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PubMed1997

Genetic predictors of common disease: apolipoprotein E genotype as a paradigm.

PURPOSE: Genetic variation of a common genetic polymorphism at the structural locus for apolipoprotein E (apoE) has been associated with risk of elevated serum lipids, coronary artery disease, and Alzheimer disease, all of which are multifactoral disorders and are inherited in a complex fashion. Although the apoE polymorphism is only one risk factor in a complex pattern of inheritance, it gives us a foothold into the understanding of the genetic architecture of these disorders. However, apoE also exemplifies the complications that can arise in the use of genetic markers to predict disease. This paper considers the study of apolipoprotein E genotype effects as an example of the following analytical complications: changes in allele frequencies and allele effects with age, pleiotrophic effects of genetic loci, the existence of more than one alternative allele at a locus, and the expectation of a variety of interactions. METHODS: Publications that exemplify these complications are cited and discussed. No original analyses are presented. RESULTS: There is evidence that the relative frequency of the apoE epsilon4 allele declines with age after the sixth decade of life and that the effects of the APOE allele on lipids also may be age-dependent. Grouping of genotypes may not accurately characterize the effects of individual genotypes. Interactions between APOE genotype and a number of factors, including family history of dementia, are demonstrated for the effects of APOE in Alzheimer disease as well as for the effects of apoE on serum lipids. CONCLUSION: Careful attention must be paid to these and other analytical issues when genotype is a predictor.

Alleles↗
PubMed2005

Familial occurrence of the IMAGe association: additional clinical variants and a proposed mode of inheritance.

The IMAGe (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies) association (online inheritance in man 300290) is a recently reported disorder comprising intrauterine growth retardation (IUGR), metaphyseal dysplasia, adrenal hypoplasia, and genital anomalies. Four children (three males, one female) from a large pedigree (five generations) were studied. Additional members (n = 10), who died during the neonatal period, were born with IUGR and/or hyperpigmentation and are presumed to have been affected, too. All patients in this series were diagnosed during the newborn period. Minimal clinical features and laboratory findings differ with previously reported patients, suggesting variants in their clinical expression. Adrenal insufficiency was variable within patients. All had severe IUGR and marked postnatal growth failure. Sequence analysis of DNA using an automated cycle from two patients revealed no mutation in the dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1. Analysis of the pedigree showed that the disease is inherited via the maternal line, even in the dead children with suspicion of the disease. Hence, the pattern of inheritance in this family of this unusual disorder might be explained in terms of the genomic imprinting hypothesis with expression through maternal transmission involving an autosomal gene. This transmission may have considerable implications for genetic counseling. Furthermore, pediatric endocrinologists must be aware of the possible occurrence of this life-threatening condition in the offspring of nonaffected women when related to a family member with the association of IUGR, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies.

Adrenal Insufficiency↗
PubMed1999

Inheritance of the barred plumage pattern of the Silver Campine Fowl, together with its relationship to other patterned fowl.

1. An investigation was conducted among the progeny from a cross between a Silver Campine male and a Silver Spangled Hamburgh bantam female into the inheritance of the autosomal transverse barring of the Campine. 2. Both parental breeds possess the marble chickdown phenotype which has been shown to depend upon homozygosity of 3 genes; the birchen allele E*R at the E-locus, the eumelanin restrictor DB*B and the feather pattern arranging gene PG*P whilst the spangled feather pattern of the Silver Spangled Hamburgh has been attributed to homozygosity of E*R, DB*B, ML*M and PG*P, where ML*M is the eumelanin extension melanotic. 3. Examination in F1 and F2 generations of both chickdowns and adult plumage demonstrate that of the 4 loci, segregation occurs only for ML*M and hence the genotype of the Silver Campine to be homozygous E*R, DB*B, ML*N and PG*P. 4. The relationships between the genotypes of the Campine and those of other breeds with autosomal transversely barred plumage and between the Campine and those of other patterned fowl based on the E*R allele are discussed and presented in tabular form. In addition patterned fowl based on alleles other than E*R at the E-locus are included in order to demonstrate the effect of substituting E*R.

Alleles↗
PubMed1978

Dominant inheritance of Scheuermann's juvenile kyphosis.

Familial occurrence of Scheuermann's juvenile kyphosis is well known, but no specific mode of inheritance has been recognized. We describe five families in which the disease seems to follow and autosomal dominant pattern of inheritance.

Adolescent↗
PubMed1997

Reticulate hyperpigmentation.

Disorders that are characterized by a reticulate pattern of pigmentation are reviewed. Dyskeratosis congenita (DKC) is the prototype of these. In addition to reticulate hyperpigmentation, mucosal leukoplakia, bone marrow dysfunction, cytogenetic instability, and a predisposition to malignancy are characteristic of DKC. The most common pattern of inheritance is X-linked, with heterozygous females showing variable expression, most likely depending on tissue-specific patterns of random X-inactivation. Other reticulate pigmentary disorders reviewed include the Naegeli-Franceschetti-Jadassohn syndrome, X-linked reticulate pigmentary disorder, dermatopathia pigmentosa reticularis, Dowling-Degos disease, dyschromatosis, confluent and reticulated papillomatosis of Gougerot and Carteaud, reticulate acropigmentation of Kitamura, and Revescz syndrome. Diagnosis, treatment, and sometimes genetic counseling remain problematic for these entities. The pathophysiology of these disorders is unknown, but will certainly be aided greatly by the future identification of the underlying genes.

Bone Marrow Diseases↗
PubMed1993

The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B.

Plasma low density lipoproteins (LDL) comprise multiple discrete subclasses, differing in size, density, and chemical composition. Gradient gel electrophoresis of LDL has demonstrated three common subclass patterns based on the predominant LDL subclass: large LDL, designated subclass pattern A; small LDL particles, designated subclass pattern B; and an intermediate pattern. Genetic studies have demonstrated that these patterns are inherited, but several lines of evidence suggest that environmental factors are important in the phenotypic expression of the pattern. The LDL B pattern is associated with increased levels of plasma triglyceride, reduced high density lipoprotein (HDL), and obesity. To better define the role of environmental factors on LDL phenotypic expression, we determined LDL patterns in patients with the acquired immunodeficiency syndrome (AIDS), an infection characterized by hypertriglyceridemia and weight loss. Similar to previous studies, plasma triglyceride levels were increased, whereas plasma cholesterol, LDL cholesterol, and HDL cholesterol levels were decreased in the AIDS subjects compared to those in age-matched controls. The percentage of AIDS subjects with the LDL B phenotype was increased 2.5-fold, demonstrating an increased prevalence of the LDL B phenotype in an acquired form of hypertriglyceridemia. For each LDL phenotype in AIDS, serum triglyceride levels were higher than the same phenotypic pattern in controls, with the most marked elevations in triglycerides found in AIDS subjects with the LDL B phenotype. In contrast to what was observed in controls, HDL cholesterol levels were decreased in all AIDS subjects and were unrelated to LDL pattern. Total and LDL cholesterol levels were higher in controls with the LDL B phenotype than in those with the LDL A phenotype, but there was no difference in total and LDL cholesterol in AIDS subjects with LDL B compared to A. On multiple regression analysis in subjects with AIDS, plasma triglyceride levels, age, and HDL cholesterol all contribute to the occurrence of the LDL B phenotype, but elevations in plasma triglyceride levels are the strongest independent predictor. Body mass index was not a predictor of LDL B phenotype in AIDS. These results suggest that disturbances in triglyceride metabolism that are caused by AIDS lead to the appearance of the LDL subclass B phenotype and provide further evidence that environmental or disease states that perturb lipid metabolism can produce an increased prevalence of the LDL B phenotype.

Acquired Immunodeficiency Syndrome↗
PubMed1969

Congenital dysprothrombinemia: an inherited structural disorder of human prothrombin.

A large family has been studied, 11 of whose members have half-normal plasma concentrations of biological prothrombin activity. The pattern of inheritance is autosomal. By use of a specific immunoassay, affected family members have been shown to possess normal quantities of immunoreactive prothrombin, whose immunologic properties seem identical with those of the normal zymogen. Prothrombin isolation from the plasma of one such individual gave normal yields of protein but half-normal amounts of prothrombin activity. Activation of this material in the "intrinsic" and "extrinsic" systems, in concentrated sodium citrate, or by trypsin, gives rise to half, or less, of the thrombin clotting and esterase activities expected from a comparable normal prothrombin preparation. During the clotting of blood from an affected individual, all material with the mobility of prothrombin disappears. Immunoelectrophoresis of the serum reveals a normal nonthrombin "pro piece," and an additional activation product with an electrophoretic mobility intermediate between that of prothrombin and of "pro piece." These results suggest that affected individuals are heterozygotes in whom half the prothrombin molecules synthesized are structurally abnormal, since they undergo some alterations during activation, but are incapable of releasing the active enzyme, thrombin.

Adolescent↗
PubMed2005

The problems with risk selection; scientific and psychosocial aspects.

Between 9,000 and 18,000 new cases of breast cancer per year in the United States are associated with a genetically defined predisposition. Mutations in BRCA1 and 2 account for greater than 60% of inherited breast cancer. Mutations in additional undiscovered high and low penetrance genes may account for the other 40% of inherited breast cancer cases and possibly a subset of familial breast cancer cases that lacks an autosomal-dominant pattern of inheritance. False-negative rates resulting from gene sequencing of BRCA1 and 2 may be as high as 10%-15%, making the identification of high-risk individuals a complex and often futile process for both patient and physician. As a consequence of technical limitations in BRCA1 and 2, genetic testing and the lack of comprehensive breast cancer prediction models that take into account both genetic and environmental factors, we are unable to quantify future breast cancer risk for many patients. This uncertainty often leads to the exclusion of high-risk individuals in screening and prevention trials, which is perhaps most evident in breast cancer screening trials incorporating the use of magnetic resonance imaging (MRI) to identify early cancers. These studies demonstrate that MRI increases the sensitivity of a screening protocol in mutation carriers and succeeds at detecting earlier stage cancers. Eligibility criterion for most of these trials was documented mutations in BRCA1 and 2 or future breast cancer risk predicted by family history or models, thereby possibly excluding women at significantly elevated risk that testing failed to identify or whose risk is not adequately reflected based on current models used in risk assessment. We may be turning very high-risk women away from screening trials, recommending yearly mammography and clinical breast exam, when neither will be adequate for detecting their cancers early. In addition, the impact of risk-reducing strategies including bilateral prophylactic oophorectomy (BSO) and tamoxifen has not been analyzed in these studies. For example, a 40-year-old BRCA2 carrier may only have a 10% and 50% lifetime risk of ovarian and breast cancer, respectively, and interventions including tamoxifen and breast MRI screening may significantly reduce the risk of both getting breast cancer and dying from it, thereby obviating the need for early screening or prophylactic surgeries, permitting these women to defer the quality of life struggles until they are older. A larger sample size is needed to determine the degree to which different subgroups of high-risk patients will benefit from MRI screening, with particular attention to women who have undergone BSO or who are taking tamoxifen. The challenges in risk selection are numerous and produce more questions than answers with regard to screening and management of high-risk individuals. In the future, we hope that early detection tools, risk-reduction strategies, and risk assessment preclude the need for prophylactic surgeries, inappropriate selection of patients for screening, and the associated decisions that compromise our patients' quality of life.

Breast Neoplasms↗
PubMed1995

Fine mapping of a putatively imprinted gene for familial non-chromaffin paragangliomas to chromosome 11q13.1: evidence for genetic heterogeneity.

Autosomal, dominantly inherited, non-chromaffin paragangliomas are tumors of the head and neck region occurring with a frequency of 1:30,000. Genomic imprinting probably influences the expression of the disorder, because tumor development is limited to individuals who have inherited the trait from their father. By linkage analysis and haplotyping of a single large family in which the pattern of inheritance is consistent with genomic imprinting, we have mapped the gene to a 5 cM region of chromosome 11q13.1 between D11S956 and PYGM. A maximum lod score of 7.62 at theta = 0.0 was obtained for D11S480. This interval does not overlap with a recently assigned locus for glomus tumors in other families: 11q22.3-q23.3. Furthermore, analysis of a second family showing the imprinting phenomenon resulted in the exclusion of the 5 cM area as the location of the disease gene, whereas an indication for linkage was obtained (Z = +2.65) with markers from the distal locus. These observations argue for the presence of two distinct imprinted genes for glomus tumors on 11q. A model for tumor initiation and progression is presented based on all available information.

Adult↗
PubMed1978

The relation of sex, smoking status, birth rank, and parental age to beta2-glycoprotein I levels and phenotypes in a sample of Australian Caucasian adults.

The serum level of beta2-glycoprotein I has been measured in a sample of 532 healthy, unrelated Caucasians resident in Melbourne. The distribution of levels is bimodal but lacks complete separation of the two modes. Samples with levels below 14.0 mg/100 ml are considered to be type I, and those above this level to be type N. The present sample contains 42 subjects of the former phenotype and 490 of the latter. The phenotypes are distributed equally between males and females and between smokers and nonsmokers and are unrelated to age, birth rank, or parental age. The gene frequencies for the Melbourne sample are compared with those found in various European samples. The beta2-glycoprotein I level of type N males is higher than that of females, and smokers have a higher level than nonsmokers. The positive regression of level on age is significant when corrections are made for sex and smoking status. beta2-glycoprotein I level is highly correlated with pseudocholinesterase activity. The pattern of inheritance of phenotypes has been examined in 17 families with a total of 56 children. In all families, this pattern is consistent with the currently accepted mode of autosomal codominant transmission.

Australia↗
PubMed1986

Regulation of IncFII plasmid DNA replication. A quantitative model for control of plasmid NR1 replication in the bacterial cell division cycle.

A quantitative model for the regulation of replication of the low copy number IncFII plasmid NR1 in the Escherichia coli cell division cycle has been developed. The initiation of NR1 replication requires a cis-acting initiator protein whose synthesis is regulated by several mechanisms. The NR1 regulatory processes include co-operative protein-protein interactions in the formation of an active transcription repressor, the interaction of repressor with a rightward operator site in the control of transcription of the initiator gene, and the interaction of an inhibitor RNA transcript with the initiator mRNA in the control of translation of the initiation protein. A statistical thermodynamic model was used to predict probable configurations of the regulatory processes in a single growing cell. These probabilities were coupled by a kinetic model to the events of the cell cycle, such as initiation of mRNA transcription and protein translation, and the initiation of plasmid DNA replication. Parameter values were chosen so that the simulated values for plasmid copy number and the intracellular concentrations of repressor protein and mRNA agreed with experimentally determined estimates. A number of different copy number mutants that have altered one or another of the regulatory processes were simulated by the model. The contributions of each of the regulatory processes toward the overall stability of inheritance of plasmid NR1 in a population of cells in culture were examined. These simulations predict a very stable pattern of inheritance for plasmid NR1 despite its low copy number, in agreement with experimental observation.

Cell Cycle↗
PubMed2001

Alagille syndrome with colonic polyposis.

Alagille syndrome is a rare inherited condition, which typically manifests during the first year of life as an episode of prolonged cholestasis. Although the pattern of inheritance is autosomal dominant with almost complete penetrance, highly variable expression may delay the diagnosis, and with passing time the clinical findings may be more difficult to recognize. This has clinical implications, as patients with Alagille syndrome are at risk for late complications such as hepatocellular carcinoma. We report a case of a 35-yr-old patient with Alagille syndrome who was diagnosed with colonic polyposis raising the possibility of an association between the two.

Adult↗
PubMed2002

Molecular biological and genetic approaches to the evaluation of inherited electrophysiologic disorders.

Although previously thought of as sporadic errors in development, some arrhythmias are now established to have a hereditary basis. The genetic and molecular bases of inherited cardiac arrhythmias are being recognized with increased frequency. Environmental and somatic influences may complicate classical identification of the patterns of inheritance. In several examples of inherited heart disease with a distinct molecular and genetic foundation, multiple gene defects appear to be responsible for similar phenotypes. In addition, specific genotypes may lead to differing severity of phenotype and differential prognostic risks. There is also variability in phenotypic expression, even among identical genotypes within a family, complicating risk stratification. Improved understanding of rare familial arrhythmia disorders may increase our overall comprehension of the pathophysiology of rhythm disturbances in general. The inherited arrhythmia disorders can be classified under three broad headings -- those familial arrhythmias that originate above the ventricles, familial arrhythmias originating within the ventricles and familial disorders affecting impulse propagation and cardiac conduction. Familial occurrences of tachyarrhythmias and bradyarrhythmias have been reported for each of these types of disorders. Recent discoveries of genetic etiologies have shed new light on the mechanisms underlying arrhythmogenesis and molecular genetics of cardiac electrophysiology.

Animals↗
PubMed1980

[Ullrich syndrome: a hypotonic disorder of early infancy, difficult to define as an entity].

Three cases, a female and two males, with the diagnosis of Ullrich syndrome are presented. Major clinical findings included congenital hypotonia, joint contractures, high-arched palate, prominent calcaneus, scoliosis, hyperhidrosis and normal intelligence. The course was not progressive or even underwent slow improvement. Our cases followed the autosomal recessive pattern of inheritance. Muscle enzymes were all within the normal ranges. EMG showed findings that were consistent with a chronic myogenic pattern. Muscle biopsy revealed variation in the size of muscle fiber diameters and large increase of the connective tissue without evidence of dystrophic changes. We consider Ullrich syndrome as a nonspecific muscle disturbance of unexplained nature, related, but not identical, to both congenital muscular dystrophy and myogenic type of arthrogryposis multiplex congenita.

Calcaneus↗
PubMed1981

Mendelian genetics and cytogenetics in otolaryngology.

The numerous inherited disorders involving the head and neck are best understood against the background of Mendelian genetics. An appreciation of patterns of inheritance and the factors that modify or simulate then allows the clinician to weigh the importance of family history, to evaluate the basic mechanisms involved in the disorder, and to give advice concerning future generations.

Child↗
PubMedDate not supplied

Maternal Thp lethality in the mouse is a nuclear, not cytoplasmic, defect.

The Thp mutation, an allele of the mouse T/t complex, differs from other known mutations in that its effects are determined by the sex of the parent from which it is inherited; when inherited from the female parent, it is invariably lethal at the embryonic stage, but, most embryos which inherit the mutation from the male parent survive. Thus most heterozygous embryos carrying the maternally derived mutation die in the second half of pregnancy, while the exceptional embryos surviving to parturition give oedematous, cyanotic individuals that die within 24 h. The lethal maternal effect of Thp may be transmitted either through the cytoplasm of the ovum (oogenic defect) or through the female pronucleus (embryogenic defect). Here we have sought to decide between these possibilities by performing reciprocal nuclear transplantations between one-cell embryos from Thp/+ and +/+ females. Our observation that this maternally inherited lethal effect of Thp persists when Thp/+ pronuclei are transplanted into +/+ cytoplasm suggests that the defect responsible for the pattern of inheritance lies in the pronuclei and not the cytoplasm.

Alleles↗
PubMed1995

Severe type I protein C deficiency in a compound heterozygote for Y124C and Q132X mutations in exon 6 of the PROC gene.

We report the genetic abnormalities in the protein C genes of a Spanish child with neonatal purpura fulminans and disseminated intravascular coagulation, associated with undetectable protein C levels. Direct sequencing of the nine protein C gene exons and their splice junctions indicated that the proband is a compound heterozygote with two mutant protein C gene alleles, Y124C and Q132X, that do not express protein C in plasma. The Y124C mutation was inherited from the mother and is due to a novel A to G transition at nucleotide 3416, which results in the substitution of cysteine for tyrosine 124, a highly conserved amino acid in EGF-like domains. The paternal inherited mutation (Q132X) is a C to T transition at nucleotide 3439, which replaces glutamine 132 with a Stop codon signal. This mutation, if expressed, should result in the synthesis of a truncated protein of 131 amino acids. Y124C or Q132X are present in the heterozygous state in the asymptomatic parents and siblings of the proband, all of which have half the normal plasma levels of protein C. Q123X has also been identified in families where type I PC deficiency is inherited as a clinically dominant trait. Therefore, the presence of the same mutation in a family showing a clinically recessive pattern of inheritance indicates that other factors, apart from the type of protein C gene mutation, are responsible for the clinical expression of protein C deficiency.

Alleles↗