Penetrance: The percent frequency with which a dominant or homozygous recessive gene or gene combination manifests itself in the phenotype of the carriers. (From Glossary of Genetics, 5th ed)Pedigree: The record of descent or ancestry, particularly of a particular condition or trait, indicating individual family members, their relationships, and their status with respect to the trait or condition.Genes, Dominant: Genes that influence the PHENOTYPE both in the homozygous and the heterozygous state.Heterozygote: An individual having different alleles at one or more loci regarding a specific character.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.Phenotype: The outward appearance of the individual. It is the product of interactions between genes, and between the GENOTYPE and the environment.Genetic Linkage: The co-inheritance of two or more non-allelic GENES due to their being located more or less closely on the same CHROMOSOME.Genetic Predisposition to Disease: A latent susceptibility to disease at the genetic level, which may be activated under certain conditions.Optic Atrophy, Hereditary, Leber: A maternally linked genetic disorder that presents in mid-life as acute or subacute central vision loss leading to central scotoma and blindness. The disease has been associated with missense mutations in the mtDNA, in genes for Complex I, III, and IV polypeptides, that can act autonomously or in association with each other to cause the disease. (from Online Mendelian Inheritance in Man,, MIM#535000 (April 17, 2001))Lod Score: The total relative probability, expressed on a logarithmic scale, that a linkage relationship exists among selected loci. Lod is an acronym for "logarithmic odds."Alleles: Variant forms of the same gene, occupying the same locus on homologous CHROMOSOMES, and governing the variants in production of the same gene product.Germ-Line Mutation: Any detectable and heritable alteration in the lineage of germ cells. Mutations in these cells (i.e., "generative" cells ancestral to the gametes) are transmitted to progeny while those in somatic cells are not.Family Health: The health status of the family as a unit including the impact of the health of one member of the family on the family as a unit and on individual family members; also, the impact of family organization or disorganization on the health status of its members.Genotype: The genetic constitution of the individual, comprising the ALLELES present at each GENETIC LOCUS.DNA Mutational Analysis: Biochemical identification of mutational changes in a nucleotide sequence.Genetic Testing: Detection of a MUTATION; GENOTYPE; KARYOTYPE; or specific ALLELES associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing.Genes, BRCA1: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human CHROMOSOME 17 at locus 17q21. Mutations of this gene are associated with the formation of HEREDITARY BREAST AND OVARIAN CANCER SYNDROME. It encodes a large nuclear protein that is a component of DNA repair pathways.Genes, Modifier: GENES with ALLELES that affect the PHENOTYPE associated with a nonallelic gene.Models, Genetic: Theoretical representations that simulate the behavior or activity of genetic processes or phenomena. They include the use of mathematical equations, computers, and other electronic equipment.Age of Onset: The age, developmental stage, or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual.Founder Effect: A phenomenon that is observed when a small subgroup of a larger POPULATION establishes itself as a separate and isolated entity. The subgroup's GENE POOL carries only a fraction of the genetic diversity of the parental population resulting in an increased frequency of certain diseases in the subgroup, especially those diseases known to be autosomal recessive.Hirschsprung Disease: Congenital MEGACOLON resulting from the absence of ganglion cells (aganglionosis) in a distal segment of the LARGE INTESTINE. The aganglionic segment is permanently contracted thus causing dilatation proximal to it. In most cases, the aganglionic segment is within the RECTUM and SIGMOID COLON.Chromosome Mapping: Any method used for determining the location of and relative distances between genes on a chromosome.Haplotypes: The genetic constitution of individuals with respect to one member of a pair of allelic genes, or sets of genes that are closely linked and tend to be inherited together such as those of the MAJOR HISTOCOMPATIBILITY COMPLEX.Homozygote: An individual in which both alleles at a given locus are identical.Genes, Recessive: Genes that influence the PHENOTYPE only in the homozygous state.Jews: An ethnic group with historical ties to the land of ISRAEL and the religion of JUDAISM.Genetic Heterogeneity: The presence of apparently similar characters for which the genetic evidence indicates that different genes or different genetic mechanisms are involved in different pedigrees. In clinical settings genetic heterogeneity refers to the presence of a variety of genetic defects which cause the same disease, often due to mutations at different loci on the same gene, a finding common to many human diseases including ALZHEIMER DISEASE; CYSTIC FIBROSIS; LIPOPROTEIN LIPASE DEFICIENCY, FAMILIAL; and POLYCYSTIC KIDNEY DISEASES. (Rieger, et al., Glossary of Genetics: Classical and Molecular, 5th ed; Segen, Dictionary of Modern Medicine, 1992)Gene Frequency: The proportion of one particular in the total of all ALLELES for one genetic locus in a breeding POPULATION.Genetic Diseases, Inborn: Diseases that are caused by genetic mutations present during embryo or fetal development, although they may be observed later in life. The mutations may be inherited from a parent's genome or they may be acquired in utero.Genes, BRCA2: A tumor suppressor gene (GENES, TUMOR SUPPRESSOR) located on human chromosome 13 at locus 13q12.3. Mutations in this gene predispose humans to breast and ovarian cancer. It encodes a large, nuclear protein that is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev 2000;14(11):1400-6)Dystonia Musculorum Deformans: A condition characterized by focal DYSTONIA that progresses to involuntary spasmodic contractions of the muscles of the legs, trunk, arms, and face. The hands are often spared, however, sustained axial and limb contractions may lead to a state where the body is grossly contorted. Onset is usually in the first or second decade. Familial patterns of inheritance, primarily autosomal dominant with incomplete penetrance, have been identified. (Adams et al., Principles of Neurology, 6th ed, p1078)Mutation, Missense: A mutation in which a codon is mutated to one directing the incorporation of a different amino acid. This substitution may result in an inactive or unstable product. (From A Dictionary of Genetics, King & Stansfield, 5th ed)Family: A social group consisting of parents or parent substitutes and children.Syndrome: A characteristic symptom complex.Genetic Markers: A phenotypically recognizable genetic trait which can be used to identify a genetic locus, a linkage group, or a recombination event.Heterozygote Detection: Identification of genetic carriers for a given trait.Crosses, Genetic: Deliberate breeding of two different individuals that results in offspring that carry part of the genetic material of each parent. The parent organisms must be genetically compatible and may be from different varieties or closely related species.Dystonia: An attitude or posture due to the co-contraction of agonists and antagonist muscles in one region of the body. It most often affects the large axial muscles of the trunk and limb girdles. Conditions which feature persistent or recurrent episodes of dystonia as a primary manifestation of disease are referred to as DYSTONIC DISORDERS. (Adams et al., Principles of Neurology, 6th ed, p77)BRCA2 Protein: A large, nuclear protein, encoded by the BRCA2 gene (GENE, BRCA2). Mutations in this gene predispose humans to breast and ovarian cancer. The BRCA2 protein is an essential component of DNA repair pathways, suppressing the formation of gross chromosomal rearrangements. (from Genes Dev. 2000;14(11):1400-6)Amyloid Neuropathies, Familial: Inherited disorders of the peripheral nervous system associated with the deposition of AMYLOID in nerve tissue. The different clinical types based on symptoms correspond to the presence of a variety of mutations in several different proteins including transthyretin (PREALBUMIN); APOLIPOPROTEIN A-I; and GELSOLIN.Genetic Counseling: An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered.Genetic Variation: Genotypic differences observed among individuals in a population.Angiomatosis: A condition with multiple tumor-like lesions caused either by congenital or developmental malformations of BLOOD VESSELS, or reactive vascular proliferations, such as in bacillary angiomatosis. Angiomatosis is considered non-neoplastic.Hemochromatosis: A disorder of iron metabolism characterized by a triad of HEMOSIDEROSIS; LIVER CIRRHOSIS; and DIABETES MELLITUS. It is caused by massive iron deposits in parenchymal cells that may develop after a prolonged increase of iron absorption. (Jablonski's Dictionary of Syndromes & Eponymic Diseases, 2d ed)Polymorphism, Single Nucleotide: A single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population.Syndactyly: A congenital anomaly of the hand or foot, marked by the webbing between adjacent fingers or toes. Syndactylies are classified as complete or incomplete by the degree of joining. Syndactylies can also be simple or complex. Simple syndactyly indicates joining of only skin or soft tissue; complex syndactyly marks joining of bony elements.Abnormalities, MultipleLikelihood Functions: Functions constructed from a statistical model and a set of observed data which give the probability of that data for various values of the unknown model parameters. Those parameter values that maximize the probability are the maximum likelihood estimates of the parameters.Proto-Oncogene Proteins c-ret: Receptor protein-tyrosine kinases involved in the signaling of GLIAL CELL-LINE DERIVED NEUROTROPHIC FACTOR ligands. They contain an extracellular cadherin domain and form a receptor complexes with GDNF RECEPTORS. Mutations in ret protein are responsible for HIRSCHSPRUNG DISEASE and MULTIPLE ENDOCRINE NEOPLASIA TYPE 2.Craniofacial Abnormalities: Congenital structural deformities, malformations, or other abnormalities of the cranium and facial bones.DNA, Mitochondrial: Double-stranded DNA of MITOCHONDRIA. In eukaryotes, the mitochondrial GENOME is circular and codes for ribosomal RNAs, transfer RNAs, and about 10 proteins.Epistasis, Genetic: A form of gene interaction whereby the expression of one gene interferes with or masks the expression of a different gene or genes. Genes whose expression interferes with or masks the effects of other genes are said to be epistatic to the effected genes. Genes whose expression is affected (blocked or masked) are hypostatic to the interfering genes.Retinoblastoma: A malignant tumor arising from the nuclear layer of the retina that is the most common primary tumor of the eye in children. The tumor tends to occur in early childhood or infancy and may be present at birth. The majority are sporadic, but the condition may be transmitted as an autosomal dominant trait. Histologic features include dense cellularity, small round polygonal cells, and areas of calcification and necrosis. An abnormal pupil reflex (leukokoria); NYSTAGMUS, PATHOLOGIC; STRABISMUS; and visual loss represent common clinical characteristics of this condition. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, p2104)Genetics, Medical: A subdiscipline of human genetics which entails the reliable prediction of certain human disorders as a function of the lineage and/or genetic makeup of an individual or of any two parents or potential parents.Chromosomes, Human, Pair 19: A specific pair of GROUP F CHROMOSOMES of the human chromosome classification.RNA, Transfer, Ile: A transfer RNA which is specific for carrying isoleucine to sites on the ribosomes in preparation for protein synthesis.Cardiomyopathy, Hypertrophic, Familial: An autosomal dominant inherited form of HYPERTROPHIC CARDIOMYOPATHY. It results from any of more than 50 mutations involving genes encoding contractile proteins such as VENTRICULAR MYOSINS; cardiac TROPONIN T; ALPHA-TROPOMYOSIN.Bone Morphogenetic Protein Receptors, Type II: A subtype of bone morphogenetic protein receptors with low affinity for BONE MORPHOGENETIC PROTEINS. They are constitutively active PROTEIN-SERINE-THREONINE KINASES that can interact with and phosphorylate TYPE I BONE MORPHOGENETIC PROTEIN RECEPTORS.Prealbumin: A tetrameric protein, molecular weight between 50,000 and 70,000, consisting of 4 equal chains, and migrating on electrophoresis in 3 fractions more mobile than serum albumin. Its concentration ranges from 7 to 33 per cent in the serum, but levels decrease in liver disease.Myoclonus: Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some CENTRAL NERVOUS SYSTEM DISEASES; (e.g., EPILEPSY, MYOCLONIC). Nocturnal myoclonus is the principal feature of the NOCTURNAL MYOCLONUS SYNDROME. (From Adams et al., Principles of Neurology, 6th ed, pp102-3).Neoplastic Syndromes, Hereditary: The condition of a pattern of malignancies within a family, but not every individual's necessarily having the same neoplasm. Characteristically the tumor tends to occur at an earlier than average age, individuals may have more than one primary tumor, the tumors may be multicentric, usually more than 25 percent of the individuals in direct lineal descent from the proband are affected, and the cancer predisposition in these families behaves as an autosomal dominant trait with about 60 percent penetrance.Inheritance Patterns: The different ways GENES and their ALLELES interact during the transmission of genetic traits that effect the outcome of GENE EXPRESSION.Breast Neoplasms: Tumors or cancer of the human BREAST.Mice, Transgenic: Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.Optic Atrophies, Hereditary: Hereditary conditions that feature progressive visual loss in association with optic atrophy. Relatively common forms include autosomal dominant optic atrophy (OPTIC ATROPHY, AUTOSOMAL DOMINANT) and Leber hereditary optic atrophy (OPTIC ATROPHY, HEREDITARY, LEBER).Exons: The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.Dystonic Disorders: Acquired and inherited conditions that feature DYSTONIA as a primary manifestation of disease. These disorders are generally divided into generalized dystonias (e.g., dystonia musculorum deformans) and focal dystonias (e.g., writer's cramp). They are also classified by patterns of inheritance and by age of onset.Mice, Inbred C57BLRetinitis Pigmentosa: Hereditary, progressive degeneration of the neuroepithelium of the retina characterized by night blindness and progressive contraction of the visual field.Paraganglioma, Extra-Adrenal: A relatively rare, usually benign neoplasm originating in the chemoreceptor tissue of the CAROTID BODY; GLOMUS JUGULARE; GLOMUS TYMPANICUM; AORTIC BODIES; and the female genital tract. It consists histologically of rounded or ovoid hyperchromatic cells that tend to be grouped in an alveolus-like pattern within a scant to moderate amount of fibrous stroma and a few large thin-walled vascular channels. (From Stedman, 27th ed)Microsatellite Repeats: A variety of simple repeat sequences that are distributed throughout the GENOME. They are characterized by a short repeat unit of 2-8 basepairs that is repeated up to 100 times. They are also known as short tandem repeats (STRs).Point Mutation: A mutation caused by the substitution of one nucleotide for another. This results in the DNA molecule having a change in a single base pair.Genetic Association Studies: The analysis of a sequence such as a region of a chromosome, a haplotype, a gene, or an allele for its involvement in controlling the phenotype of a specific trait, metabolic pathway, or disease.Ovarian Neoplasms: Tumors or cancer of the OVARY. These neoplasms can be benign or malignant. They are classified according to the tissue of origin, such as the surface EPITHELIUM, the stromal endocrine cells, and the totipotent GERM CELLS.Eye Abnormalities: Congenital absence of or defects in structures of the eye; may also be hereditary.

Evidence that mutations in the X-linked DDP gene cause incompletely penetrant and variable skewed X inactivation. (1/637)

X chromosome inactivation results in the random transcriptional silencing of one of the two X chromosomes early in female development. After random inactivation, certain deleterious X-linked mutations can create a selective disadvantage for cells in which the mutation is on the active X chromosome, leading to X inactivation patterns with the mutation on the inactive X chromosome in nearly 100% of the individual's cells. In contrast to the homogeneous patterns of complete skewed inactivation noted for many X-linked disorders, here we describe a family segregating a mutation in the dystonia-deafness peptide (DDP) gene, in which female carriers show incompletely penetrant and variable X inactivation patterns in peripheral blood leukocytes, ranging between 50:50 and >95:5. To address the genetic basis for the unusual pattern of skewing in this family, we first mapped the locus responsible for the variable skewing to the proximal long arm (Xq12-q22) of the X chromosome (Z=5. 7, P=.002, LOD score 3.57), a region that includes both the DDP and the XIST genes. Examination of multiple cell types from women carrying a DDP mutation and of peripheral blood leukocytes from women from two unrelated families who carry different mutations in the DDP gene suggests that the skewed X inactivation is the result of selection against cells containing the mutant DDP gene on the active X chromosome, although skewing is apparently not as severe as that seen for many other deleterious X-linked mutations. Thus, DDP is an example of an X-linked gene for which mutations cause partial cell selection and thus incompletely skewed X inactivation in peripheral blood leukocytes.  (+info)

Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. (2/637)

Combining data from a genomic screen in 70 families with a high risk for prostate cancer (PC) with data from candidate-region mapping in these families and an additional 71 families, we have localized a potential hereditary PC-susceptibility locus to chromosome 1p36. Because an excess of cases of primary brain cancer (BC) have been observed in some studies of families with a high risk for PC, and because loss of heterozygosity at 1p36 is frequently observed in BC, we further evaluated 12 families with both a history of PC and a blood relative with primary BC. The overall LOD score in these 12 families was 3.22 at a recombination fraction (theta) of .06, with marker D1S507. On the basis of an a priori hypothesis, this group was stratified by age at diagnosis of PC. In the younger age group (mean age at diagnosis <66 years), a maximum two-point LOD score of 3.65 at straight theta = .0 was observed, with D1S407. This linkage was rejected in both early- and late-onset families without a history of BC (LOD scores -7.12 and -6.03, respectively, at straight theta = .0). After exclusion of 3 of the 12 families that had better evidence of linkage to previously described PC-susceptibility loci, linkage to the 1p36 region was suggested by a two-point LOD score of 4.74 at straight theta = .0, with marker D1S407. We conclude that a significant proportion of these families with both a high risk for PC and a family member with BC show linkage to the 1p36 region.  (+info)

Analysis of affected sib pairs, with covariates--with and without constraints. (3/637)

Covariate models have previously been developed as an extension to affected-sib-pair methods in which the covariate effects are jointly estimated with the degree of excess allele sharing. These models can estimate the differences in sib-pair allele sharing that are associated with measurable environment or genes. When there are no covariates, the pattern of identical-by-descent allele sharing in affected sib pairs is expected to fall within a small triangular region of the potential parameter space, under most genetic models. By restriction of the estimated allele sharing to this triangle, improved power is obtained in tests for genetic linkage. When the affected-sib-pair model is generalized to allow for covariates that affect allele sharing, however, new constraints and new methods for the application of constraints are required. Three generalized constraint methods are proposed and evaluated by use of simulated data. The results compare the power of the different methods, with and without covariates, for a single-gene model with age-dependent onset and for quantitative and qualitative gene-environment and gene-gene interaction models. Covariates can improve the power to detect linkage and can be particularly valuable when there are qualitative gene-environment interactions. In most situations, the best strategy is to assume that there is no dominance variance and to obtain constrained estimates for covariate models under this assumption.  (+info)

Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction. (4/637)

The Smads are a family of nine related proteins which function as signaling intermediates for the transforming growth factor beta (TGF-beta) superfamily of ligands. To discern the in vivo functions of one of these Smads, Smad3, we generated mice harboring a targeted disruption of this gene. Smad3 null mice, although smaller than wild-type littermates, are viable, survive to adulthood, and exhibit an early phenotype of forelimb malformation. To study the cellular functions of Smad3, we generated Smad3 null mouse embryonic fibroblasts (MEFs) and dermal fibroblasts. We demonstrate that null MEFs have lost the ability to form Smad-containing DNA binding complexes and are unable to induce transcription from the TGF-beta-responsive promoter construct, p3TP-lux. Using the primary dermal fibroblasts, we also demonstrate that Smad3 is integral for induction of endogenous plasminogen activator inhibitor 1. We subsequently demonstrate that Smad3 null MEFs are partially resistant to TGF-beta's antiproliferative effect, thus firmly establishing a role for Smad3 in TGF-beta-mediated growth inhibition. We next examined cells in which Smad3 is most highly expressed, specifically cells of immune origin. Although no specific developmental defect was detected in the immune system of the Smad3 null mice, a functional defect was observed in the ability of TGF-beta to inhibit the proliferation of splenocytes activated by specific stimuli. In addition, primary splenocytes display defects in TGF-beta-mediated repression of cytokine production. These data, taken together, establish a role for Smad3 in mediating the antiproliferative effects of TGF-beta and implicate Smad3 as a potential effector for TGF-beta in modulating immune system function.  (+info)

Mutation and haplotype studies of familial Mediterranean fever reveal new ancestral relationships and evidence for a high carrier frequency with reduced penetrance in the Ashkenazi Jewish population. (5/637)

Familial Mediterranean fever (FMF) is a recessive disorder characterized by episodes of fever with serositis or synovitis. The FMF gene (MEFV) was cloned recently, and four missense mutations were identified. Here we present data from non-Ashkenazi Jewish and Arab patients in whom we had not originally found mutations and from a new, more ethnically diverse panel. Among 90 symptomatic mutation-positive individuals, 11 mutations accounted for 79% of carrier chromosomes. Of the two mutations that are novel, one alters the same residue (680) as a previously known mutation, and the other (P369S) is located in exon 3. Consistent with another recent report, the E148Q mutation was observed in patients of several ethnicities and on multiple microsatellite haplotypes, but haplotype data indicate an ancestral relationships between non-Jewish Italian and Ashkenazi Jewish patients with FMF and other affected populations. Among approximately 200 anonymous Ashkenazi Jewish DNA samples, the MEFV carrier frequency was 21%, with E148Q the most common mutation. Several lines of evidence indicate reduced penetrance among Ashkenazi Jews, especially for E148Q, P369S, and K695R. Nevertheless, E148Q helps account for recessive inheritance in an Ashkenazi family previously reported as an unusual case of dominantly inherited FMF. The presence of three frequent MEFV mutations in multiple Mediterranean populations strongly suggests a heterozygote advantage in this geographic region.  (+info)

Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance. (6/637)

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance. Most patients have a heterozygous mutation in the APT1 gene, which encodes Fas (CD95, APO-1), mediator of an apoptotic pathway crucial to lymphocyte homeostasis. Of 17 unique APT1 mutations in unrelated ALPS probands, 12 (71%) occurred in exons 7-9, which encode the intracellular portion of Fas. In vitro, activated lymphocytes from all 17 patients showed apoptotic defects when exposed to an anti-Fas agonist monoclonal antibody. Similar defects were found in a Fas-negative cell line transfected with cDNAs bearing each of the mutations. In cotransfection experiments, Fas constructs with either intra- or extracellular mutations caused dominant inhibition of apoptosis mediated by wild-type Fas. Two missense Fas variants, not restricted to patients with ALPS, were identified. Variant A(-1)T at the Fas signal-sequence cleavage site, which mediates apoptosis less well than wild-type Fas and is partially inhibitory, was present in 13% of African American alleles. Among the ALPS-associated Fas mutants, dominant inhibition of apoptosis was much more pronounced in mutants affecting the intracellular, versus extracellular, portion of the Fas receptor. Mutations causing disruption of the intracellular Fas death domain also showed a higher penetrance of ALPS phenotype features in mutation-bearing relatives. Significant ALPS-related morbidity occurred in 44% of relatives with intracellular mutations, versus 0% of relatives with extracellular mutations. Thus, the location of mutations within APT1 strongly influences the development and the severity of ALPS.  (+info)

Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition. (7/637)

Immunoglobulin A (IgA) deficiency (IgAD) is characterized by a defect of terminal lymphocyte differentiation, leading to a lack of IgA in serum and mucosal secretions. Familial clustering, variable population prevalence in different ethnic groups, and a predominant inheritance pattern suggest a strong genetic predisposition to IgAD. The genetic susceptibility to IgAD is shared with a less prevalent, but more profound, defect called "common variable immunodeficiency" (CVID). Here we show an increased allele sharing at 6p21 in affected members of 83 multiplex IgAD/CVID pedigrees and demonstrate, using transmission/diseqilibrium tests, family-based associations indicating the presence of a predisposing locus, designated "IGAD1," in the proximal part of the major histocompatibility complex (MHC). The recurrence risk of IgAD was found to depend on the sex of parents transmitting the defect: affected mothers were more likely to produce offspring with IgAD than were affected fathers. Carrier mothers but not carrier fathers transmitted IGAD1 alleles more frequently to the affected offspring than would be expected under random segregation. The differential parent-of-origin penetrance is proposed to reflect a maternal effect mediated by the production of anti-IgA antibodies tentatively linked to IGAD1. This is supported by higher frequency of anti-IgA-positive females transmitting the disorder to children, in comparison with female IgAD nontransmitters, and by linkage data in the former group. Such pathogenic mechanisms may be shared by other MHC-linked complex traits associated with the production of specific autoantibodies, parental effects, and a particular MHC haplotype.  (+info)

Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. (8/637)

Since little is known about chromosomal locations harboring type 2 diabetes-susceptibility genes, we conducted a genomewide scan for such genes in a Mexican American population. We used data from 27 low-income extended Mexican American pedigrees consisting of 440 individuals for whom genotypic data are available for 379 markers. We used a variance-components technique to conduct multipoint linkage analyses for two phenotypes: type 2 diabetes (a discrete trait) and age at onset of diabetes (a truncated quantitative trait). For the multipoint analyses, a subset of 295 markers was selected on the basis of optimal spacing and informativeness. We found significant evidence that a susceptibility locus near the marker D10S587 on chromosome 10q influences age at onset of diabetes (LOD score 3.75) and is also linked with type 2 diabetes itself (LOD score 2.88). This susceptibility locus explains 63.8%+/-9.9% (P=. 000016) of the total phenotypic variation in age at onset of diabetes and 65.7%+/-10.9% (P=.000135) of the total variation in liability to type 2 diabetes. Weaker evidence was found for linkage of diabetes and of age at onset to regions on chromosomes 3p, 4q, and 9p. In conclusion, our strongest evidence for linkage to both age at onset of diabetes and type 2 diabetes itself in the Mexican American population was for a region on chromosome 10q.  (+info)

  • Plot functions include pedigrees of simulated families and predicted penetrance curves based on specified parameter values. (
  • Penetrance is the probability that a person carrying a disease-associated genotype will develop the disease within a given time period. (
  • A disease is said to show complete penetrance if a person carrying a disease associated genotype always develops the condition. (
  • Cardiac penetrance was high in young asymptomatic LMNA genotype-positive family members with frequent AV block and VT, highlighting the importance of early family screening and cardiological follow-up. (
  • For this population, we estimate that the penetrance of the HFE C282Y homozygous genotype, with respect to hepatocellular carcinoma, was between 1.31 % and 2.1% for males and was zero for females. (
  • Maternal high-fat diet interacts with embryonic Cited2 genotype to reduce Pitx2c expression and enhance penetrance of left-right patterning defects. (
  • High and low penetrance: If an allele is highly penetrant, then the trait it produces will almost always be apparent in an individual carrying the allele. (
  • An allele with low penetrance will only occasionally produce the trait with which it is associated. (
  • Penetrance can be difficult to determine reliably, even for genetic diseases that are caused by a single polymorphic allele. (
  • Genome association studies may assess the influence of such variants on the penetrance of an allele. (
  • Determining the penetrance of the C282Y allele can be influenced when the medical community evaluates homozygotes. (
  • For example Huntingtons disease has 95% penetrance whereby 5% of those with the dominant allele for Huntingtons don't acquire the disease and 95% do. (
  • MAIN OUTCOME MEASURES: The penetrance of the variant rs74315329 was estimated from the percentage of the carriers of the risk allele of the variant who had high IOP (ocular hypertension) or glaucoma. (
  • In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms. (
  • A condition, most commonly inherited in an autosomal dominant manner, is said to show complete penetrance if clinical symptoms are present in all individuals who have the disease-causing mutation. (
  • For many hereditary diseases, the onset of symptoms is age related, and is affected by environmental factors such as nutrition and smoking, as well as genetic cofactors and epigenetic regulation of expression: Age-related cumulative frequency: Penetrance is often expressed as a frequency of disease at different ages. (
  • For hereditary hemochromatosis, a disease caused by excess intestinal iron absorption, the degree of penetrance has been a subject of controversy for many years and illustrates the challenges facing investigators seeking a quantitative measure of penetrance. (
  • The Lappalainen Lab will focus its research efforts on advancing scientific knowledge of a widely acknowledged but not well understood phenomenon called variable penetrance, where the severity of the effect of disease-causing variants differs among individuals who carry them. (
  • The Lappalainen Lab will examine the important implications of variable penetrance in human evolution and disease. (
  • This will be the first comprehensive work on characterizing how important this phenomenon is and how it can affect penetrance of disease-causing variants. (
  • Evaluation of LRRK2 G2019S penetrance: relevance for genetic counseling in Parkinson disease. (
  • We report the results of a family-based study of LRRK2 G2019S penetrance in Parkinson disease. (
  • If you were to think about it as an equation, penetrance is the number of individuals displaying clinical features of a condition, divided by the number of individuals with a disease-causing mutation, multiplied by 100. (
  • Mitochondrial DNA variants that are linked to disease can exhibit variable expression and penetrance. (
  • Studying haplogroup background and its impact on disease penetrance will help ensure similar levels of diagnostic accuracy to all populations (van der Walt et al. (
  • This supports the theory that haplogroup background is important in the expression and penetrance of disease in humans. (
  • Mutations in LRRK2 represent the most common causes of Parkinson's disease (PD) identified to date, but their penetrance is incomplete and probably due to the presence of other genetic or environmental factors required for development of the disease. (
  • Macular telangiectasia (MacTel) is an adult-onset autosomal dominant disease with reduced penetrance. (
  • Partial penetrance can be viewed as nature's way of curing the disease. (
  • In this widely acknowledged but not well understood phenomenon, called variable penetrance, the severity of the effect of disease-causing variants differs among individuals who carry them. (
  • Variable penetrance has long posed a challenge for predicting the severity of a disease, even for diseases with a strong genetic association. (
  • They found an enrichment of combinations of regulatory and coding variants, called haplotypes, that act as protective against disease by decreasing the penetrance of coding variants associated with disease development. (
  • Finally, they designed an experiment using CRISPR/Cas9 genome editing technology to test the modified penetrance hypothesis with a coding variant that is known to be associated with a disease. (
  • This finding provides an important framework for scientists moving forward to experimentally test specific disease SNPs to determine if they could be affected by modified penetrance. (
  • Now that we have demonstrated a mechanism for modified penetrance, the long-term goal of the research is better prediction of whether an individual is going to have a disease using their genetic data by integrating the regulatory and coding variants," Dr. Lappalainen said. (
  • Genome-wide association studies have identified a number of common low-penetrance genetic variants, but their contribution to disease risk differs between populations. (
  • Neither the highly variable penetrance of the optic neuropathy ─ which is always much greater in males ─ or the presence of extraocular signs can be exclusively explained by the presence of primary mutations that are necessary but not sufficient to cause the disease. (
  • A woman at-risk for a rare fatal prion disease joined with a bioinformatics team to analyze shared data that provided insights about penetrance and treatment. (
  • Thus, our study suggests a much lower penetrance for rs74315329 for ocular hypertension (and thus glaucoma), in comparison with that reported previously. (
  • We also estimate the strength of the selection pressure against CNVs and correlate this against their overall penetrance. (
  • Correlation between the overall penetrance and selection coefficients of CNVs. (
  • Results: The overall penetrance of PETs during the second decade of life was42%(8 of 19). (
  • The study links modified penetrance to specific diseases at the genome-wide level, which has exciting implications for future prediction of the severity of serious diseases such as cancer and autism spectrum disorder. (
  • Context: Data are scarce on the penetrance of multiple endocrine neoplasia type 1 (MEN1)-related nonfunctioning pancreatic neuroendocrine tumors (NF-PETs) and insulinomas in young MEN1 patients. (
  • We studied the penetrance of HCM and the short- and long-term outcomes of clinical screening and predictive genetic testing of child relatives of patients with HCM. (
  • Penetrance in this case can be defined as the frequency with which individuals of particular genotypes develop either iron overload or clinical manifestations. (
  • My seminar will illustrate how clinical presentations and penetrance were just as challenging to the research that nominated those genetic targets, and will re-consider missed (future) opportunities. (
  • To better understand the reduced penetrance and maternal penetrance bias associated with SCA8 we analyzed the sequence configurations and instability patterns of the CTG repeat in affected and unaffected family members. (
  • Here we show that a maternal high-fat diet more than doubles the penetrance of laterality defects and, surprisingly, induces palatal clefting in Cited2-deficient embryos. (
  • In the cancer patients and individuals with autism, they found an enrichment of haplotypes predicted to increase the penetrance of coding variants associated with cancer and autism spectrum disorder, respectively. (
  • Additional documented symptoms include short-term memory loss, executive functional deficits, cognitive decline, parkinsonism, peripheral neuropathy, lower-limb proximal muscle weakness, and autonomic dysfunction.To study the penetrance of the fragile X-associated tremor/ataxia syndrome (FXTAS) among premutation carriers.Family-based study of 192 individuals (premutation carriers and controls) whose families belong to the Northern or Southern California Fragile X Associations. (
  • We analyzed the presence of parkin sequence variants (mutations or polymorphisms) and exon rearrangements in LRRK2 mutations carriers (both PD patients and unaffected relatives) in order to detect a possible modifier effect on penetrance. (
  • However, comparisons between their penetrance for SCZ or DD/ASD/CM, or estimates of the total penetrance for any of these disorders have not yet been made. (
  • The improved estimates of penetrance will provide crucial information for genetic counselling. (
  • This study provides accurate estimates of G2019S penetrance by minimizing the selection bias. (
  • Our data indicate that Df1 /+ embryos are able to overcome a localized arterial growth impairment and thereby reduce the penetrance of birth defects. (
  • Environmental modifiers: Penetrance may be affected by environmental factors. (
  • The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. (