compare the proportions of 12 clinical parameters between AR and AD patients. There was no significant difference between both groups for myopia, glaucoma, cataract, short stature, brachydactyly, thick skin, muscular build, and mental retardation. Significant results were found for microspherophakia (94% in AR, 74% in AD, Fischer 0.007), ectopia lentis (64% in AR, 84% in AD, Fischer 0.016), joint limitations (49% in AR, 77% in AD, Fischer 0.010), and cardiac anomalies (39% in AR, 13% in AD, Fischer 0.004). Nevertheless, we failed to distinguish AR from AD inheritance in individual cases. These results support the clinical homogeneity but the genetic heterogeneity of WMS.
Inherited deficiency of ferrochelatase results in erythropoietic protoporphyria (EPP). Genetic heterogeneity at the locus for human ferrochelatase was investigated. Analysis of genomic DNA of patients with EPP and of control subjects by restriction endonuclease techniques using ten different enzymes detected polymorphisms only at sites recognized by EcoRI, HincII, PstI and TaqI. None of these polymorphisms alone was specific for expression of the disease since each was observed in control subjects as well. Three of these polymorphisms (at EcoRI, HincII and PstI sites) were always associated, indicating linkage. These and other studies demonstrate that the ferrochelatase gene is markedly heterogeneous. It is not yet clear whether some of the mutations associated with these polymorphisms contribute to expression of EPP.
The genetic characteristics, of 38 field isolates of bovine viral diarrhoea virus (BVDV) collected in 1999 from sick or healthy and persistently infected cattle of dairy farms situated in northern Italy, were investigated. A partial 5'-untranslated region (5'-UTR) sequence of each isolate was determined and a phylogenetic analysis was performed. All the isolates were classified as belonging to the BVDV-1 genotype and could be assigned to different BVDV-1 groups, namely BVDV-1b (n = 20), BVDV-1d (n = 6) and BVDV-1e (n = 10). Two remaining isolates could be classified as BVDV-1f and BVDV-1h, respectively. These results provided evidence for genetic heterogeneity of BVDV in Italy, and contribute to a better knowledge of the circulation of BVDV strains, and to their classification.
BACKGROUND: Cerebral cavernous malformation (CCM) is a form of intracranial vascular disease that may arise sporadically or be dominantly inherited. Linkage studies have revealed genetic heterogeneity among the dominantly inherited forms suggesting the existence of at least three loci called CCM1, CCM2 and CCM3. METHODS: In the present study, we screened five families with dominantly inherited CCM for CCM1 gene mutations with denaturing high performance liquid chromatography (DHPLC). Then, we performed linkage analysis and haplotyping on these five families using highly polymorphic markers at the candidate CCM loci. RESULTS: None of the five families tested with DHPLC were found to have mutations in the CCM1 gene. Based on haplotyping, we identified three families segregating alleles for CCM2, while two families segregated alleles for CCM3. Using linkage analysis, we could confirm that one family (IFCAS-1) had a positive Lod score of 2.03 (p<0.0001) at the CCM2 locus using marker D7S678. CONCLUSIONS: The present study is the first one to replicate linkage at the CCM2 locus and provides a fifth family identified as such. It also supports the concept of genetic heterogeneity in CCM, identifying four other families that showed no mutations in the CCM1 gene.
BACKGROUND: A new type of nephronophthisis (NPH) has been recently identified in a large Venezuelan kindred: adolescent nephronophthisis (NPH3) causes end-stage renal disease (ESRD) at a median age of 19 years. The responsible gene (NPHP3) maps to 3q21-q22. NPH3 shares with juvenile nephronophthisis (NPH1) the same disease manifestations such as polyuria, polydipsia, and secondary enuresis. Histopathological findings consist of tubular basement membrane changes, cysts at the corticomedullary junction, and a chronic sclerosing tubulointerstitial nephropathy. The only difference is a younger age at ESRD in NPH1 (median age of 13 years) when compared with NPH3. METHODS: In order to evaluate whether there might be a fourth locus of isolated nephronophthisis, we studied eight NPH families without extrarenal disease manifestations and without linkage to the NPH1 locus (NPHP1) on chromosome 2q12-q13. ESRD was reached at ages ranging from 7 to 33 years. Individuals were haplotyped with microsatellites covering the genetic locus of NPHP3. Infantile NPH (NPH2) was excluded in all families by the clinical history and histological findings. RESULTS: In four of the examined families haplotype analysis was compatible with linkage to the NPHP3 locus. In one of these families identity by descent was observed. In contrast, in another four families linkage was excluded for NPHP3. CONCLUSION: Four NPH-families were neither linked to NPHP1 nor to NPHP3, indicating further genetic heterogeneity within the group of nephronophthisis. The finding of further genetic heterogeneity in NPH has important implications for genetic counselling.
We studied the relations between genetic heterogeneity of pre-C region of hepatitis B virus (HBV) DNA and outcome of HBV infection in 5 infants with perinatal infection, 3 born to anti-hepatitis B e antigen (HBeAg), and 2 to HBeAg positive mothers. HBV infection developed in the babies at 3-4 months of age, but it resolved with seroconversion to anti-HBs in infants born to anti-HBe positive mothers, while the infection became chronic in the 2 babies born to HBeAg positive mothers. HBV-DNA extracted from the first hepatitis B surface antigen (HBsAg) positive serum sample of each baby was amplified and directly sequenced for the pre-core region. HBV-DNA sequences from 3 babies born to anti-HBe positive mothers showed at position 1896 the contemporary presence of 2 nucleotides (G+A), indicating a mixture of wild-type and "e minus" variant HBV. These findings suggest a possible co-transmission of the 2 viruses from anti-HBe positive mothers to newborns. HBV-DNA from babies born to HBeAg positive mothers showed wild-type sequences only. The results of this study suggest that the outcome of HBV infection in newborns depends not only on the host's immunocompetence and on viremia level in maternal blood, but also on heterogeneity of HBV. Transmission of mixed HBV populations appears associated with an early immunoelimination of the virus, while infection with wild-type HBV alone contributes to induction of chronicity.
Charcot-Marie-Tooth neuropathy type 2 (CMT2) is a common inherited axonal neuropathy. The locus for one form of CMT2 (CMT2A) is assigned to the short arm of chromosome 1. There is genetic heterogeneity in CMT2 because additional pedigrees do not demonstrate linkage to chromosome 1 and are designated as CMT2B. Further clinical heterogeneity is suggested by CMT2 pedigrees with diaphragm and vocal cord weakness and are designated as CMT2C. To address the possible genetic distinction between CMT2A and CMT2C, we tested markers from the CMT2A locus for linkage in a large CMT2C pedigree. There was no evidence to support linkage of the CMT2C gene to the region of the CMT2A locus on chromosome 1. CMT2C is not an allelic variant of CMT2A. This analysis provides further evidence for genetic heterogeneity within inherited axonal neuropathies.
We have assessed several age-sensitive indicators of immune status in young (i.e., 6 to 11-month-old) mice of a genetically heterogeneous population to see if these varied in parallel and to determine if one or more of the status indices predicted life span or cancer incidence. We report that the number of memory (i.e., CD44hi) T cells within the CD8 subset is correlated with number of memory cells in the CD4 population, and inversely correlated with the number of naive (i.e., CD45RBhi) CD4 cells at both 6 and 11 months of age, suggesting that the conversion of naive to memory cells may occur at similar rates in both T cell subsets. Mice that ranked high in the proportion of memory T cells (within the CD4 and CD8 pools) at 6 months of age tended to retain their ranking at 11 months, suggesting that the pace or extent of memory cell formation may be a consistent trait that distinguishes mice at least within a genetically heterogeneous population. Mice that at 6 months of age exhibited high levels of CD4 or CD8 memory T cells, low levels of naive CD4 cells, or low levels of T cells able to proliferate in response to Con A and IL-2 were found to be significantly more likely than their littermates to die within the first 18 months of life. Cases of follicular cell lymphoma, lymphocytic and lymphoblastic lymphoma, and hepatic hemangiosarcoma were seen within the group of mice dying at early ages.(ABSTRACT TRUNCATED AT 250 WORDS)
We investigated the biochemical and genetic heterogeneity of protein A from Staphylococcus aureus. SpA genes (spas) of various strains were heterogeneous when detected as DraI and EcoRV fragments of chromosomal DNA. Polymerase chain reaction using primers to detect DNA encoding the IgG-binding domains in spa revealed that they numbered between 2 and 5. Protein A from several S. aureus strains showed two types of reactivities to immunoglobulins in normal canine serum according to the number of active domains.
Genetic analysis of seven oat varieties for eight traits which are the yield components was performed when studying the varieties and the F1 hybrids from their diallel crosses. Involvement of epistatic genes in genetic control of all the traits excluding the panicle density was established. By analysing the diallel tables with excluded data from the varieties with epistatic genes, it was revealed that hyperdominance is inherent to genetic control of the majority of traits studied. The dominant gene action exceeds the additive gene action. The genes "u" increasing the phenotypic displaying of the trait are always dominant and their frequency in the variety set under consideration is higher than the frequency of the genes "v" for all traits studied.