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Results for “Multifactorial Inheritance”

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PubMed2001

Disposition of sperm donors with resultant abnormal pregnancies.

We wished to determine how clinicians manage sperm donors whose offspring have chromosomal or structural abnormalities. A directed, multiple-choice survey was given to reproductive endocrinologists and obstetrical geneticists to assess management of sperm donors whose offspring have chromosomal or structural abnormalities. The questionnaire was completed by 66 reproductive endocrinologists and obstetrical geneticists. Abnormalities and the most common inheritance modes included: Trisomy 21 (aneuploidy, maternal origin), Turner syndrome (aneuploidy, paternal origin), cleft lip/palate (multifactorial), VATER sequence (vertebral defects, imperforate anus, tracheo-esophageal fistula, radial and renal dysplasia, sporadic inheritance), and Hurler syndrome (autosomal recessive). Response choices were: (i) remove donor from programme, (ii) inform potential recipients of prior pregnancy outcomes and continue to use donor, or (iii) further study donor to assess karyotype/mutations. Inheritance mode appeared to influence decisions to remove donors from sperm banks; however, no clear consensus was noted. Guidelines exist for screening potential gamete donors, but not for managing donors whose offspring has a chromosomal or structural abnormality. Guidelines must be developed to manage sperm donors with untoward pregnancy outcomes.

Chromosome Aberrations↗

PubMed1993

A single major-gene defect underlying cardiac conotruncal malformations interferes with myocardial growth during embryonic development: studies in the CTD line of keeshond dogs.

The common forms of isolated congenital heart disease are usually not inherited in a Mendelian pattern, and most are considered multifactorial threshold traits. A large subset consisting of a group of malformations of the ventricular outflow region, termed "conotruncal defects" (CTDs), include subarterial ventricular septal defects, tetralogy of Fallot, and persistent truncus arteriosus. Similar aggregations of CTDs have been reported in human families and in the keeshond breed of dog. The results of our early breeding experiments utilizing noninbred keeshonds were not consistent with any hypothesis of a fully penetrant monogenic inheritance. Here we report a recent series of genetic and embryologic studies conducted after more than 10 generations of selective inbred matings between affected-CTD-line dogs. The results are now consistent with a defect at a single autosomal locus, the Mendelian pattern of transmission having been obscured prior to selective inbreeding by genetic background. On the basis of morphometric embryologic studies, the mutant CTD allele causes conotruncal malformations in homozygous animals by interfering with myocardial growth in the conotruncus during the critical window when the conotruncal cushions fuse to form the conotruncal septum.

Animals↗

PubMed1985

Hypopituitarism and septooptic "dysplasia" in first cousins.

Although familial forms of hypopituitarism are known, to our knowledge familial septooptic "dysplasia" in association with hypopituitarism has not been reported. We describe two first cousins with panhypopituitarism, one of whom had septooptic dysplasia. We discuss the possibility that septooptic dysplasia-hypopituitarism may be inherited as an autosomal dominant, or recessive, or multifactorial trait.

Adult↗

PubMed2006

Genes and the environment in neurodegeneration.

Neurodegenerative diseases are a heterogeneous group of pathologies which includes complex multifactorial diseases, monogenic disorders and disorders for which inherited, sporadic and transmissible forms are known. Factors associated with predisposition and vulnerability to neurodegenerative disorders may be described usefully within the context of gene-environment interplay. There are many identified genetic determinants for neurodegeneration, and it is possible to duplicate many elements of recognized human neurodegenerative disorders in animal models of the disease. However, there are similarly several identifiable environmental influences on outcomes of the genetic defects; and the course of a progressive neurodegenerative disorder can be greatly modified by environmental elements. In this review we highlight some of the major neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, and prion diseases.) and discuss possible links of gene-environment interplay including, where implicated, mitochondrial genes.

Alzheimer Disease↗

PubMed1999

The genetics of smoking initiation and quantity smoked in Dutch adolescent and young adult twins.

Not much is known about the genetic and environmental determinants of various aspects of substance use in adolescents. This study examined whether the inheritance of initiation of tobacco use in adolescents is independent of the inheritance of the number of cigarettes smoked. Alternative multifactorial threshold models were applied to data on tobacco use in 1676 Dutch adolescent twin pairs. The three models that were considered are (i) the single liability dimension model, (ii) the independent liability dimension model, and (iii) the combined model (CM). The results showed that there is not one underlying continuum of liability to smoking. The CM was the best-fitting model. This model postulates that there are separate initiation and quantity dimensions but allows for the possibility that there are some individuals who are so low on the liability to level of consumption that they are not using tobacco. There were no differences between males and females in the magnitude of the genetic and environmental influences on individual differences in smoking initiation and quantity smoked. Smoking initiation was influenced by genetic factors (39%) and shared environmental influences (54%). Once smoking is initiated genetic factors determine to a large extent (86%) the quantity that is smoked.

Adolescent↗

PubMed2001

Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2.

Isolated strabismus affects 1-5% of the general population. Most forms of strabismus are multifactorial in origin; although there is probably an inherited component, the genetics of these disorders remain unclear. The congenital fibrosis syndromes (CFS) represent a subset of monogenic isolated strabismic disorders that are characterized by restrictive ophthalmoplegia, and include congenital fibrosis of the extraocular muscles (CFEOM) and Duane syndrome (DURS). Neuropathologic studies indicate that these disorders may result from the maldevelopment of the oculomotor (nIII), trochlear (nIV) and abducens (nVI) cranial nerve nuclei. To date, five CFS loci have been mapped (FEOM1, FEOM2, FEOM3, DURS1 and DURS2), but no genes have been identified. Here, we report three mutations in ARIX (also known as PHOX2A) in four CFEOM2 pedigrees. ARIX encodes a homeodomain transcription factor protein previously shown to be required for nIII/nIV development in mouse and zebrafish. Two of the mutations are predicted to disrupt splicing, whereas the third alters an amino acid within the conserved brachyury-like domain. These findings confirm the hypothesis that CFEOM2 results from the abnormal development of nIII/nIV (ref. 7) and emphasize a critical role for ARIX in the development of these midbrain motor nuclei.

Amino Acid Sequence↗

PubMed1996

Survey of CAG/CTG repeats in human cDNAs representing new genes: candidates for inherited neurological disorders.

Expansion of polymorphic CAG and CTG repeats in transcripts is the cause of six inherited neurodegenerative or neuromuscular diseases and may be involved in several other genetic disorders of the central nervous system. To identify new candidate genes, we have undertaken a large-scale screening project for CAG and CTG repeats in human reference cDNAs. We screened 100 128 brain cDNAs by hybridization. We also scanned GenBank expressed sequence tags for the presence of long CAG/CTG repeats in the extremities of cDNAs from several human tissues. Of the selected clones, 286 were found to represent new genes, and 72 have thus far been shown to contain CAG/CTG repeats. Our data indicate that CAG/CTG repeated 10 or more times are more likely to be polymorphic, and that new 3'-directed cDNAs with such repeats are very rare (1/2862). Nine new cDNAs containing polymorphic (observed heterozygote frequency: 0.05-0.90) CAG/CTG repeats have been currently identified in cDNAs. All of the cDNAs have been assigned to chromosomes, and six of them could be mapped with YACs to 1q32-q41, 3p14, 4q28, 3p21 and 12q13.3, 13q13.1-q13.2, and 19q13.43. Three of these clones are highly polymorphic and represent the most likely candidate genes for inherited neurodegenerative diseases and, perhaps, neuropsychiatric disorders of multifactorial origin.

Brain↗

PubMed1994

Etiological subgroups in non-syndromic isolated cleft palate. A genetic-epidemiological study of 52 Danish birth cohorts.

Isolated cleft palate (CP) is considered to be a heterogeneous trait with an important genetic contribution to the etiology. Multifactorial-threshold models of non-syndromic CP inheritance assume a female predominance. The present study of 52 Danish birth cohorts, using several ascertainment sources, identified 2301 CP cases. It was found that, although females tended to be more severely affected than males, the overall sex ratio was close to one. For the latter half of the study period (1962-87), which probably had the best ascertainment, the sex ratio for non-syndromic CP was 0.95 (95% C.I. 0.85-1.07). Marked difference in sex ratios for non-syndromic overt CP including the hard palate (CPH) and non-syndromic overt CP of the soft palate only (CPS) (0.69 vs 1.00, p < 1.00, p < 0.05) suggested that these two conditions may be etiologically distinct, a hypothesis which is embryologically plausible. In agreement with this hypothesis, Danish family data from surgically treated CP cases showed a strong tendency to segregate only one of the CP subtypes within families. Future studies are recommended to test the existence of a possible etiological difference between CPH and CPS.

Child↗

PubMed1992

Hereditary Lewy-body parkinsonism and evidence for a genetic etiology of Parkinson's disease.

The first systematic genetic study of Parkinson's disease (PD) was carried out by Mjönes in 1949. His results indicated autosomal dominant transmission with 60% penetrance. These conclusions, however, were long discounted because oligosymptomatic and atypical relatives were counted as secondary cases without clear justification. Subsequent surveys of patient and twin studies failed to confirm evidence of familial concentration and the hypothesis of a genetic etiology was over-shadowed by interest in possible environmental neurotoxins. A growing accumulation of pedigrees of histologically confirmed Lewy-body PD over the past several years has refocused attention on genetic factors. Fluorodopa positron emission tomography (PET) studies in oligosymptomatic co-twins of probands and recent clinicopathologic studies of atypical cases have provided retrospective support for Mjönes' methodology. A survey of a personal series of PD patients showed that the majority of those for whom pedigree information was available were familial. This along with another recently reported series confirm Mjönes' data showing similar segregation ratios for siblings and parents, a low ratio of maternal:paternal transmission and a marked asymmetry in the distribution of ancestral secondary cases. These findings favor monogenic autosomal dominant inheritance and show reason to argue against a multifactorial etiology or heteroplasmy. The clinical evidence justifies searching for gene loci linked to PD. Available methods are briefly outlined. Preliminary investigations have examined possible allelic associations, e.g., with alleles of MAO-A and debrisoquine hydroxylase and linkage to the tyrosine hydroxylase gene on chromosome 11p15.5 has been excluded in one study of juvenile familial parkinsonism. Linkage mapping studies are presently underway.

Brain↗

PubMed1979

Genetic analysis of multiple sclerosis in Orkney.

In a family study of all patients with multiple sclerosis (MS) in Orkney, the number of inbred among patients, although high for Britain, is not higher than the number among controls, and the inbreeding coefficients appear to eliminate recessive involvement of rare genes from the aetiology. The kinship coefficients show that the ancestries of patients and controls are closely enmeshed, and eliminate from the aetiology involvement of recently introduced genes dominant or codominant in effect. Family histories show that single locus inheritance is unlikely unless penetrance is very low. Multifactorial genetic involvement is much more likely, and it is compatible with all recent findings; on this hypothesis heritability estimates, not altogether satisfactory because of the limited number of patients in the population, suggest that the genetic contribution to the aetiology of the disease in Orkney is only moderate.

Consanguinity↗

PubMed1998

[Presbycusis].

Presbycousis represents a poorly defined clinical entity despite a number of investigations that have been carried out. After a careful review of present knowledge, the authors state that this clinical entity may be regarded as a multifactorial syndrome, due to extrinsic as well as inherited noxious factors.

Age Factors↗

PubMed1995

[Familial bladder cancer].

Despite little evidence for a hereditary cause of most cases of bladder cancer, two different patterns of genetic involvement have been suggested: an autosomal dominant pattern that accounts for a very small number of cases and a multifactorial, polygenic pattern involving genetic and environmental interaction. Inherited homozygous defect of the glutathione S-transferase M1 gene is a good example of the latter pattern. Molecular genetic analysis has revealed two distinct molecular pathways to bladder tumorigenesis. Papillary noninvasive tumors as well as invasive disease harbor the chromosome 9 allelic loss, while carcinoma in situ contains a p53 gene mutation without an alteration of chromosome 9. The p53 gene mutations are closely associated with high grade, high stage urothelial cancers and immunohistochemical detection of the p53 protein alterations may be promising prognostic marker. Analysis of the p53 gene mutation pattern suggested a monoclonal origin for multicentric occurrence of urothelial cancers.

Family Health↗

PubMed1976

On the formation of rho- petites in yeast. I. Multifactorial mitochondrial crosses (rho+ X rho+) involving a mutation conferring temperature-sensitivity of rho factor stability.

The inheritance of an extrakaryotic mutation conferring temperature-sensitive growth on non-fermentable substrates and a high frequency of mutation to rho- has been studied. Multifactorial crosses (rho+ X rho+) involving this mutation TS8 and mitochondrial mutations conferring resistance to chloramphenicol, erythromycin, oligomycin or paromomycin revealed: a) Mutation TS8 is localized on the mitDNA, referring to a new gene locus TSM1. b) Locus TSM1 appears to be weakly linked to the locus PAR1 and to the loci RIB1 and RIB3 but unlinked to the locus OLI1. c) The position of TSM1 is between PAR1 and the two closely linked loci RIB1 and RIB3, OLI1 is outside and not linked to the segment PAR-TSM-RIB. d) Mutation TS8 does not significantly influence the process of mitochondrial recombination and its control by the mitochondrial locus omega.

Chromosome Mapping↗

PubMed2004

The pathogenesis of Machado Joseph Disease: a high manganese/low magnesium initiated CAG expansion mutation in susceptible genotypes?

The origin of the progressive spinocerebellar ataxic disorder 'Machado Joseph Disease (MJD)' has been attributed solely to an expansion mutation resulting from an autosomal dominant inheritance of an unstable CAG repeat in chromosome 14q32.1 of the MJD gene that encodes for the synthesis of ataxin 3. The faulty gene has purportedly been disseminated since the Middle Ages into Azorean, Dutch and Makassan communities by an international trading community based in NE-central Portugal. However, following improvements in MJD surveillance, the MJD afflicted families that have been identified in increasing numbers of familial clusters of MJD being discovered around the world--e.g. in Aboriginal, Yemenite, Asian and Japanese populations--cannot be connected back to the original Portuguese founder families, but rather implicates an environmental factor, superimposed on a genetic flaw. An analytical study of the isolated ecosystems supporting both the Portuguese and non-Portuguese MJD affected communities demonstrates a common abnormal hallmark of high manganese (Mn)/low magnesium (Mg) status, suggesting that this aberrant mineral ratio inactivates the Mn/Mg catalyzed endonuclease 1 enzyme in the biosystems of those who are dependent upon these ecosystems. Endonuclease activity is crucial for protecting against the expansion/contraction of the trinucleotide repeats in the genes that encode for proteins such as Ataxin 3--the 'mutant' chaperone protein that hallmarks the central nervous system (CNS) of MJD sufferers. It is proposed that MJD, and possibly the other more common expansion mutation diseases such as Friedrich's Ataxia and Huntingdon's Chorea, are multifactorial diseases caused by a hitherto unrecognised autosomal dominant inherited failure to regulate Mn/Mg metabolism in populations living in high Mn/low Mg ecosystems. Mg supplementation of the 'at risk' populations during the 'in utero' developmental stages could be all that is required to maintain healthy endonuclease turnover, thereby protecting MJD susceptible genotypes against this fatal, progressive neurodegenerative disease.

Endonucleases↗

PubMed1999

CD4 and CD8 T lymphocyte inheritance. Evidence for major autosomal recessive genes.

The CD4/CD8 ratio has long been used for the follow-up and monitor of many infectious diseases. Following the demonstration in 1983 that the CD4/CD8 ratio in the mouse is under genetic control, it was subsequently shown to be controlled by a major locus in man. To define the mode of inheritance of the CD4/CD8 ratio, we addressed the absolute number of CD4 and CD8 cells in a large unselected control sample and in members of 70 nuclear families. Pedigrees of nuclear families were analyzed by complex segregation analysis. Data was adjusted prior to this analysis to remove the effects of relevant covariates. The non-genetic-transmission and the multifactorial model could be easily rejected for both CD4 and CD8 cells. Among the different inheritance models, involving both a major gene and a multifactorial (MFT) component, a major autosomal recessive gene with a residual MFT effect controlling the high number of CD4 and a major autosomal recessive gene with a residual MFT effect controlling the high number of CD8 cells were the significantly best-fitting ones. Our findings have some practical implications. Among all, the knowledge of the CD4+ cell number and the proportion between CD4+ and CD8+ T cells could be a useful parameter in predicting human immunodeficiency virus infection outcome.

Adolescent↗

PubMed2004

Hypospadias in the neonate.

Hypospadias is a common developmental disorder of the urogenital tract, occurring in approximately 1 in 125 live male births. Defined as an atypical urethral opening anywhere along the shaft of the penis, scrotum, or perineum, hypospadias is often associated with a deficient prepuce and chordee. Hypospadias usually occurs as an isolated defect, but can be part of a recognized syndrome or associated with other genital anomalies. The etiology of nonsyndromic hypospadias is unknown, and is believed to be multifactorial. Recent studies have implicated factors such as familial inheritance, low birth weight, assisted reproductive technology, advanced maternal age, paternal subfertility, and endocrine-disrupting chemicals in the pathogenesis of hypospadias. Infants with hypospadias should not undergo circumcision. Currently, most infants with hypospadias undergo surgical reconstruction between 4 and 8 months of age. Parents of a newborn with hypospadias may be anxious and have many questions about their infant's condition. They should be given the opportunity to speak to a pediatric urologist as early as possible. This article provides a guide to the embryologic origins of hypospadias and a photographic atlas to aid bedside clinicians in identifying the spectrum of hypospadias in the newborn.

Female↗

PubMed2006

Schizophrenia susceptibility genes: emergence of positional candidates and future directions.

Schizophrenia is a devastating psychiatric disorder that affects approximately 1% of the population worldwide. It is characterized by so-called 'positive symptoms'--including delusions and hallucinations--'negative symptoms'--including blunted emotions and social isolation--and cognitive deficits--including impairments in attention and working memory. Studies of the inheritance of schizophrenia have revealed that it is a multifactorial disease that is characterized by multiple genetic susceptibility elements, each contributing a modest degree of risk. Linkage studies have identified several potential schizophrenia susceptibility loci, and in recent years major progress has been made in the identification of positional candidate susceptibility genes from these loci. A central goal of future research will be to use this genetic knowledge to generate specific animal models, characterize genetic interactions, investigate the disease pathophysiology and assist drug-discovery efforts.

Animals↗

PubMed2002

[Possibilities and limitations of genetic research; an advisory report from the Advisory Council on Health Research].

The Raad voor Gezondheidsonderzoek [Advisory Council on Health Research] has issued a report entitled 'New applications of genetic information in health care: which knowledge is needed?' The report is limited to areas where research is likely to have consequences within the relatively short time-span of a few years. These include genetics in diagnostics and screening, pharmacogenetics, and certain inherited diseases in adult age. Complex diseases such as multifactorial ones are not addressed. The report provides a useful overview of the prospects and problems in genetic research and how it will be applied in the years to come. Societal consequences of genetic research are also discussed. To enhance the understanding of complex diseases, epidemiological studies with long-term follow-up that combine genetic data with other data are essential. At the same time, potential privacy risks should be acknowledged and scientists should take extreme care in collecting, handling and analysing such data. The Netherlands Federation of Societies for Medical Research has produced guidelines which researchers should follow when carrying out their research.

Ethics, Medical↗