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Results for “Multifactorial Inheritance”

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PubMed1981

Age at onset of genetic diseases: an application for Sartwell's model of the distribution of incubation periods.

For diseases of well-defined genetic etiology and with onset after birth, the age at onset corresponds to the incubation period of the disease. The lognormal model, as used by Sartwell to study the distribution of incubation periods in infectious diseases (Am J Hyg 1950;51:310-8), was applied in this study to the distribution of the ages at onset of genetic diseases. The literature was reviewed for reports of genetic diseases having frequency distributions of ages at onset. Fourteen diseases with well-specified genetic etiology as well as nine other diseases where the contribution of the genetic component to the etiology is not well defined were studied. A graphic method as well as a goodness of fit test were applied to the different age at onset distributions to assess their conformity to the lognormal model. For most of the genetic diseases that have an underlying biochemical abnormality, the age at onset distributions approximated a logarithmic normal model. In seven series of cases of diseases with an established pattern of inheritance but with no defined biochemical abnormalities, only two showed a good fit to the lognormal model. For diseases with ill-defined genetic etiology or strong environmental influences, these distributions of the age at onset did not fit the lognormal model. In a multifactorial model for disease etiology, the present method may be used as a crude way for differentiating the relative importance of etiologic factors acting before and after birth.

Adolescent↗

PubMed2001

Nephronophthisis and ulcerative colitis in siblings: a new association.

Nephronophthisis (NPH) is a chronic tubulointerstitial nephritis leading to terminal renal insufficiency. The disease is heterogeneous, but usually the inheritance pattern is autosomal recessive. In 80% of cases, the disease is caused by a homozygous deletion in NPHP1 gene in chromosome 2q13. Ulcerative colitis is an inflammatory bowel disease with chronic diarrhea, rectal bleeding and characteristic histological findings. Its etiology is suggested to be multifactorial, consisting of genetic susceptibility and unknown exogenous factors. We present two siblings with NPH and ulcerative colitis. As NPH in this family is not linked to 2q13, this association may represent a new, syndromic form of NPH.

Adult↗

PubMedDate not supplied

Familial hemiplegic migraine: a ion channel disorder.

At present, little information is available on the genetics of common migraines, most likely to be considered a multifactorial disease. Recently, the CACNA1A gene encoding the brain-specific P/Q type calcium channel alpha(1) subunit, has been cloned and mutations in this gene, located on chromosome 19p13, have been shown to be involved in familial hemiplegic migraine (FHM), a rare autosomal dominantly inherited subtype of migraine with aura. Being part of the migraine spectrum, FHM represents a good model to study the genetics of more common forms of migraine. Different classes of mutations within the CACNA1A gene have been associated with different diseases, thus identifying a new member among 'channelopathies'. Variable clinical expression and genetic heterogeneity of FHM will be discussed.

Calcium Channels↗

PubMed1995

Molecular basis of human hypertension: the role of angiotensin.

On the basis of recent advances in molecular biology and statistical genetics, it has become possible to search for chromosome regions that contain genes predisposing to hypertension and to directly link specific mutations on candidate genes to hypertension. As the human genome has been extensively mapped, highly informative, polymorphic markers are available, which can be used to detect genes in their proximity with 'hypertensinogenic' alleles. Some of these markers have been shown to be tightly linked to the genes of the renin-angiotensin system. Furthermore, the coding and regulatory regions of the genes encoding for renin, ACE, angiotensinogen and the AT1 receptor have been partially characterized. This provides a basis for further definition of specific polymorphisms within these genes that are of functional importance and that can be used to examine their contribution to the inheritance of primary hypertension. The first studies of these links have already emerged and have been reviewed in this article. Several problems arise in performing such linkage studies in human primary hypertension, however. It is difficult to define the genetic background of heterogeneous, multigenetic and multifactorial diseases such as human hypertension. Extensive studies of population genetics, including the analysis of large numbers of generations and controlled breeding experiments, cannot be performed, for obvious reasons. Blood pressure is not a convenient study trait, because it exhibits great intraindividual variance and also because of the relatively low reliability of just a few indirect measurements obtained under loosely controlled environmental conditions. Twenty-four-hour ambulatory blood pressure measurements may improve such investigations in the near future. Ravogli et al (1990) reported that the 24-hour ambulatory systolic blood pressure is higher in normotensive subjects of hypertensive parents than in normotensive subjects of normotensive parents--a finding that had not been previously reported using the conventional method of measurement. Hypertension as a trait per se is also problematic: its classification (above 140/90 mmHg) is purely artefactual, and its aetiology is highly heterogeneous. Thus, we have to keep in mind that even strong gene effects, if present in only a small subgroup of hypertensives, may not be detected in these studies. Attempts are being made to strengthen the analysis by characterizing physiologically distinct subgroups. In addition, the investigation of intermediate phenotypes, such as plasma parameters, which are more reliable and less subject to variations, may be helpful.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiotensin II↗

PubMed1995

[Genetic analysis and elaboration of principles for predicting malignant tumors in families of patients with stomach cancer and primary multiple malignant neoplasms].

The results of familial population analysis of stomach cancer and multiple primary malignant tumors (MPMTs) are presented. The data obtained provide evidence for the multifactorial nature of stomach cancer. Hereditary factors accounted for 32% of the general predisposition of individuals to stomach cancer. The age-related character of stomach cancer was established. Genetic heterogeneity of this tumor is suggested by the data obtained. Significant genetic commonness in the inheritance of stomach, colon, Genetic Analysis and Prognosis for Malignant Tumors in breast, endometrial, and ovarian cancer in families of MPMT patients was demonstrated on the basis of the obtained genetic correlations between tumor types in MPMT patients and solitary tumors in members of their families. The greatest genetic load was shown for families of MPMT patients, as compared with families of patients with solitary tumors, the coefficient of MPMT inheritance being equal to 77.4%. The data on the genetic character of stomach cancer and MPMT formed the basis for the identification of criteria for developing methodological approaches to the screening of individuals from risk groups to facilitate early diagnosis and prevention of cancer.

Age Distribution↗

PubMed2003

Gene therapy targeting hematopoietic cells: better not leave it to chance.

Gene therapy targeting hematopoietic cells has arrived at a new stage of potency. While the potential for curing inherited disorders of the immune system has been demonstrated in clinical trials, we were also confronted with the first serious adverse events related to random insertion of foreign DNA into cellular chromosomes. As it is likely that the manifestation of severe side effects results from a multifactorial process, it will be of crucial importance to define the significance of the individual risk factors involved. The future of the field will depend on our ability to define risk classifications of clinical approaches, to continuously improve transgene technologies, and to introduce new concepts for targeted selection of transgenic cells. Interestingly, correction of genetic disorders by homologous gene repair in defined stem cell clones is on the horizon, but far from being available for clinical use.

Animals↗

PubMed1997

Inheritance of cleft palate in Italy. Evidence for a major autosomal recessive locus.

Although several studies have demonstrated familial aggregation of nonsyndromic cleft palate (CP), the mode of inheritance still remains uncertain. We report the results of complex segregation analysis performed in families of 357 consecutive newborns affected with nonsyndromic CP (i.e., CP not a component feature of malformation syndrome, sequence or association), and registered in the North East Italy and Emilia Romagna congenital malformation registries in the period 1981-1993. This sample, based on a large number of consecutive births, in a well-defined geographical area, with quality control to detect associated anomalies and malformation syndromes, is independent of the number of affected subjects in the family and of CP severity, fitness, and survival. We have analyzed, using the mixed model, the whole sample of nonsyndromic CP, including isolated (i.e., without other anomalies) CP (CPI) and CP associated with at least one other anomaly (CPA), for which a diagnosis of malformation syndrome was not possible. When nonsyndromic CP (including CPA) are considered in the analysis, there is no heterogeneity between CPA and CPI nor between CP including hard palate (CPH) and CP of the soft palate only (CPS). POINTER and COMDS programs cannot discriminate between alternative genetic models; only the hypothesis of non-genetic transmission is rejected. The COMDS analysis two-locus model, which indicates that a modifier locus (or loci) operates in addition to a single major locus (SML), does not show evidence of better fit than SML, polygenic, and multifactorial models. When the severity parameter (defined as CPH and CPS) is added, CPI and CPA show heterogeneity. Eventually, when the analysis is limited to CPI and includes information on severity, a recessive SML, with low penetrance and determining CPH, provides a significant best fit. To have defined a genetic model for CPI and provided evidence for SML inheritance suggests that genetic linkage studies could be implemented. This conclusion is in agreement with previous studies which showed a significant association between alleles of transforming growth factor alpha and CP only in humans, and that single recessive genes may play a crucial role during palatogenesis in mice as well as in Brittany spaniels. Application of the candidate genes to human CPH families could reveal whether these genes are involved.

Alleles↗

PubMed1994

Evidence for autosomal dominant inheritance and race-specific heterogeneity in early-onset periodontitis.

Early-onset periodontitis (EOP) refers to a group of severe periodontal diseases with age of onset near puberty that are characterized by rapid destruction of the tissues supporting the teeth in otherwise healthy individuals. Mixed model segregation analyses of 100 families, ascertained through 104 probands with EOP, were carried out to test major locus and multifactorial hypotheses for the etiology of EOP. Heterogeneity tests were used to compare the parameter estimates and conclusions obtained in Black families from those from non-Black families. The data in these families confirmed that the often-reported female preponderance of EOP appears to be an ascertainment bias. The segregation analysis results were consistent with an autosomal major locus being sufficient to explain the family patterns of EOP in the entire dataset, and also in both the Black and non-Black subsets. A dominant mode of transmission was most likely, with penetrance of about 70%. Although the etiologic conclusions were the same for Black and non-Black families, there was significant heterogeneity in parameter estimates. In particular the Black allele frequency was 0.016 versus the non-Black frequency of 0.001.

Adolescent↗

PubMed1981

Prenatal detection of inherited disorders.

The following is a review of current concepts of prenatal detection. Transabdominal amniocentesis is recognized to be an integral adjunct to prenatal care. The analysis of cultured amniotic fluid cells collected at about 16 weeks of gestation provides in utero diagnosis of nearly all chromosomal aberration syndromes, several metabolic disorders which are due to a specific enzymic deficiency due to single gene disorders, and some multifactorial disorders, such as prenatal diagnosis of neural tube defects by estimation of alphafeto protein in amniotic fluid. Various aspects of amniocentesis are discussed.

Amniocentesis↗

PubMed1996

Severe autosomal dominant hypertension and brachydactyly in a unique Turkish kindred maps to human chromosome 12.

Finding genes that cause human hypertension is not straightforward, since the determinants of blood pressure in primary hypertension are multifactorial. One approach to identifying relevant genes is to elucidate rare forms of monogenic hypertension. A relevant mutation may provide a rational starting point from which to analyse the pathophysiology of a condition affecting 20% of the world's population. In 1973 a family with autosomal dominantly inherited brachydactyly and severe hypertension, where the two traits cosegregated completely, was described. We have now re-examined this kindred, and localized the hypertension and brachydactyly locus to chromosome 12p in a region defined by markers D12S364 and D12S87. As the renin-angiotensin-system and sympathetic nervous system respond normally in this form of hypertension, the condition resembles essential hypertension. This feature distinguishes this form of hypertension from glucocorticoid remediable aldosteronism and Liddle's syndrome, which are salt-sensitive forms of monogenic hypertension with very low plasma renin activity. We suggest that identification of the gene involved in hypertension and brachydactyly and its mutation will be of great relevance in elucidating new mechanisms leading to blood pressure elevation.

Adult↗

PubMed1981

Association of HLA antigens with coeliac disease among Iraqi children.

Forty children with coeliac disease were subjected to HLA-A and B antigens typing using the two-way lymphocytotoxicity technique. An increase in the frequency of HLA-B8 and B12 was found in patients as compared to the control group. Family studies conducted in 4 selected families have indicated that four out of five siblings who inherited the HLA-B8 antigen from their parents have contracted coeliac disease. In one of the families both siblings had HLA-B8 but only one of them contracted coeliac disease. It is suggested that the association of coeliac disease with HLA-antigen could be multifactorial, i.e. the disease could be attributed to the presence of more than one antigen.

Celiac Disease↗

PubMed1989

Ivemark's "asplenia" syndrome: a single gene disorder.

Congenital heart defects as a group represent a significant proportion of congenital malformations. Most are isolated and multifactorially determined; a relatively small proportion are due to a single gene defect, and result in an increased risk of recurrence among first-degree relatives. We have reported the cases of three male siblings with Ivemark's "asplenia" syndrome to support an autosomal recessive mode of inheritance. We have stressed the importance of early recognition of mendelian disorders with associated cardiac malformations to provide meaningful counseling regarding prognosis, medical management, and risk of recurrence.

Adult↗

PubMed2001

Multifactor-dimensionality reduction reveals high-order interactions among estrogen-metabolism genes in sporadic breast cancer.

One of the greatest challenges facing human geneticists is the identification and characterization of susceptibility genes for common complex multifactorial human diseases. This challenge is partly due to the limitations of parametric-statistical methods for detection of gene effects that are dependent solely or partially on interactions with other genes and with environmental exposures. We introduce multifactor-dimensionality reduction (MDR) as a method for reducing the dimensionality of multilocus information, to improve the identification of polymorphism combinations associated with disease risk. The MDR method is nonparametric (i.e., no hypothesis about the value of a statistical parameter is made), is model-free (i.e., it assumes no particular inheritance model), and is directly applicable to case-control and discordant-sib-pair studies. Using simulated case-control data, we demonstrate that MDR has reasonable power to identify interactions among two or more loci in relatively small samples. When it was applied to a sporadic breast cancer case-control data set, in the absence of any statistically significant independent main effects, MDR identified a statistically significant high-order interaction among four polymorphisms from three different estrogen-metabolism genes. To our knowledge, this is the first report of a four-locus interaction associated with a common complex multifactorial disease.

Alleles↗

PubMed2004

Genetic disorders of sheep in New Zealand: a review and perspective.

Genetic disorders of sheep that have occurred in New Zealand are reviewed and discussed with regard to phenotype, inheritance and, where known, genotype. Inbreeding was a major factor in the emergence of some of them. The various disorders reflect a continuum, ranging from simple monogenic diseases or malformations due to dysfunctional gene products, those monogenic disorders dependant on environmental interactions, malformations due to homeotic gene dysfunctions, and multifactorial diseases for which genetic factors are associated with disease susceptibility. Chromosomal aberrations, although of limited importance, have contributed to an understanding of the physical chromosome map and derivative linkage map of sheep.

Journal Article↗

PubMed1990

[Comparative clinico-genetic studies of senile dementia and Alzheimer's disease].

The families of 128 probands with senile dementia (SD) and Alzheimer's disease (AD) were entered into the study. The correlation between the familial and sporadic cases of the disease was established. A geneticomathematic analysis was employed to estimate the clinicogenealogical findings. Two genetic models (monogenous and multifactorial) were tested. The contribution of the genetic factors to SD and AD liability was assessed. As a result of a comparative clinicogenetic study of SD and AD it was found that there is no doubt about the contribution made by the genetic factors to the origin of the Alzheimer type dementia (ATD). The rate of the afflicted relatives considerably exceeded the population rates of the investigated patterns of dementia. The limit estimations of the genetic similarity between the manifestations of AD and SD, both in the monogenous and multifactorial models, were obtained, which rejects the presence of the common major gene responsible for liability to these patterns of the ATD. It was assumed that AD and SD are characterized by the presence of the common genes modifiers. In addition, the difference was established between the types of inheritance in persons afflicted with these diseases: an oligogenic type of inheritance in SD, a quasidominant type with incomplete penetrance of homo- and heterozygotes in AD.

Adult↗

PubMed1998

The wide spectrum of myofibrillar myopathy suggests a multifactorial etiology and pathogenesis.

BACKGROUND: Myofibrillar myopathy (MFM) is characterized by nonhyaline lesions (foci of myofibrillar destruction) and hyaline lesions (cytoplasmic inclusions composed of compacted myofibrillar residues) on light and electron microscopy. Immunocytochemistry demonstrates the abnormal expression of desmin and numerous other proteins. The clinical, laboratory, and histologic features of MFM are heterogeneous, making a diagnosis difficult. RESULTS: We diagnosed eight patients with MFM over the preceding 3 years. MFM was inherited in an autosomal dominant pattern in one patient, developed sporadically in five patients, and was induced by an experimental chemotherapy, Elinafide (Knoll, Parsippany, NJ), in two patients. Age at onset ranged from 14 to 64 years. The pattern of weakness was variable but involved proximal and distal muscles. Five patients had evidence of a cardiomyopathy. Electromyography demonstrated muscle membrane instability and small, polyphasic motor unit potentials. Serum creatine kinase levels were normal to moderately elevated (<10x normal). Light and electron microscopy demonstrated the characteristic pattern of nonhyaline and hyaline lesions and the associated abnormalities on immunocytochemistry. CONCLUSIONS: Patients demonstrate a wide spectrum of clinical, laboratory, and histologic abnormalities. Chemotherapy-induced MFM has abnormalities on immunocytochemistry similar to the those of hereditary and sporadic cases. The pathogenesis of MFM is likely heterogeneous. However, MFM is distinctive in that it can preferentially affect distal muscles and has a frequent association with cardiomyopathy. The cardiomyopathy may be amenable to treatment with pacemaker insertion or cardiac transplantation.

Adult↗

PubMed2005

Heritability of craniofacial characteristics between parents and offspring estimated from lateral cephalograms.

OBJECTIVE: The purpose of the study was to estimate the heritability of different cephalometric parameters, according to lateral cephalograms, between parents and their offspring in an Icelandic population. METHODS: The material was collected at the Faculty of Odontology, University of Iceland. The subjects were 363 children (6 years of age) and their parents. Material was also collected from the same group of children at the age of 16 years. Twenty-two reference points were identified on each cephalogram, and 33 variables were calculated, both angular and linear. Heritability was calculated at ages 6 and 16. RESULTS: Daughters had more variables that reached the level of significance than did sons. Daughters showed similar heritability to both parents at both age levels, but more variables were highly significant ( P < or = .001) in the daughter-father groups. Sons showed stronger heritability to their mothers at both ages. The variables showing the greatest heritability were those representing the position of the lower jaw, the anterior and posterior face heights, and the cranial base dimensions. Heritability was notably low for the dental variables. CONCLUSIONS: Genetic aberrations can be detected for complex polygenetic multifactorial traits. Cephalometric data can support predictions, and analysis of parental data could have predictive value for offspring.

Adolescent↗

PubMed1996

[The pattern of predisposition to rheumatism].

The present study was based on the results of many-year studies of the Mongoloid populations the Tofalars (793 and 661 persons in 1973 and 1984, respectively), the Dolgans (n = 952) the Taimyr Yakuts (n = 452), the Todji Tuvins (n = 819) and a sample from 200 families of rheumatic patients in Moscow and Moscow Region. The interpopulation gene differentiation expressed through the generalized genetic distance (8) and the prevalence of rheumatism correlated (r = 0.63). There was also a correlation between the mean heterozygocity of the populations and the spread of rheumatism-the determination rate was 72%. Therefore, structural features of the populations have a definite impact on the prevalence of rheumatism and suggest that there is a genetic component in the determination of the disease. A segregative analysis indicated the adequacy of a multifactorial model for the majority of the studied populations, the contribution of a genetic component to the determination of varying susceptibility to rheumatism ranged from 71% in the population of the Tofalars to 100% in the populations of the Dolgans and the Tuvins. The results of testing the type of rheumatism inheritance using a SAL-2 model, the data of a regression analysis of susceptibility heritability and inbreedity of the populations, and a component resolution of phenotypic dispersion of susceptibility are indicative of its involvement, along with an additive component, in the determination of rheumatism. Clinical and genetic findings also suggest that there is a genetic heterogeneity both of rheumatism as a whole (verified +likely) and verified rheumatism (without and with cardiac diseases).

Asian People↗