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Results for “Variant interpretation”

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PubMed2006

Intraparotid pseudoglandular schwannoma.

A unique intraparotid location of a rare pseudoglandular schwannoma is described. Although the diagnosis of schwannoma could readily be substantiated, accurate subtyping was initially mislabeled. The pitfall was in failing to acknowledge the presence of multiple well-formed gland-like structures, which is instantly thought to be cystically dilated salivary ducts. Immunohistochemically, epithelial-appearing cells lining the duct-like spaces proved to be schwannian in nature. Interpretation of an immediately recognizable gland-like architecture is more problematic when a pseudoglandular variant originates from a nerve coursing through the gland, as here.

Adult↗

PubMed1991

Antigenic and genetic variation in influenza A (H1N1) virus isolates recovered from a persistently infected immunodeficient child.

Antigenic and genetic variations have been analyzed in eight consecutive isolates recovered from a child with severe combined immunodeficiency syndrome persistently infected with naturally acquired type A (H1N1) influenza virus over a 10-month period. Hemagglutination inhibition reactions and T1 oligonucleotide fingerprinting demonstrated that these viruses were related to strains causing outbreaks in the United States at that time (1983 to 1984) but that antigenic and genetic differences between consecutive isolates could be detected. This variation between isolates was examined further by sequencing the RNAs encoding the HA1 region of the hemagglutinin (HA) and the nucleoprotein (NP) in five of the consecutive isolates. Multiple point mutations were detected in both genes, and a deletion of one amino acid was detected in the HA. Depending on the isolates compared, 5.8 x 10(-3) to 17 x 10(-3) substitutions per nucleotide site per year were detected in the RNAs encoding the HA1, and 3.5 x 10(-3) to 24 x 10(-3) substitutions per nucleotide site per year were detected in the NP gene. Fifty-four percent of the base changes in the HA1 and 73% in the NP led to amino acid substitutions. A progressive accumulation of mutations over time was not observed, suggesting that the genetic diversity of these viruses may best be interpreted as the result of shifts in the population equilibrium (quasi-species) of replicating variant genomes.

Amino Acid Sequence↗

PubMed2000

CT and MR arthrography of the normal and pathologic anterosuperior labrum and labral-bicipital complex.

Interpretation of computed tomographic and magnetic resonance arthrograms of the shoulder is complicated by normal variants of the labrum and glenohumeral ligaments. A superior sublabral recess is located at the 12 o'clock position and represents a normal recess between the superior labrum and the cartilage of the glenoid cavity. A sublabral foramen is located at the 2 o'clock position and represents localized detachment of the labrum from the glenoid rim. Buford complex is characterized by absence of the anterosuperior labrum and cordlike thickening of the middle glenohumeral ligament. Imaging features of damage to the anterior labrum include absence or detachment of the labrum and an irregular frayed appearance. Superior labrum anterior-to-posterior (SLAP) lesions are classified as type I (tear confined to the superior labrum), type II (labrum and biceps tendon detached from the superior glenoid), type III (bucket handle tear of the superior labrum), or type IV (bucket handle tear of the superior labrum with lateral extension into the biceps tendon). Increased distance between the labrum and the glenoid, an irregular appearance of the labral margin, or lateral extension of the separation may suggest a SLAP lesion rather than a normal anatomic variant. However, differentiation between normal variants and pathologic conditions and between various types of SLAP lesions remains difficult.

Adolescent↗

PubMed1997

Association between the angiotensinogen 235T-variant and essential hypertension in whites: a systematic review and methodological appraisal.

Recently, an allelic variant of the angiotensinogen gene (AGT 235T) has been associated with increased risk of hypertension. However, this finding has not been confirmed by all investigators. A meta-analysis was performed to examine the association between the AGT 235T-allele and hypertension in whites and to identify potential reasons for the controversial results. All relevant articles published between 1992 and 1996 were identified through multiple sources. The studies were methodologically appraised, and the frequency of the AGT 235T-allele was extracted. The 235T-allele frequency was pooled using the common odds ratio (OR) estimator by Mantel-Haenszel. Homogeneity was assessed using the Breslow-Day test. Together these studies present data on 5493 patients. The AGT 235T-allele was significantly associated with hypertension (OR: 1.20; 95% [CI]: 1.11 to 1.29; P<.0001). This association increased in studies with positive family history (OR: 1.42; 95% CI: 1.25 to 1.61, P<.0001), recruitment of cases from referral centers (OR: 1.39; 95% CI: 1.20 to 1.62, P<.0001), and more severe hypertension (OR: 1.34; 95% CI: 1.22 to 1.47, P<.0001). However, the presence of methodological problems in all studies gives rise to serious concerns regarding bias and confounding. Despite a statistically significant, albeit weak, association between the AGT 235T variant and hypertension that has been confirmed through sensitivity analysis, this finding has to be interpreted with caution, as the methodological weaknesses of the individual studies are likely to have biased the outcome of the meta-analysis. Clearly, more rigorous methods need to be applied in association studies on the genetics of human hypertension.

Alleles↗

PubMed2026

[Analysis of clinical spectrum and genotype characteristics of 9 cases of Fabry disease].

Objective: To investigate the genetic characteristics and clinical phenotypes across different genotypes in patients with Fabry disease. Methods: Clinical data of 9 confirmed FD patients treated from June 2019 to December 2025 at the Affiliated Huai'an No.1 people's Hospital of Nanjing Medical University were retrospectively analyzed. The diagnostic criteria for FD included α-galactosidase A (α-GalA) activity, GLA gene sequencing, globotriaosylsphingosine levels, and renal biopsy findings, supplemented by clinical symptoms and signs. Genetic testing was performed on both the proband and their family members. Proband underwent next-generation sequencing of the GLA gene using the long-range PCR. Family members were verified by conventional PCR combined with Sanger sequencing. Variants were classified according to the 2015 American College of Medical Genetics and Genomics guidelines for sequence variation interpretation. Results: Of the 9 patients, 4 were males and 5 were females. The mean α-Gal A activity was (0.47±0.13) μmol·L-1·h-1 in males and (2.38±0.91) μmol·L-1·h-1 in females. The mean age at diagnosis was (43.0±16.7) years. The main clinical manifestations included renal impairment in 7 cases (proteinuria, chronic kidney disease, or end-stage renal disease), cardiac involvement in 8 cases (myocardial hypertrophy, arrhythmia, etc.), and autonomic nervous system symptoms in 6 cases (hypohidrosis). Pathogenic or likely pathogenic GLA variants were identified in all 9 patients, of which 8 were classified as pathogenic and 1 as a variant of uncertain significance. Three patients underwent family screening: in one case, the variant was possibly inherited from the maternal grandmother; one case was confirmed as a de novo mutation; and in one case, paternal inheritance could not be excluded. Renal biopsy in one patient revealed characteristic myeloid bodies and zebra bodies. Among the 9 patients, 1 received agalsidase α and 8 received agalsidase β, with one case developing infusion-associated reactions after 12 infusions. During the follow-up period, one patient died due to cardiac complications. Conclusions: FD patients exhibit a broad clinical spectrum and diverse genotypes. Atypical presentations should be closely monitored to enable early diagnosis and treatment, thereby improving prognosis.

Humans↗

PubMed1994

Magnetic resonance imaging of bone marrow disorders of the knee.

Bone marrow abnormalities around the knee are encountered frequently when performing MR imaging. Some of these so-called abnormalities may represent normal variations of the bone marrow contents and have no clinical significance. On other occasions, MR imaging may be the only technique that demonstrates a bone marrow lesion. Edema, osteonecrosis, infection, and tumor are entities frequently detected and assessed with MR imaging. We now, perhaps for the first time, are able to visualize and assess directly the bone marrow and its disorders. Knowledge of normal anatomy, variants, and pathologic signs coupled with meticulous imaging techniques are of paramount importance for accurate interpretation of such MR images.

Bone Marrow↗

PubMed1978

[Similarities between human fetal glia cells and glioma cell type in tissue cultures].

Comparative studies were carried out on cell cultures of human fetal brain tissue and of gliomas of different tissue structures. In the cultures of fetal brain tissue maintained for 180 days, four cell-types could be distinguished: 1 large polygonal cells showing epithelial type growth; 2 groups of small round cells; 3 bipolar spongioblasts; and 4 giant astrocytes. The monolayers consisting of large cells formed a nursing layer for the small round cells and could be considered neuroepithelial cells. The small round cells forming groups were regarded as immature gliacytes which created migrational forms by means of active motion. The bipolar spongioblasts were considered a variant of the immature gliacytes. The giant astrocytes displayed the lowest plasticity; their appearance was interpreted as a true differentation and not simply as a change in form of one of the cell types. The cells of the fetal brain tissue could not be identified with the cells of the adult human brain. Still, all the four cell types appeared in the cultures of gliomas with different textures and different degrees of malignity. It seems that with respect to gliogenesis, among the four described cell types the immature gliacytes are of the greatest importance.

Astrocytoma↗

PubMed1994

[Loose bodies of the temporomandibular joint. A rare pathology].

Loose bodies of the temporomandibular joint (TMJ) are an uncommon condition which can be caused by various complaints that can now be diagnosed with high resolution CT. The authors report on 10 cases observed from 1983 to 1992 which were studied with both conventional radiography and CT. The most common conditions were synovial chondromatosis and osteochondrosis dissecans. In the two cases of synovial chondromatosis, the demonstration of ossified loose bodies made the diagnosis easier. The cases of osteochondrosis dissecans presented with more complex diagnostic problems: in two instances the characteristic subchondral bone fragment in the condylar head was clearly visible, but in the third case this small fragment was difficult to identify as it had migrated backwards, making the disorder troublesome to diagnose. An osteophyte fracture and the presence of a bone fragment following condylar head fracture were easily diagnosed by correctly assessing the associated articular changes resulting from an arthrosic and a traumatic condition, respectively. The only case of loose body due to previous TMJ remodeling was easily diagnosed as the totally ossified formation was not seen on the preoperative X-ray film. Finally, two very similar cases, characterized by the presence of an elongated radiopaque formation in the site of the posterior meniscal ligament, were difficult to interpret as no such case is reported in the literature. In both cases an anatomical variant was presumed, characterized by posterior meniscal ligament ossification.

Adult↗

PubMed1990

Histiocytoid (epithelioid) hemangioma of the testis. The so-called vascular variant of "adenomatoid tumor".

Adenomatoid tumors are well-recognized neoplasms generally considered to be of mesothelial derivation. We describe an unusual vascular neoplasm that arose in the testis of a 29-year-old and resembled an adenomatoid tumor by light microscopy. An orchiectomy was performed, and the patient is alive and disease-free 3 years later. The 2-cm tumor was composed of small tubules lined by mesothelial-like cells with uniform, vesicular nuclei. However, some lumina contained erythrocytes, and immunohistochemically, the luminal cells reacted with antibodies to vimentin, Factor VIII-related antigen, and Ulex europaeus I lectin but not cytokeratin or epithelial membrane antigen. A cuff of muscle-specific actin-positive cells surrounded the luminal cell layer. This adenomatoid-like vascular neoplasm is more properly interpreted as a histiocytoid (epithelioid) hemangioma. Although some authors have considered microscopically similar lesions to represent a vascular variant of adenomatoid tumor, we prefer to reserve the term "adenomatoid tumor" for microscopically appropriate proliferations that have mesothelial features.

Adenoma↗

PubMed2025

Predicting dynamic expression patterns in budding yeast with a fungal DNA language model.

Predicting gene expression from DNA sequence remains challenging due to complex regulatory codes. We introduce a masked DNA language model pretrained on 165 fungal genomes closely related to budding yeast that captures conserved regulatory grammar. Fine-tuning the LM on yeast RNA-seq data-including high-resolution transcriptional regulator induction time courses generated in this study-yielded Shorkie, a model that substantially improves gene expression prediction compared to baselines trained without self-supervision. Shorkie identified canonical transcription factor (TF) binding motifs and tracked their usage across induction experiments. Furthermore, Shorkie accurately predicted variant effects, outperforming leading sequence-to-expression models in cis-eQTL classification and achieving high concordance with massively parallel reporter assays. Interpretability analyses revealed Shorkie's ability to resolve promoter dynamics, splicing signals, and temporal changes in regulatory motif usage. This framework demonstrates that evolutionary-scale pretraining combined with transfer learning substantially improves our ability to decode gene regulation from sequence, providing insights into noncoding variants and regulatory networks.

Journal Article↗

PubMed2004

Application of a diagnostic algorithm for inherited thrombocytopenias to 46 consecutive patients.

BACKGROUND AND OBJECTIVES: The Italian Gruppo di Studio delle Piastrine recently developed a diagnostic algorithm to assist clinicians in the diagnosis of inherited thrombocytopenias. This algorithm is based on the simplest possible diagnostic investigations and can also be used in centers that are not highly specialized. The aim of the present study was to validate this diagnostic algorithm by applying it to a case series of genetic thrombocytopenias. DESIGN AND METHODS: The diagnostic algorithm was applied retrospectively to 46 consecutive patients observed during the last five years at a single institution. Twenty-eight were affected by defined illnesses or their variants, while 18 had a disorder that did not fit the criteria for any known genetic thrombocytopenia. The study was based on the evaluation of clinical records and laboratory tests. RESULTS: The diagnostic algorithm recognized: 4 homozygous and 4 heterozygous Bernard-Soulier syndromes, 11 MYH9-related diseases, one von WillebrandOs disease type 2B, one gray platelet syndrome and one X-linked thrombocytopenia with thalassemia. Moreover, it identified 4 patients with the clinical and laboratory features of heterozygous Bernard-Soulier syndrome not caused by mutations in the coding region of the GPIbalpha, GPIbbeta, GPIX or GPV genes, and two patients with the clinical phenotype of MYH9-related disease but without MYH9 mutations. Since the diagnostic flow chart did not allow prompt recognition of two subjects with MYH9-related disease, we introduced a small change to the previously proposed flow chart to obviate this defect. INTERPRETATION AND CONCLUSIONS: The diagnostic algorithm correctly diagnosed 26 of 28 patients with known disorders or phenotypic variants of known disorders. By a simple modification of the investigation sequence, its sensitivity reached 100%. The algorithm also identified 18 patients with new, as yet uncharacterized forms of genetic thrombocytopenia.

Algorithms↗

PubMed2000

Torquability of microcatheter guidewires: the resulting torsional moment.

Guidewires for microcatheters used for the subselective catheterization of small vessels must meet high quality requirements in regard to handling, steerability, radiopacity and physical properties. The aim of this paper is to classify one of the factors that determine the physical and mechanical parameters of a number of existing microcatheter guidewires. A torsion-testing equipment for guidewires was devised. Nitinol wires were tested and compared with the austenitic stainless steel variants. 13 different commercial wires were tested. Tensile strength, shear modulus and wire diameter are the determining factors of the torsional rigidity of guidewires. By interpreting the measured torsional momentums various statements concerning the torsional rigidity of different wires can be made. The properties of guidewires are characteristic features of a system and friction and flexible strength examinations have to be carried out to design new variants of wires to meet the requirements of interventional physicians.

Algorithms↗

PubMed2002

Genomic organization, transcript variants and comparative analysis of the human nucleoporin 155 (NUP155) gene.

Nucleoporin 155 (Nup155) is a major component of the nuclear pore complex (NPC) involved in cellular nucleo-cytoplasmic transport. We have acquired the complete sequence and interpreted the genomic organization of the Nup155 orthologos from human (Homo sapiens) and pufferfish (Fugu rubripes), which are approximately 80 and 8 kb in length, respectively. The human gene is ubiquitously expressed in many tissues analyzed and has two major transcript variants, resulted from an alternative usage of the 5' cryptic or consensus splice donor in intron 1 and two polyadenylation signals. We have also cloned DNA complementary to RNAs of the Nup155 orthologs from Fugu and mouse. Comparative analysis of the Nup155 orthologs in many species, including H. sapiens, Mus musculus, Rattus norvegicus, F. rubripes, Arabidopsis thaliana, Drosophila melanogaster, and Saccharomyces cerevisiae, has revealed two paralogs in S. cerevisiae but only a single gene with increasing number of introns in more complex organisms. The amino acid sequences of the Nup155 orthologos are highly conserved in the evolution of eukaryotes. Different gene orders in the human and Fugu genomic regions harboring the Nup155 orthologs advocate cautious interpretation of synteny in comparative genomic analysis even within the vertebrate lineage.

3T3 Cells↗

PubMed2002

Geographic and haplotype structure of candidate type 2 diabetes susceptibility variants at the calpain-10 locus.

Recently, a positional cloning study proposed that haplotypes at the calpain-10 locus (CAPN10) are associated with increased risk of type 2 diabetes, or non-insulin-dependent diabetes mellitus, in Mexican Americans, Finns, and Germans. To inform the interpretation of the original mapping results and to look for evidence for the action of natural selection on CAPN10, we undertook a population-based genotyping survey of the candidate susceptibility variants. First, we genotyped sites 43, 19, and 63 (the haplotype-defining variants previously proposed) and four closely linked SNPs, in 561 individuals from 11 populations from five continents, and we examined the linkage disequilibrium among them. We then examined the ancestral state of these sites by sequencing orthologous portions of CAPN10 in chimpanzee and orangutan (the identity of sites 43 and 19 was further investigated in a limited sample of other great apes and Old World and New World monkeys). Our survey suggests larger-than-expected differences in the distribution of CAPN10 susceptibility variants between African and non-African populations, with common, derived haplotypes in European and Asian samples (including one of two proposed risk haplotypes) being rare or absent in African samples. These results suggest a history of positive natural selection at the locus, resulting in significant geographic differences in polymorphism frequencies. The relationship of these differences to disease risk is discussed.

Africa↗

PubMed2006

On the synthesis and interpretation of consistent but weak gene-disease associations in the era of genome-wide association studies.

Emerging technologies are allowing researchers to study hundreds of thousands of genetic variants simultaneously as risk factors for common complex diseases. Both theoretical considerations and empirical evidence suggest that specific genetic variants causally associated with common diseases will have small effects (risk ratios mostly <2.0). However, the combination of even a few small effects (e.g. effects of fewer than 20 common genetic variants) could account for a sizeable population attributable fraction of common diseases and shed important light on disease pathogenesis and environmental determinants. Nevertheless, the inauguration of genome-wide association studies only magnifies the challenge of differentiating between the expected, true weak associations from the numerous spurious effects caused by misclassification, confounding and significance-chasing biases. Standards are urgently needed for presenting and interpreting cumulative evidence on gene-disease associations, especially for consistent but weak associations. Criteria for synthesis of the evidence should include sound methods for study conduct and analysis, biological plausibility, experimental evidence and adequate replication in large-scale, collaborative studies. Efforts by the Human Genome Epidemiology Network (HuGENet) are currently ongoing to streamline and operationalize these criteria for data on genetic associations with common diseases.

Cohort Studies↗

PubMed1991

Differential release of active proteinase inhibitors by two rat mammary adenocarcinoma variants possessing different metastatic potentials.

The ability of tumor cells to express elevated levels of proteinases capable of degrading tissue matrix and basement membrane components in vitro has been correlated to their invasive and metastatic potential. Many in vitro invasion assays have been performed either in the presence of serum or with tumor cells that had been previously grown in serum. Since serum contains large amounts of active proteinase inhibitors, their presence could complicate interpretations. We have, therefore, attempted to measure the amounts of serine proteinase inhibitors released into culture medium by two rat mammary adenocarcinoma metastatic variants selected in vitro for serum-independent growth and differing in their in vivo metastatic behavior. Concentrated spent media (CSM) derived from cultures of poorly metastatic MTLn2(T42D) and highly metastatic MTLn3(T17D) tumor cells, grown in the presence and absence of fetal bovine serum (FBS) for 20-24 h, were compared for the presence of serine proteinase inhibitors capable of inactivating alpha-chymotrypsin. Our results show that when MTLn2(T42D) and MTLn3(T17D) tumor cells were exposed to FBS, the CSM of MTLn2(T42D) exhibited nearly 5-fold greater amounts of active proteinase inhibitors than that of MTLn3(T17D). The amount of proteinase inhibitory activity detected in the CSM of tumor cells not exposed to FBS was not eliminated but declined by 82% and 37% for MTLn2(T42D) and MTLn3(T17D), respectively. Analysis for enzyme-inhibitor (E-I) complex formation by nonreducing sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography confirmed the kinetic results and revealed that the major inhibitor present in CSM/FBS of both variants forms a heat- and sodium dodecyl sulfate-stable E-I complex with an apparent molecular weight of approximately 79,000, identical to that formed when FBS or purified alpha 1-proteinase inhibitor is incubated with [alpha-125I]chymotrypsin. E-I complexes with apparent molecular weights of 44,000 and 50,000 were formed from CSM/bovine serum albumin of MTLn3(T17D) and MTLn2(T42D), respectively, that were not detected when [alpha-125I]chymotrypsin was incubated with bovine serum albumin. We infer from these observations that, in culture, poorly metastatic MTLn2(T42D) tumor cells, as compared to their highly metastatic MTLn3(T17D) counterparts, exhibit an increased capacity to retain and subsequently release significantly greater amounts of serum-derived active proteinase inhibitors. Moreover, the detection of proteinase activity by kinetic analysis and E-I complexes by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiography in CSM prepared from cultures not exposed to FBS indicates that both variants have the capacity to produce their own inhibitors.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗

PubMed1990

Perspectival appearing and Gibson's theory of visual perception.

Although Gibson (1979) did not explicitly discuss the perspectival appearing of the ecological environment, his important ecological approach to visual perception can accommodate both (a) the stream of visual-perceptual experience that flows at the heart of the visual system's total activity of ordinary visual preceiving (ordinary seeing), and (b) the dimension of the visual experiential stream that is the ecological environment's perspectival appearing to the visual perceiver. In the present article, perspectival appearing is located at the level of brain centers of the visual system, where processes are determined by the spatiotemporally structured visual stimulus flux. And the stream of visual experience is interpreted as itself possessing a kind of perspective structure (as does the visual stimulus flux), including variant and invariant features that the visual system isolates and extracts from experience, producing the perceiver's cognitive visual "awareness-of" (Gibson, 1979) the environment and self in the environment.

Attention↗

PubMed2026

Origins and timing of somatic variants in the brain.

Somatic variants accumulate in human brain cells throughout the lifespan. Variant allele fraction has traditionally been used as a proxy for both the developmental timing of somatic variants and their functional effect, based on the assumption that earlier mutations are shared by larger cell populations and therefore have greater potential for severe phenotypes. However, recent discoveries challenge this simplified model. Variables such as developmental bottlenecks, lineage restriction, and cellular and molecular context play critical roles in shaping the distribution and functional impact of somatic variants in the brain. These insights support a shift toward a context-dependent framework for interpreting somatic mosaicism.

Humans↗