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PubMed2001

Neutrophil-specific granule deficiency: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein--epsilon.

Neutrophil-specific granule deficiency (SGD) is a rare congenital disorder. The neutrophils of individuals with SGD display atypical bi-lobed nuclei, lack expression of all secondary and tertiary granule proteins, and possess defects in chemotaxis, disaggregation, receptor up-regulation, and bactericidal activity, resulting in frequent and severe bacterial infections. Previously, a homozygous mutation in the CCAAT/enhancer binding protein-epsilon (C/EBPepsilon) gene was reported for one case of SGD. To substantiate the role of C/EBPepsilon in the development of SGD and elucidate its mechanism of inheritance, the mutational status of the gene was determined in a second individual. An A-nucleotide insertion in the coding region of the C/EBPepsilon gene was detected. This mutation completely abolished the predicted translation of all C/EBPepsilon isoforms. Microsatellite and nucleotide sequence analyses of the C/EBPepsilon locus in the parents of the proband indicated that the disorder may have resulted from homozygous recessive inheritance of the mutant allele from an ancestor shared by both parents. The mutant C/EBPepsilon(32) protein localized in the cytoplasm rather than the nucleus and was unable to activate transcription. Consistent with this, a significant decrease in the levels of the messenger RNAs (mRNAs) encoding the secondary granule protein human 18-kd cationic antimicrobial protein (hCAP-18)/LL-37 and the primary granule protein bactericidal/permeability-increasing protein were observed in the patient. The hCAP-18 mRNA was induced by overexpression of C/EBPepsilon(32) in the human myeloid leukemia cell line, U937, supporting the hypothesis that C/EBPepsilon is a key regulator of granule gene synthesis. This study strongly implicates mutation of the C/EBPepsilon gene as the primary genetic defect involved in the development of neutrophil SGD and defines its mechanism of inheritance.

Adult↗
PubMed2006

Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palestinian population.

Recessively inherited phenotypes are frequent in the Palestinian population, as the result of a historical tradition of marriages within extended kindreds, particularly in isolated villages. In order to characterise the genetics of inherited hearing loss in this population, we worked with West Bank schools for the deaf to identify children with prelingual, bilateral, severe to profound hearing loss not attributable to infection, trauma or other known environmental exposure. Of 156 families enrolled, hearing loss in 17 families (11 per cent) was due to mutations in GJB2 (connexin 26), a smaller fraction of GJB2-associated deafness than in other populations. In order to estimate how many different genes might be responsible for hearing loss in this population, we evaluated ten families for linkage to all 36 known human autosomal deafness-related genes, fully sequencing hearing-related genes at any linked sites in informative relatives. Four families harboured four novel alleles of TMPRSS3 (988DeltaA = 352stop), otoancorin (1067A > T = D356V) and pendrin (716T > A = V239D and 1001G > T = 346stop). In each family, all affected individuals were homozygous for the critical mutation. Each allele was specific to one or a few families in the cohort; none were widespread. Since epidemiological tests of association of mutations with deafness were not feasible for such rare alleles, we used functional and bioinformatics approaches to evaluate their consequences. In six other families, hearing loss was not linked to any known gene, suggesting that these families harbour novel genes responsible for this phenotype. We conclude that inherited hearing loss is highly heterogeneous in this population, with most extended families acting as genetic isolates in this context. We also conclude that the same genes are responsible for hearing loss in this population as elsewhere, so that gene discovery in these families informs the genetics of hearing loss worldwide.

Arabs↗
PubMed2001

Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients.

PURPOSE: The study was undertaken to evaluate the frequency of inherited medullary thyroid carcinoma (MTC) among patients with apparent sporadic disease. A stepwise algorithm was used depending on clinical indices and the age of patient at MTC diagnosis. PATIENTS AND METHODS: One hundred sixteen patients with MTC verified by postoperative pathologic examination were subjected to genetic analysis of RET exons 10, 11, 13, 14, and 16 by means of polymerase chain reaction, restriction endonuclease digestion, and DNA sequencing. RESULTS: Among 116 apparent sporadic MTC patients, we identified eleven (9.5%) RET germline mutation carriers. Seven of these (6.0%) were found by routine analysis (exons 10 and 11). The frequency of inherited disease among patients younger than 45 years at diagnosis was 10.2% by analysis of typical mutations in exons 10 and 11. Extended genetic analysis (sequencing of exons 11, 13, 14, and 16) yielded 6.1% additional diagnoses, giving a risk of 16.3% in this age group. One previously unreported mutation in exon 11 affected codon 649 (TCG>TTG, Ser>Leu). In the true sporadic MTC patients younger than 30 years at diagnosis, frequencies of 36% and 4.5% in polymorphic variants L769L and S836S, respectively, were observed. The frequency for L769L was higher than in older patients (P <.05). CONCLUSION: The frequency of inherited disease among apparent sporadic medullary thyroid carcinoma patients is close to 10% in the Polish population of MTC patients. The extended analysis of all known RET proto-oncogene mutation sites is obligatory in patients younger than 45 years at diagnosis, but we also see the need to analyze the impact of rarer mutations in older patients.

Adult↗
PubMed1991

Inherited selective intestinal cobalamin malabsorption and cobalamin deficiency in dogs.

Inherited selective intestinal malabsorption of cobalamin (Cbl) was observed in a family of giant schnauzer dogs. Family studies and breeding experiments demonstrated simple autosomal recessive inheritance of this disease. Affected puppies exhibited chronic inappetence and failure to thrive beginning between 6 and 12 wk of age. Neutropenia with hypersegmentation, anemia with anisocytosis and poikilocytosis, and megaloblastic changes of the bone marrow were present. Serum Cbl concentrations were low, and methylmalonic aciduria and homocysteinemia were present. Parenteral, but not oral, cyanocobalamin administration rapidly eliminated all signs of Cbl deficiency except for low serum Cbl concentrations. Cbl malabsorption in affected dogs was documented by oral administration of [57Co]cyanocobalamin with or without simultaneous oral administration of intrinsic factor or normal dog gastric juice. Quantitation and function studies of intrinsic factor and transcobalamin-II from affected dogs revealed no abnormality. Other gastrointestinal functions and ileal morphology were normal, indicating a selective defect of Cbl absorption at the level of the ileal enterocyte. Immunoelectron microscopy of ileal biopsies showed that the receptor for intrinsic factor-Cbl complex was absent from the apical brush border microvillus pits of affected dogs. This canine disorder resembles inherited selective intestinal Cbl malabsorption (Imerslund-Gräsbeck syndrome) in humans, and is a spontaneously occurring animal model of early onset Cbl deficiency.

Animals↗
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↗
PubMed1991

Autosomal dominant inheritance of autoantibodies to thyroid peroxidase and thyroglobulin--studies in families not selected for autoimmune thyroid disease.

Recently the tendency to produce autoantibodies to thyroid peroxidase (TPO Ab) and thyroglobulin (Tg Ab) was shown to be inherited as an autosomal dominant characteristic in women but not in men. Because of potential bias in this study which was carried out in families with autoimmune thyroid disease (AITD), the inheritance of thyroid autoantibodies has been evaluated in 49 families unselected for autoimmune thyroid disease. Among these families (24 with facioscapulohumeral disease, 10 with Friedreich's ataxia, and 15 with schizophrenia) the prevalences of TPO Ab and Tg Ab were 27.8% and 26.7%, respectively, in women and 9.2% and 11.7%, respectively, in men. In 40 families where one or more individual had TPO Ab and/or Tg Ab, segregation analysis showed that the tendency to make antibodies was consistent with a Mendelian dominant trait in women but not in men. In young women, however, the prevalence of both TPO Ab and Tg Ab increased with age, rising from 14% and 10%, respectively, at age 15-24 to 35% and 40% at age 35-44. As this is inconsistent with a simple dominant hypothesis, a further segregation analysis by age was carried out in the families unselected for thyroid disease together with 16 pedigrees with AITD previously studied and two additional large AITD families. The results of the combined analysis provided strong support for the hypothesis of dominant inheritance but also showed significant reduction in gene expression among women aged 15-24 yr.

Adolescent↗
PubMed1996

Genetic basis, mode of inheritance and evolutionary changes of migratory directions in palaearctic warblers (Aves: Sylviidae)

The genetic basis, mode of inheritance and recent evolutionary changes of migratory directions in birds are discussed on the basis of published and new experimental evidence. Displacement experiments with wild-caught migrants and orientation tests with hand-reared passerines illustrate that inexperienced young birds possess genetic information about the direction and approximate distance of migration, but not about the geographic location of the winter quarters. Hand-raised blackcaps Sylvia atricapilla from east and west of the Central European migratory divide, when tested under identical conditions, exibited population-specific migratory directions in orientation cages. Cross-breeding of birds from these two populations demonstrated an intermediate mode of inheritance of this behavioural character. New data on the orientation of an F2 generation suggest that the directional information is encoded by only a few major genes. Migratory adaptations may have evolved recently, in some cases rapidly, as is illustrated by the establishment of a new migration route of central European blackcaps to winter quarters in the British Isles. This new route is shown (in a captive breeding experiment) to be based on a novel, genetically programmed westnorthwesterly migratory direction. It must have spread from almost zero to 7-11 % frequency in parts of central Europe within only three decades. The novel direction is also inherited phenotypically intermediately; its rapid evolution may be mediated by assortative mating based on differential arrival times at the breeding grounds. The evolutionary flexibility of migratory adaptations is discussed in relation to changes in the environment, both natural and accelerated by man.

Journal Article↗
PubMed1978

The mode of inheritance in idiopathic cardiomyopathy, preliminary report.

Genetic analyses of 565 first-degree relatives of 99 patients with ICM suggests that ICM has both simple dominant and recessive modes of inheritance. There was no clinical form of ICM specific to the mode of inheritance, both hypertrophic and congestive types almost equally observed both modes of inheritance. Two pairs of identical twins who suggested the simple recessive mode were reported.

Adolescent↗
PubMed1992

Tumor-suppressor genes: cardinal factors in inherited predisposition to human cancers.

A predisposition to the development of certain specific and familial cancers is associated with the inheritance of a single mutated gene. In the best-characterized cases, this primary mutation is a loss of function mutation consistent with viability but resulting in neoplastic change consequent to the acquisition of a second somatic mutation at the same locus. Such genes are referred to as tumor-suppressor genes. Classical examples are the Rb-1 gene associated with the development of retinoblastoma and the p53 gene, which is associated with a wider range of neoplasms, including breast cancer. Other tumor-suppressor genes have been isolated which are associated with Wilms' tumor, neurofibromatosis, and inherited and sporadic forms of colorectal cancer. Some of these genes appear to act as negative regulators of mitotic cycle genes, and others may have different properties. The nature of these genes is discussed, as is the evidence for the involvement of tumor-suppressor genes in other inherited, and sporadic, forms of cancer. Some recent data on the Wilms' tumor gene, WT1, and on the involvement of the p53 gene in breast cancer are presented, and the importance of genomic imprinting in contributing to the excess of suppressor gene mutations in chromosomes of paternal origin is considered.

Breast Neoplasms↗
PubMed1995

Inheritance law in an aging society.

An exploratory analysis of states' inheritance law changes between 1961 and 1990 was conducted in order to discern major trends and their implications for older families. Results suggested that states were modifying their laws in ways similar to suggestions of the law community's Uniform Probate Code, with about one third of the states adopting the Code itself. Consequently, inheritance law has become less traditional and paternalistic and more like "facilitative law," that is, flexible, accommodating, and supportive of family autonomy and decisionmaking authority. These changes and new laws that simplify procedures, protect the dependent and vulnerable, treat marital property more like community property, recognize variant family forms, and enable extrafamilial bequests, may serve to minimize family disruption, conserve resources, and allow families to tailor property divisions and procedures to particular needs and wishes. An impact study is proposed for disclosing the actual effects on inheritance law reforms. Also, while trends observed in this study were fairly evident, states' adoption of new laws was uneven and selective, inviting continuing trend analyses and further research into the reasons for interstate variation.

Age Factors↗
PubMed2004

Inherited prothrombotic defects in Budd-Chiari syndrome and portal vein thrombosis: a study from North India.

We studied 57 patients with Budd-Chiari syndrome (BCS) and 48 with portal vein thrombosis (PVT) for underlying inherited prothrombotic defects such as protein C, protein S, and antithrombin III deficiencies. Genetic mutations for factor V Leiden, prothrombin gene 20210A, and methyltetrahydrofolate reductase (MTHFR) C677T were studied in 29 patients in each group. Inherited prothrombotic defects were detected in 16 (28%) of 57 patients with BCS and 7 (15%) of 48 patients with PVT. Factor V Leiden mutation was the most common prothrombotic defect in BCS (5/29 [17%]) followed by protein C deficiency (7/57 [12%]) and protein S deficiency (4/57 [7%]), whereas in PVT, protein C deficiency was the most common inherited prothrombotic defect (4/48 [8%]) followed by protein S deficiency (2/48 [4%]). The factor V Leiden mutation was detected in only 1 (3%) of 29 cases of PVT. The heterozygous MTHFR C677T mutation was detected in 7 (24%) of 29 patients with BCS and 6 (21%) of 29 patients with PVT. Antithrombin III deficiency, homozygous MTHFR C677T mutation, and prothrombin G20210A mutation were not detected in any patients.

Adolescent↗
PubMed2005

Molecular diagnostic testing for inherited thrombophilia using Invader.

Physicians in the United States and Europe began testing patients who had idiopathic thrombotic events for inherited risk factors in 1990s. The College of American Pathologists (CAP) offered proficiency testing for molecular genetic screening for thrombophilia in 1997. Today, a hypercoagulable workup including screening for inherited thrombophilia defects is becoming part of the standard of care in many parts of the world (1). Who, what, and when to test continue to be controversial and challenging questions (2); however, laboratories developing new or improved mutation detection methodologies have used the most commonly screened inherited thrombophilia polymorphism, factor V Leiden (R506Q), for many years (3). In the most recent CAP survey (MGL-A 2003), the most commonly employed method used in one-third of all participating clinical laboratories testing for factor V Leiden and prothrombin G20210A was the non-PCR-based method called Invader, developed by Third Wave Technologies. The remainder of the clinical laboratories reported testing for these variants using PCR-restriction fragment length polymorphism (RFLP), allele-specific PCR, and allele-specific hybridization. Emerging mutation detection technologies include DNA resequencing approaches such as pyrosequencing (4) fluorescence polarization detection (5), genotyping on microelectronic DNA chips like Nanogen's nanochip (6), and oligonucleotide hybridization with photocrosslinking (7). Invader technology is currently a medium-throughput, 96-well plate format assay that is sufficient for most hospital clinical laboratories. Although this assay format is not currently performed in a microarray format, Invader is amenable to performance on a solid support; specifically, the reaction can be performed on the surface of microspheres and the resulting fluorescence measured using flow cytometry (8). This chapter presents the method as well as some suggestions for utilizing the Invader system for mutation/polymorphism screening in general and for thrombophilia testing in particular.

Factor V↗
PubMed1999

Gene amplification as a common cause of inherited thyroxine-binding globulin excess: analysis of one familial and two sporadic cases.

T4-binding globulin (TBG) is the major thyroid hormone transport protein in humans. Inherited abnormalities in the level of serum TBG have been classified as partial deficiency, complete deficiency and excess. A single nucleotide deletion or substitution in the TBG gene, located on Xq22, has been detected in partial and complete deficiencies. As for inherited TBG excess, the gene amplification has been recognized in two Japanese families recently. In this study, an additional three Japanese families, one familial (F-I) and two sporadic TBG excess (F-II, F-III), were analyzed. Serum TBG levels in hemizygous males were 73, 47 and 42 microg/ml, three- to two-fold the normal value. The molecule had normal properties in terms of heat stability and isoelectric focussing pattern. The gene dosage of TBG was evaluated by coamplification with autosomal betaGlobin or X-chromosomal Duchenne Muscular Dystrophy (DMD) and subsequent quantitation by HPLC. The TBG/betaGlobin ratios of the affected male and female of F-I were 3.09- and 3.86-times, respectively, compared to that of the normal males. The TBG/DMD ratios were 2.93- and 2.09-times, respectively. These results are compatible with three copies of the TBG gene on the affected X-chromosome. Similarly, a twofold increase in gene dosage was demonstrated in the affected males of sporadic cases. Their mothers with normal TBG values had the same TBG gene dosage as normal females, suggesting that de novo gene duplication arose in gametes probably during meiosis. Amplification of the TBG gene was not recognized in these three families by in situ hybridization of prometaphase chromosomes. Though the mechanism remains unproved, gene amplification of TBG was considered to be a common cause for inherited TBG excess.

Female↗
PubMed1997

Clinical and genetic analysis of an inherited case of thyroid adenoma/cancer.

We studied a family in which thyroid neoplasms appeared to occur through genetic inheritance. Six blood relations, including the two probands, had thyroid carcinoma, and six others had benign thyroid tumors. When both parents had a thyroid neoplasm, their children frequently had thyroid neoplasms; this was confirmed through two generations of this family. To clarify the mechanism of inheritance, we performed chromosomal analysis, Southern blot analysis of three variable number of tandem repeats markers and HLA typing on two probands, and examined their RET proto-oncogenes, and p53 and RB tumor suppressor genes. We could not find any positive data on genetic analysis, although our data were limited. In conclusion, we studied a family in which thyroid neoplasms have occurred partly through genetic inheritance, although environmental factors may have influenced the occurrence of thyroid diseases. A search for a predisposing gene, using the microsatellite technique, is required to clarify the gentic factors involved.

Adenoma↗
PubMed2005

Construction of linkage maps in full-sib families of diploid outbreeding species by minimizing the number of recombinations in hidden inheritance vectors.

This article investigates the construction of linkage maps by means of the reconstruction of hidden inheritance vectors. An inheritance vector provides a description of the origin of marker alleles in an individual in terms of a binary code indicating the grandparental origin of the alleles. The practical application that is considered is the full-sib family of a diploid outbreeding species. Essentially, map construction is considered as an optimization problem in which marker data are used as restrictions on hidden inheritance vectors. Simulated annealing, a form of combinatorial optimization, is used to minimize the number of recombinations between adjacent markers. The new algorithm is applied to simulated data as well as to practical data obtained from a cross between two apple cultivars. For the practical data, a detailed procedure for examining the reliability of individual markers and their positions on the map is presented. Extensions of the method for more complicated population structures are discussed.

Algorithms↗
PubMed2006

Inheritance patterns of transcript levels in F1 hybrid mice.

Genetic analysis of transcriptional regulation is a rapidly emerging field of investigation that promises to shed light on the regulatory networks that control gene expression. Although a number of such studies have been carried out, the nature and extent of the heritability of gene expression traits have not been well established. We describe the inheritance of transcript levels in liver tissue in the first filial (F1) generation of mice obtained from reciprocal crosses between the common inbred strains A/J and C57BL/6J. We obtain estimates of genetic and technical variance components from these data and demonstrate that shrinkage estimators can increase detectable heritability. Estimates of heritability vary widely from transcript to transcript, with one-third of transcripts showing essentially no heritability (<0.01) and one-quarter showing very high heritability (>0.50). Roughly half of all transcripts are differentially expressed between the two parental strains. Most transcripts show an additive pattern of inheritance. Dominance effects were observed for 20% of transcripts and a small number of transcripts were identified as showing an overdominance mode of inheritance. In addition, we identified 314 transcripts with expression levels that differ between the reciprocal F1 animals. These genes may be related to maternal effect.

Animals↗
PubMed2003

Inheritance of methyl-parathion resistance in Nebraska western corn rootworm populations (Coleoptera: Chrysomelidae).

Field populations of western corn rootworm, Diabrotica virgifera virgifera LeConte, were collected from three different sites (York Co., Phelps Co., and Saunders Co.) in Nebraska during 1996. Adult bioassays of these three populations were conducted with different concentrations of methyl-parathion and at a diagnostic concentration (1.0 microg/ml) to determine resistance levels among these populations. Self and reciprocal crosses were made between the two resistant and one susceptible laboratory-reared populations. Dose-responses and dominance ratios calculated for the four reciprocal crosses indicated that resistance was incompletely dominant in both strains, although in one of the strains there was an indication of sex linkage. However, evaluation of native polyacrylamide gels stained for nonspecific esterases and nonspecific esterase activity of parents and F1 progeny of the crosses suggested that esterase inheritance was completely dominant and autosomal. The results of this study were inconclusive with regard to the precise nature of inheritance, because the bioassays and esterase assays could not discriminate between heterozygotes and homozygotes. However, they do provide insight into the potential for developing simple diagnostic assays to assess resistance frequencies. Based on the inheritance studies described in this investigation, we can begin to generate information on specific genetic factors that dictate the evolutionary divergence of discrete resistant populations and facilitate modeling efforts designed to approximate the movement of genes for resistance among populations.

Animals↗