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PubMed1987

[Clinico-genetic analysis of omphalocele].

The study of 302 cases of omphalocele in foetus and newborns revealed genetic heterogeneity of this congenital malformation. Multiple birth defects were found in 54.3% of probands, including 11% of cases (Wiedemann-Beckwith syndrome being neglected), diagnosed as syndromes with hereditary etiology. The spectrum of anomalies associated with omphalocele in non-classified complexes corresponds to that for caudal regression and cloaca extrophy syndromes. A positive syntropy index for these anomalies shows that these combinations are not coincidental. The increase of omphalocele incidence among relatives of probands with descending gradient, depending on relationship, is demonstrated, which testifies to multifactorial determination of some omphalocele cases. Empirical risk for sibs was 0.6 +/- 0.3% and the index of inheritance was 50.7 +/- 11.4%.

Adult↗

PubMed1980

Prenatal diagnosis of Meckel syndrome.

Prenatal diagnosis of the Meckel syndrome was made at 15 weeks of gestation after the birth of a previous child with the same autosomal recessively inherited syndrome. This report emphasises the importance for Genetic counseling of delineating the Meckel syndrome from the multifactorial cases of neural tube defects and also illustrates the possibility of antenatal diagnosis.

Abnormalities, Multiple↗

PubMed1998

Genetic epidemiology of schizophrenia: review and reassessment.

When a rigorous methodological approach is utilized, a substantial majority of recent studies provide evidence for the familial transmission of schizophrenia. Although the absolute rates of schizophrenia among relatives of schizophrenics tend to be lower than those reported in the earlier studies due to the restrictiveness of contemporary definitions of schizophrenia, the risk to relatives compared to that of controls has remained quite consistent. This observation that relatives of schizophrenics have an elevated risk for schizophrenia compared to controls is consistent with theories of both genetic and environmental transmission. Twin studies of schizophrenia have consistently reported greater concordance rates for monozygotic than dizygotic twins. Although this indicates the importance of genetic factors, the less than 100% concordance for monozygotic twins observed in every study indicates that nongenetic factors also play a role in the etiology of schizophrenia. Further, adoption studies offer an opportunity to unconfound genes and environment. The findings of adoption studies confirm that there are genetic components for schizophrenia. Even though we have shown that family, twin, and adoption studies have provided strong evidence for the role of genetic factors in schizophrenia, the mode of transmission remains unclear. The results of mathematical modeling studies do not support the single gene model. There is somewhat more support for the multifactorial polygenic model, but the model has also been rejected in several studies. Thus, the pattern of inheritance of schizophrenia has eluded an unambiguous characterization. Genetic linkage analysis promised to clarify the mechanisms of transmission, but early positive reports were subsequently overturned and, to date, there are no consistently replicated positive linkage findings for schizophrenia. There is now a world-wide search for the location of the genes on specific chromosomes which are responsible for schizophrenia. The clinical implications of current work to the future of locating a schizophrenic gene or genes will be discussed.

Chromosome Mapping↗

PubMed2004

Association between platelet endothelial cellular adhesion molecule 1 (PECAM-1/CD31) polymorphisms and acute myocardial infarction: a study in patients from Sicily.

Adhesion of circulating cells to the arterial surface is among the first detectable events in atherogenesis. Cellular adhesion molecules, expressed by the vascular endothelium and by circulating leucocytes, mediate cell recruitment and their transendothelial migration. Platelet endothelial cellular adhesion molecule 1 (PECAM-1/CD31), involved in this migration, has been associated with the developmental course of atherosclerosis. A few studies have investigated an association between coronary heart disease and single nucleotide polymorphisms (SNPs) located in functionally important domains of the PECAM-1/CD31 gene. In particular, Ser563Asn and Gly670Arg SNPs have been described as susceptibility factors involved in acute myocardial infarction (AMI) in the Japanese male population. To confirm these observations, we studied 96 male patients (mean age 40 years; age range 20-46) affected by AMI and 118 healthy male controls (mean age 38 years, age range: 20-55), and analysed for the following PECAM-1/CD31 SNPs: Val125Leu, Asn563Ser and Gly670Arg. The frequency of the Gly670Arg polymorphism was significantly higher in patients with AMI (58.9% vs. 48.3%; P = 0.019), whereas the frequencies of the other two SNPs (Leu125Val and Ser563Asn) were not significantly different between patients and controls. By comparing the observed number of 670Arg/Arg genotypes in the patients with the expected number, calculated from the allele frequency in a healthy population, a significance of P = 0.02 (odds ratio, 2.04; 95% CI: 1.1-3.7) was obtained, supporting a recessive model of inheritance. Hence, the differences between patients and controls are significant, but relatively small. However, as AMI is a multifactorial disease, any single mutation will only provide a small or modest contribution to the risk, which also depends on environmental interaction. All in all, we believe that the results of the present study would add support to the role of pro/anti-inflammatory genotypes in determining susceptibility or resistance to immune-inflammatory diseases, including atherosclerosis.

Adult↗

PubMed2006

Posttransplant recurrence of proteinuria in a case of focal segmental glomerulosclerosis associated with WT1 mutation.

Posttransplant recurrence of inherited focal segmental glomerulosclerosis (FSGS) is still an enigma owing to the evident paradox of the molecular origin of proteinuria. A young girl with FSGS for WT1 mutation (IVS9+4C>T) and Frasier syndrome received a renal transplant at the age of 11 years. After an initial good outcome with recovery of renal function, proteinuria re-appeared after 7 days and steadily increased up to a nephrotic range. Determination of plasma permeability activity showed concomitant high Palb (0.7). At this point, plasmapheresis was started and after nine cycles with 1500 mL exchange and albumin re-infusion, proteinuria decreased to normal range and is still normal after 3 years. This is the first description of posttransplant recurrence of proteinuria in Frasier syndrome that should be included in potential outcome of renal transplant in this category of patients. This observation confirms the concept that recurrence of proteinuria may occur in inherited forms of FSGS so far reported only for patients carrying NPHS2 mutations and reinforces the idea on multifactorial origin of the disease.

Adolescent↗

PubMed1993

Genetic exchange of determinants for capsular polysaccharide biosynthesis between Klebsiella pneumoniae strains expressing serotypes K2 and K21a.

The production of a capsular polysaccharide (CPS; K antigen) is characteristic of Klebsiella pneumoniae, but CPS structure varies among strains, and many different serotypes are now known. In this study, cps gene clusters encoding the elements of capsular polysaccharide biosynthesis were exchanged by homologous recombination between strains expressing different serotypes. The wild-type K. pneumoniae strains used for genetic exchange were KPA1 (cpsK2), expressing K2 CPS, and KPB1 (cpsK21a), expressing K21a CPS. Plasmid R68.45 was used to mobilize fragments of chromosomal DNA from auxotrophic derivatives of donor strains. Auxotrophic his alleles introduced into recipient strains provided selectable markers to coinherit the adjacent cps gene clusters from donors expressing a heterologous CPS. Each of the capsule-switched recombinants, KPA5 (cpsK21a) and KPB20 (cpsK2), was shown to have a CPS that was immunologically identical to the serotype of the respective donor. The recombinants retained their respective recipient strain background, as evidenced by a genetic marker and demonstration of a distinctive restriction fragment length polymorphism in genomic DNA. KPB1 CPS contained a sequence (mannose-alpha-2-mannose) that binds to a macrophage lectin and may be responsible for their higher susceptibility to macrophage binding and phagocytosis compared with KPA1, whose CPS lacked such sequences. The recombinant strains expressing heterologous cps genes inherited the macrophage-binding phenotype of the donor, thus confirming that relative susceptibility to phagocytosis was determined by the capsule type expressed. KPA1 was highly virulent in a mouse lethality assay, which is a feature typical of K2 strains, whereas KPB1 was not virulent in mice. Recombinant KPA5 retained relatively high virulence in mice, even though it produced the heterologous K21a CPS, which suggests that a virulence factor other than capsule biosynthesis is encoded by the KPA genomic strain background. In contrast, KPB20 gained marginal virulence in the mouse lethality assay through the inheritance and expression of the K2 CPS from the virulent strain. Thus, pathogenesis in K. pneumoniae may be multifactorial. Specific antibody was used to stabilize the CPS on the surface of K. pneumoniae, and the structural organization of the homologous and heterologous capsules was examined by electron microscopy. Recombinant KPB20, expressing heterologous K2 CPS, had a uniform layer of capsule surrounding the organism that was similar to that seen on the surfaces of the parental strains. However, KPA5, expressing the heterologous K21a CPS, was unusual in that the uniform capsular layer was physically separated from the cell wall by approximately 50 nm.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1987

Genetic and environmental factors in alcohol abuse and antisocial personality.

Previous analyses of adoptees from Lutheran Social Services of Iowa developed a multifactorial model of adoptee alcohol abuse that related abuse to three factors: biologic background of alcohol-related problems, biologic background of antisocial problems and exposure to an adoptive family where family members had alcohol-related problems. The present study examines an independently collected sample of adoptees from a different agency--the Iowa Children's and Family Services, and confirms the multifactorial model previously found in the Lutheran Social Service data. The model shows a specificity of type of inheritance and type of environmental influence: biologic family alcohol-related problems predict increased alcohol abuse in adoptee, biologic family antisocial behaviors predict increased antisocial personality diagnoses in adoptee, and environmental factors of alcohol-related problems in the adoptive family predict increased adoptee alcohol abuse.

Adoption↗

PubMed2001

Genetic evaluation of cancer: the importance of family history.

Although the etiology of most cancers is thought to be sporadic and multifactorial, 5% to 10% of breast, ovarian, and colon cancers result from defects or mutations in specific genes inherited by a person through the germline. Distinctions may be made between hereditary and sporadic cancers. Because the risk of developing cancer is greater for persons from a hereditary cancer family than for the general public, these people should be considered for early detection and prevention options. Testing for selected cancer genes is available commercially, and physicians must determine which patients are appropriate candidates for these tests. Risk-reduction strategies and options for high-risk patients as well as legal and ethical issues pertaining to genetic counseling and testing will be considered.

Adult↗

PubMed1999

Clinical hereditary characteristics in nasopharyngeal carcinoma through Ye-Liang's family cluster.

OBJECTIVE: To investigate the incidence of nasopharyngeal carcinoma (NPC) and the clinical characteristics in this family through a long-term follow-up, and to seek the hereditary factor of NPC. This research was also designed to provide some clinical data for etiological study. METHODS: A genealogical tree of Ye-Liang's family was drawn and reported in 1972 after a complete survey. Further follow-up from that time to 1997 was performed. Human leucocyte antigens (HLA) were investigated, and physical follow-up was done in domestic members of this family. For oversea members of this family, correspondence follow-up was performed. RESULTS: In the last 25 years, the incidence of malignancies in Ye-Liang's family increased from 10 cases to 18 cases, and incidence of NPC increased from 9 cases to 15 cases. In this family, not only multiple malignancies have been found in the second generation, but also NPC has been found in the third generation. HLA-[A2-B46] haplotype was correlated with occurrence of NPC. CONCLUSIONS: Dominant racial predilection and family cluster in NPC implied that NPC is a heredity-related cancer which might involve multifactorial disorders in carcinogenesis. Further research on etiology of NPC should be focused on hereditary factor. Detection of inherited factors should be performed for forecast of carcinogenesis and reduction of NPC occurrence.

Female↗

PubMed1986

[Clinico-genetical analysis of colonic cancer. I. Occurrence, frequency in families and segregation analysis].

The data on clinico-genealogic studies of colon cancer are presented. 694 families were examined with 432 probands having rectal and 262 colonic carcinoma among them. Clear family accumulation of colon cancer (2.4 +/- 0.35%) as well as other malignant tumors (6.8 +/- 0.6%) (p less than 0.01) was shown among the relatives of the first degree of relation. The values of segregation rates obtained for clinical forms of colon cancer were lower than theoretically expected for simple monogenic types of inheritance. The analysis of incomplete penetration of genotypes showed that, though formally the inheritance of colon cancer and its clinico-anatomical forms may be described by quasi-dominant types of inheritance, the penetration values are very low: from 4.3 to 13.3% for homozygotes and from 2.1 to 6.6% for heterozygotes. It shows that the supposition about the monogenic types of the colon cancer inheritance is doubtful and suggests that the colon cancer is to be regarded on the basis of the multifactorial model.

Adult↗

PubMed1993

[Genetic approaches to Itsenko-Cushing disease].

107 patients with Itsenko-Cushing disease were examined for heredity: family history was analyzed in 75 cases, dermatoglyphics was assessed in 44 cases, I- and II-class HLA antigens were studied in 68 cases. The patients were found to have hereditary loading both by Itsenko-Cushing and other diseases (hypertension, atherosclerosis, autoimmune disorders). Clinico-genealogical evaluation made it possible to identify forms of the disease which are inherited autosome-recessively and autosome-dominantly. However, in the majority of patients the disease onset had multifactorial nature, as there were HLA-antigen associations by DR4, DR5, DR7, DRw53, DQw3. Pilot experience with genetic study of the disease showed its genetic determination in some forms, its association with hypertension and atherosclerosis, approaches to prevention, prognosis, classification. Practical recommendations on detailed family history collection in patients with Itsenko-Cushing disease have been developed.

Adult↗

PubMed2003

Genetics and clinical practice in rheumatology.

The dramatic advances made recently in human genome research are fueling considerable interest in genetic testing. A specific feature of genetic testing is that the results are final and impact not only the patient, but also the entire family. Those elements should be factored into the risk/benefit ratio evaluation. In France, legislation the differentiates diagnostic tests in symptomatic patients from predictive tests in asymptomatic patients with affected family members. Only multidisciplinary groups with both clinical and genetic expertise can order predictive tests. In all cases the physician must sign a statement that informed consent was obtained from the patient prior to testing. The test must be done in an accredited laboratory and the result communicated by the physician to the patient. Patient confidentiality must be respected, particularly regarding family members. In monogenic diseases, the diagnostic weight of genetic testing is often considerable, although the limitations should be borne in mind. In multifactorial diseases, genetic testing seeks to identify risk factors that are usually associated with a low level of risk. The result should be interpreted in the light of the clinical presentation, family history, and genetic background. The predictive value is closely dependent on the clinical presentation but is generally limited, most notably when family members are affected. Great care should be taken to avoid causing undue anxiety among individuals with positive test results. Diseases that illustrate these aspects include Paget's disease of bone, of which inherited variants caused by a mutation in a single gene on chromosome 5 have been identified recently, and rheumatoid arthritis, which is a multifactorial disease.

Connective Tissue Diseases↗

PubMed2000

After BRCA1 and BRCA2-what next? Multifactorial segregation analyses of three-generation, population-based Australian families affected by female breast cancer.

Mutations in BRCA1 and BRCA2 that cause a dominantly inherited high risk of female breast cancer seem to explain only a small proportion of the aggregation of the disease. To study the possible additional genetic components, we conducted single-locus and two-locus segregation analyses, with and without a polygenic background, using three-generation families ascertained through 858 women with breast cancer diagnosed at age <40 years, ascertained through population cancer registries in Melbourne and Sydney, Australia. Extensive testing for deleterious mutations in BRCA1 and BRCA2, to date, has identified 34 carriers. Our analysis suggested that, after other possible unmeasured familial factors are adjusted for and the known BRCA1 and BRCA2 mutation carriers are excluded, there appears to be a residual dominantly inherited risk of female breast cancer in addition to that derived from mutations in BRCA1 and BRCA2. This study also suggests that there is a substantial recessively inherited risk of early-onset breast cancer. According to the best-fitting model, after excluding known carriers of mutations in BRCA1 and BRCA2, about 1/250 (95% confidence interval [CI] 1/500 to 1/125) women have a recessive risk of 86% (95% CI 69%-100%) by age 50 years and of almost 100% by age 60 years. Possible reasons that our study has implicated a novel strong recessive effect include our inclusion of data on lineal aunts and grandmothers, study of families ascertained through women with early-onset breast cancer, allowance for multiple familial factors in the analysis, and removal of families for whom the cause (i.e., BRCA1 or BRCA2) is known. Our findings may have implications for attempts to identify new breast cancer-susceptibility genes.

Age Factors↗

PubMed1989

[Heritability of clinical forms of childhood schizophrenia].

Investigated and genetically analyzed were inheritance variants in 225 families of probands with different forms of development of child schizophrenia and 519 blood relatives as well as in 1714 relatives of the 2nd and 3rd grades. Child schizophrenia as seen from the viewpoint of the monogenic model of inheritance with total or partial penetrance of the "major" gene proved inconsistent with the characteristics of family history and population distributions in the disease. The multifactorial model appeared the most adequate to describe the susceptibility system. In the framework of this model the correlation between the susceptibility components specific for a clinical form could be derived from distinguishing between genotypic and environmental components. The data indicate that in malignant and slow progredient schizophrenia the probands were genotypically similar to a greater extent that they were in paroxysmal-progredient form, as revealed by the inheritance coefficient of the former group (28-35%) which was lower than that of the latter group (64%).

Adolescent↗

PubMed2005

Molecular biology and genetics of Alzheimer's disease.

Like several other adult onset neurodegenerative diseases, Alzheimer's disease is a multifactorial illness with both genetic and non-genetic causes. Recent genetic studies have identified four genes associated with inherited risk for AD (presenilin 1, presenilin 2, amyloid precursor protein, and apolipoprotein E). These genes account for about half of the total genetic risk for Alzheimer's disease. It is suspected that several other Alzheimer's disease-susceptibility genes exist, and their identification is the subject of ongoing research. Nevertheless, biological studies on the effects of mutations in the four known genes has led to the conclusion that all of these genes cause dysregulation of amyloid precursor protein processing and in particular dysregulation of the handling of a proteolytic derivative termed Abeta. The accumulation of Abeta appears to be an early and initiating event that triggers a series of downstream processes including misprocessing of the tau protein. This cascade ultimately causes neuronal dysfunction and death, and leads to the clinical and pathological features of Alzheimer's disease. Knowledge of this biochemical cascade now provides several potential targets for the development of diagnostics and therapeutics.

Alzheimer Disease↗

PubMed1980

Inheritance of endothelial dystrophy of the cornea.

64 families containing a proband with corneal endothelial dystrophy were examined in order to study the hereditary nature of the disease. Data concerning the frequency of occurrence, severity of the disease, ratio of affected females to males, relationship of the disease with age, and other factors were the subject of a previous report. 7 pedigrees which reflect features of endothelial dystrophy within the 64 families are presented. These features include multiple females in a family being affected, multiple consecutively affected generations, the occurrence of offspring with disease more severe than the parent, and endothelial decompensation (edema) at a relatively young age (less than 40 years of age). The importance of examining family members whenever possible rather than relying on history alone is emphasized. A statistical analysis of the inheritance pattern was performed. Endothelial dystrophy does not seem to follow a strict autosomal dominant pattern even though superficial inspection suggests autosomal dominant inheritance (both males and females affected, successive generations affected, 38% of relatives over the age of 40 years affected). Even though we were unable to determine a specific genetic mode of inheritance in these 64 families with endothelial dystrophy, we do feel that endothelial dystrophy is at least in part an inherited disease. Future investigations might prove sex-linked dominance, genetic heterogeneity, the influence of environmental factors, or a multifactorial etiology.

Adult↗

PubMed2001

The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches.

The recent completion of a rough draft of the human genome sequence has ushered in a new era of molecular genetics research into the inherited basis of a number of complex diseases such as cancer. At the same time, recent twin studies have suggested a limited role of genetic susceptibility to many neoplasms. A reappraisal of family and twin studies for many cancer sites suggests the following general conclusions: (a) all cancers are familial to approximately the same degree, with only a few exceptions (both high and low); (b) early age of diagnosis is generally associated with increased familiality; (c) familiality does not decrease with decreasing prevalence of the tumor-in fact, the trend is toward increasing familiality with decreasing prevalence; (d) a multifactorial (polygenic) threshold model fits the twin data for most cancers less well than single gene or genetic heterogeneity-type models; (e) recessive inheritance is less likely generally than dominant or additive models; (f) heritability decreases for rarer tumors only in the context of the polygenic model but not in the context of single-locus or heterogeneity models; (g) although the family and twin data do not account for gene-environment interactions or confounding, they are still consistent with genes contributing high attributable risks for most cancer sites. These results support continued search for genetic and environmental factors in cancer susceptibility for all tumor types. Suggestions are given for optimal study designs depending on the underlying architecture of genetic predisposition.

Environment↗

PubMed2006

Fundamental research is the basis for understanding and treatment of many human diseases.

There are numerous examples of how fundamental research has been required to understand and treat human disease. This article focuses on three human diseases of lipid metabolism in which advancements in understanding and treatment would not have been possible without basic research. Fabry disease is an inherited metabolic disorder caused by the lack of a specific enzyme in glycosphingolipid catabolism. Cardiovascular disease is a complex and multifactorial disease but as many as half of the cases can be attributed to abnormal levels of plasma cholesterol. The incidence of liver disease is increasing due to the current epidemic of obesity. It is only recently that curiosity-driven research has yielded valuable insight into the mechanism by which liver disease evolves.

Animals↗