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Results for “Multifactorial Inheritance”

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PubMed1990

Systemic lupus erythematosus.

Descriptive epidemiologic studies of SLE have been conducted worldwide; the most extensive data are available for Scandinavia, especially Sweden, and the United States. In the United States, blacks have threefold higher incidence, prevalence, and mortality rates compared with whites; the reasons for this excess, however, remain unknown. Analytic and genetic epidemiologic studies suggest a multifactorial etiology of SLE; results support a polygenic mode of inheritance including important roles for an autosomal dominant "autoimmune" gene and female sex hormones. Although a viral etiology remains attractive, there is little evidence to support such a hypothesis. Rather, other environmental factors including chemical exposures may be important as "triggers" of disease. Finally, observational epidemiologic studies demonstrate an increasingly favorable prognosis for patients with SLE, allowing a better understanding of long-term morbidity and impact on overall health status. Future epidemiologic studies should focus on identifying noninfectious environmental etiologic factors and improving the quality of life for all patients with SLE.

Humans↗

PubMedDate not supplied

Dissecting hypertension: the role of the 'new genetics'.

The tools of molecular genetics have recently been applied to hypertension, a common multifactorial disorder, with some success. Glucocorticoid-suppressible hyperaldosteronism, an inherited form of human hypertension due to the dominant inheritance of a chimaeric steroid 11 beta-hydroxylase/aldosterone synthase gene, has given an insight into the possible genetic factors involved in essential hypertension. Study of the aldosterone synthase and steroid 11 beta-hydroxylase genes has shown the presence of polymorphisms in both of these genes in human subjects; further studies may demonstrate genetic mutations with pathophysiological effects in patients with essential hypertension.

Cytochrome P-450 CYP11B2↗

PubMed2005

A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk.

The identification of common variants that contribute to the genesis of human inherited disorders remains a significant challenge. Hirschsprung disease (HSCR) is a multifactorial, non-mendelian disorder in which rare high-penetrance coding sequence mutations in the receptor tyrosine kinase RET contribute to risk in combination with mutations at other genes. We have used family-based association studies to identify a disease interval, and integrated this with comparative and functional genomic analysis to prioritize conserved and functional elements within which mutations can be sought. We now show that a common non-coding RET variant within a conserved enhancer-like sequence in intron 1 is significantly associated with HSCR susceptibility and makes a 20-fold greater contribution to risk than rare alleles do. This mutation reduces in vitro enhancer activity markedly, has low penetrance, has different genetic effects in males and females, and explains several features of the complex inheritance pattern of HSCR. Thus, common low-penetrance variants, identified by association studies, can underlie both common and rare diseases.

Animals↗

PubMed2005

Is Wolff-Parkinson-White syndrome a genetic disease?

Family studies, and more recent molecular genetic investigations, indicate that the Wolff-Parkinson-White (WPW) syndrome and associated preexcitation disorders can have a substantial genetic component. Because preexcitation disorders are sometimes inherited as single gene disorders, key mechanistic insights can be gained that are expected to be relevant also to the more common multifactorial forms of these traits. Potentially, such insights will inform the future management of these conditions. Where WPW is inherited as a familial trait, with or without associated cardiac defects or a systemic syndrome, there are clinical genetic ramifications that are already of practical importance.

Genetic Predisposition to Disease↗

PubMed1993

Clinical and cytogenetic survey of institutionalized mentally retarded patients with emphasis on the fragile-X syndrome.

A detailed clinical and cytogenetic survey for the fragile-X syndrome was undertaken on 201 institutionalized mentally retarded males with no previously recognized cause of retardation, and the causes of mental retardation were summarized from a total of 595 institutionalized male and female patients after the review of their medical records including clinical and cytogenetic data. Among the 201 males clinically and cytogenetically examined, five (2.5%) had abnormal chromosome findings with four (2%) having the fragile-X syndrome. Twelve of the males (6.0%) were diagnosed with a single gene disorder. In the present study, mental retardation was classified as possibly due to multifactorial causes when a genetic syndrome, chromosome abnormality or environmental insult was not identified, but mental retardation was present in one or more first and/or second degree relatives, but did not follow a recognizable inheritance pattern. Hence, mental retardation was recorded in other family members and may indicate possible multifactorial causes in 45 males (22.4%). An environmental insult was noted in 25 males (12.4%); unexplained birth defects in three males (1.5%); a specific condition or diagnosis identified, but cause unknown (e.g. Rubinstein-Taybi syndrome) in 10 males (5%); and no diagnosis made in the remaining 101 males (50.2%). Of all 595 patients (334 males and 261 females), including the 201 males who had undergone a detailed clinical and cytogenetic evaluation, 39 (6.6%) had abnormal chromosome findings, with Down's syndrome noted in 31 of the patients. Twenty-five patients (4.2%) were diagnosed with a single gene disorder while mental retardation was noted in other family members and may indicate possible multifactorial causes in 64 patients (10.8%). An environmental insult was noted in 170 patients (28.6%); unexplained birth defects in 17 patients (2.9%); a specific condition or diagnosis but cause unknown in 27 patients (4.5%); and no diagnosis made in 253 patients (42.5%). Clinical and cytogenetic screening of mentally retarded patients for the fragile-X syndrome and other causes of mental retardation is helpful in identifying individuals and their families who may benefit from genetic services such as counseling and treatment. This study was performed over an approximate 2 year period from 1987 to 1989.

Adolescent↗

PubMed1994

Ionizing radiation and genetic risks. V. Multifactorial diseases: a review of epidemiological and genetic aspects of congenital abnormalities in man and of models on maintenance of quantitative traits in populations.

This paper discusses (a) data on the epidemiological and etiological aspects of human congenital abnormalities, (b) the multifactorial threshold model and other models which have been proposed to explain their inheritance patterns and recurrence risks in families and (c) current concepts on mechanisms on the prevalence of heritable variation for quantitative traits in populations. Congenital abnormalities, which afflict an estimated 6% of all live births, are etiologically heterogeneous. The majority of these do not follow Mendelian transmission patterns, but do 'run' in families. The multifactorial threshold model is an extension of genetic principles developed for quantitative traits to all-or-none traits; in its simplest formulation, it assumes the existence in the population of an underlying normally distributed 'liability' (which is due to numerous genetic and environmental factors acting additively, each contributing a small amount of liability) and of a 'threshold' beyond which the individual is affected. For most congenital abnormalities, the nature of these factors remains unknown. Other models assume fewer causal factors although, again, these remain to be identified. The question of how considerable heritable variation for most quantitative/polygenic traits has come to exist is a long-standing one in evolutionary population genetics. Models postulating that its existence is consistent with a balance between recurrent mutation and stabilizing selection or suggesting the possible operation of other mechanisms have been published in the literature. In the absence of knowledge on mechanisms responsible for the stable prevalences of congenital abnormalities or other multifactorial conditions in the population (but which is required to predict the consequences of an increase in mutation rate on their prevalences) it is necessary (a) to adapt and use concepts derived from quantitative and evolutionary population genetics and (b) to examine how sensitive the predictions are to the assumptions used, and how consistent they are with biological realities.

Abnormalities, Radiation-Induced↗

PubMed1991

The inheritance of conotruncal malformations: a review and report of two siblings with tetralogy of Fallot with pulmonary atresia.

Congenital heart defects (CHD) are a group of structural abnormalities that in humans have a combined incidence of approximately 1%. It is estimated that 4-5% of CHD are associated with chromosome abnormalities, 1-2% are associated with single gene syndromes, 1-2% are due to known teratogens, with the rest presumably determined multifactorially. We report on a brother and sister with tetralogy of Fallot with pulmonary atresia, and review the inheritance of familial conotruncal anomalies. We feel the small number of family clusters and the rare instances of consanguinity in non-syndromal conotruncal defects are consistent with multifactorial determination. While it is prudent in counseling families with 2 or more individuals with conotruncal CHD to raise the possibility of single gene inheritance, we believe that current empiric recurrence risk estimates most accurately reflect their risks.

Abnormalities, Multiple↗

PubMed1981

Structured exploratory data analysis (SEDA) for determining mode of inheritance of quantitative traits. I. Simulation studies on the effect of background distributions.

We examine through simulations the effectiveness of a new methodology to help distinguish among monogenic, multifactorial, and sporadic trait transmission from parents to offspring in nuclear family data sets. The major gene index (MGI), which compares the deviation of the offspring from the midparental value with a function of the individual deviations between parents and offspring, aids in the discrimination of multifactorial from sporadic and monogenic models. In contrast with other methodologies, the ability of the MGI to separate multifactorial, monogenic, and sporadic models improves with increased skewness in the trait distribution. The midparental correlation coefficient serves as a further guide for indicating mode of inheritance. A new class of techniques, the offspring between parents function (OBP), is introduced that provides a more sensitive tool to help in assessing mode of transmission through the analysis of the level, shape, and undulation characteristics of the curves. Four data examples are used to illustrate the methodology: erythrocyte catechol-O-methyltransferase (COMT) activity, height, weight, and triglyceride measurements. Height appears largely multifactorial, and weight appears to be mostly sporadic, while COMT and triglyceride measurements suggest the presence of some major gene influences.

Genetics↗

PubMed2003

Sexual dysfunction and sudden death in epileptic male EL mice: inheritance and prevention with the ketogenic diet.

PURPOSE: The EL mouse is an animal model for multifactorial idiopathic epilepsy. Although EL mice have been studied extensively for >45 years, the etiology of male sudden death and its relation to seizures have not been defined. Here we investigated the cause of EL male sudden death and its relation to epilepsy. METHODS: For histopathologic analysis, the terminally ill EL mice (n = 15) were killed, and the tissues were fixed. Blood chemical composition was compared between the terminally ill EL (n = 9) and the healthy age-matched EL (n = 17) and DDY (n = 11) males. To determine the effect of the ketogenic diet (KD) on sudden male death, young male EL mice (P30) were randomly separated into two groups that were fed ad libitum with either Agway lab chow (control n = 38) or with the KD (treated, n = 39) for 5 months. The genetic predisposition to sudden death was analyzed in the backcross generation (n = 106) of a cross between EL and the nonepileptic ABP strains. RESULTS: Sudden death coincided with the onset of seizures (70-80 days) and affected 94% of male EL mice by age 300 days. Urethral plugs were observed histologically in 13 of 15 longitudinally sectioned penises. Concentrations of blood urea nitrogen, creatinine, phosphorus, and calcium in the terminally ill mice were significantly elevated when compared with those of healthy animals. None of the mice treated with the KD experienced sudden death, whereas 15 (39%) of the untreated control mice died by age 5 months. The sudden death in male EL mice was inherited as an autosomal recessive sex-limited lethal trait. CONCLUSIONS: The cause of sudden death in male EL mice arises from abnormal ejaculation, which produces a urethral plug with consequent urinary retention and acute severe uremia. The coincident onset of seizures and sudden death in EL males suggests that a sexual dysfunction is associated with epilepsy in this model.

Animals↗

PubMed1988

Relationship between Mayer-Rokitansky-Küster (MRK) anomaly and hereditary renal adysplasia (HRA).

We report the results of a study performed in a sample of women with the Mayer-Rokitansky-Küster (MRK) anomaly and in their first-degree relatives. Our results are compatible with a traditional model of multifactorial determination; however, we cannot exclude the hypothesis of autosomal dominant inheritance, with an intermediate degree of penetrance and a highly variable expressivity of a single mutant gene. In this sense, our data seem to support the idea expressed recently by Opitz [1987].

Abnormalities, Multiple↗

PubMed1979

Heredity in congenital esotropia.

As an approach to the problem of familial tendency for congenital esotropia, four families were selected because of proband (index case) who had congenital esotropia. Available family members were evaluated for strabismus and other anomalies of vision. Several possible risk factors were evaluated and the presence of high accommodative convergence-to-accommodation ratio was remarkable. Increased prevalence of congenital esotropia was found among family members as compared to the general population, but with no consistent pattern of Mendelian (single gene) inheritance. These findings are consistent with but not proof of a multifactorial (polygenic and environmental interaction) model. The implication for practicing optometrists is that families with one member affected with congenital esotropia represent a group with increased risk for recurrence.

Accommodation, Ocular↗

PubMed1978

Blount disease. A review of etiological factors in 110 patients.

The infantile form of Blount disease is common in the African Negro population of South Africa, although it is very rare in other groups in this country. A series of 110 affected children, investigated in an attempt to elucidate the pathogenesis of this condition, demonstrates an approximately equal sex incidence while geographic distribution is patchy. Bowing of the legs, which is symmetrical in 82% is usually the presenting feature and develops at the onset of ambulation. There is no preceding illness, either local or systemic, and no dietary inadequacy. The children do not differ from their peers in age of walking, weight or range of joint movements. There are no biochemical or hematological abnormalities and no radiographic evidence of involvement of joints other than the knees. Twenty-two of the patients had never been carried in the traditional "pick-a-back" position and it is therefore unlikely that this posture is a significant causative factor. The children had a total of 231 siblings, of whom 10 had bowlegs, while 16 parents had been similarly affected during their own infancy. On this basis, Mendelian dominant or recessive inheritance is unlikely although it is possible that Blount disease is multifactorial in etiology.

Africa↗

PubMed1993

[Genetic disorders in the pediatric population in Orava].

The study is focused on genetic characterization of the child population of the Orava region, where genetic isolates persisted as long as the middle of this century. Active screening for genetic pathology over a period of 5 years involved examination of 1058 children aged 0-14 years. Genetically determined pathological conditions were diagnosed in 757 children, which represents 1.67% of the child population of this region. Chromosomal aberrations were established in 55 children (0.12%), monogenic diseases in 193 children (0.43%), of these autosomal recessive conditions in 88 children (0.19%), and multifactorially determined conditions in 478 children (1.06%). Focal occurrence of an inherited disease was not recorded. Genetic load of the population studied was found to be comparable to that in panmictic populations. The occurrence of diseases inherited as autosomal recessive traits suggests that the influence of genetic isolates does no longer persist in Orava.

Adolescent↗

PubMed1992

Calcium-entry blockers-induced parkinsonism: possible role of inherited susceptibility.

The risk of developing drug-induced parkinsonism (DIP) has been related to a number of factors but it remains up to now poorly defined. The aim of this survey has been to evaluate retrospectively the possible role of inherited components in 25 patients with parkinsonism induced by chronic exposure to the calcium-entry blockers cinnarizine and flunarizine. The finding of higher occurrence of a positive family history for Parkinson's disease (PD) and/or essential tremor (ET) and of higher frequency of secondary cases with PD and/or ET among close relatives of the patients as compared to age-matched controls, suggests the involvement of genetic susceptibility in developing this drug-induced disorder. DIP could be regarded as a multifactorial disease process resulting from potential neurotoxicity of drugs on a background of inherited predisposition.

Aged↗

PubMed1998

Higher risk for renal failure in first-degree relatives of white patients with end-stage renal disease: a population-based study.

To explore the possibility that hereditary factors increase the risk for end-stage renal disease (ESRD), 669 patients with ESRD in the province of Newfoundland, Canada from 1987 to 1993 were studied. Detailed family histories were obtained from 584 (87%) consecutive probands and 499 spousal control subjects. Diseases with a Mendelian pattern of inheritance accounted for 8.4% of the cases; 4.5% of the cases were caused by autosomal dominant polycystic kidney disease (ADPKD). Glomerulonephritis was the original cause of renal failure in 25% of the probands, diabetes mellitus (DM) in 20%, unknown in 14%, interstitial kidney disease in 11%, other disease in 12%, multifactorial in 4%, and hypertension in 5%. In the group without a Mendelian pattern of inheritance, 28% of the probands had a first-, second-, or third-degree relative with renal failure associated with death or dialysis versus 15% of the controls. Compared with 0.4% of the control group, 1.2% of the first-degree relatives of probands developed renal failure (odds ratio [OR]=3.0; 95% confidence interval [CI], 1.7 to 5.2). No difference was observed when risks were compared for second-degree relatives, but a highly significant increased risk was observed for third-degree relatives (OR=2.1; 95% CI, 1.2 to 3.4). The highest rates of affected first-degree relatives occurred in probands with hypertensive renal failure (2.3%), DM (1.6%), and interstitial kidney disease (1.6%). The annual provincial incidence of ESRD, registered with the Canadian Organ Replacement Registry (CORR) from 1981 to 1993 was 79 per million, excluding the 8% of patients with Mendelian inherited disease. The similar rate of ESRD in first-degree relatives of probands without Mendelian inherited disease was 297 per million. We conclude that not only is the contribution of Mendelian inherited diseases to ESRD high, but there is also an increased risk for renal failure in first-degree relatives of probands without a Mendelian inherited renal disease in a white population.

Case-Control Studies↗

PubMed1998

The inheritance of alcoholic liver disease.

Available evidence supports the concept that alcoholic liver disease (ALD) is a multifactorial disease with a heritable component. A number of polymorphic genes with small and additive effects will thus encode susceptibilty to this 'polygenic' disease. Molecular genetic studies of ALD are in their infancy, and methods available for the genetic dissection of complex traits are discussed. Some candidate genes have been identified, and studies have been undertaken to test for association between specific alleles and ALD susceptibility. There is evidence to support a role for alleles of two genes encoding enzymes involved in the oxidative metabolism of alcohol (acetaldehyde dehydrogenase2*2 and cytochrome P4502E1 c2 allele) in susceptibility to ALD. More recently, attention has focused on cytokines, and there are now data showing association of specific alleles of both tumour necrosis factor alpha and interleukin-10 with predisposition to ALD. These candidate genes need to be subjected to rigorous evaluation in different populations. Such research should help to define more precisely the molecular mechanisms underlying the development of ALD in a sub-population (< 20%) of alcoholics, thereby improving the hepatologist's ability to develop rational treatments.

Animals↗

PubMed1999

Diastematomyelia in two sisters.

Diastematomyelia is a rare spinal cord anomaly that usually occurs in a non-syndromal, sporadic manner; however, few familial cases have been reported. We report on diastematomyelia in 2 sisters with variable expressivity. The spinal column is divided by osseous or fibrous tissue. This may be responsible for the variable expressivity. Most cases previously reported were females. This suggests X-linked dominant inheritance with lethality in hemizygous males or female sex limitation of a multifactorial trait.

Adult↗

PubMed2003

Genetics of endometriosis.

Endometriosis long has been recognized as showing heritable tendencies, with recurrence risks of 5% to 7% for first-degree relatives. The risk indicates that polygenic and multifactorial etiology is far more likely to be the cause than mendelian inheritance. The current task is to determine the number and location of genes responsible for endometriosis. Molecular advances of the past decade make identification and elucidation of these genes a reality. The authors review the basis for concluding that endometriosis is a genetic disorder of polygenic/multifactorial inheritance. Genome-wide strategies for identifying causative genes are considered and available data on association or linkage to putative candidate genes systematically reviewed.

Endometriosis↗