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Results for “Variant interpretation”

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PubMed2005

In vivo and in vitro studies of a novel cytokine, interleukin 4delta2, in pulmonary tuberculosis.

RATIONALE: Tuberculosis progresses despite potent Th1 responses. A putative explanation is the simultaneous presence of a subversive Th2 response. However, interpretation is confounded by interleukin 4delta2 (IL-4delta2), a splice variant and inhibitor of IL-4. OBJECTIVE: To study levels of mRNA encoding IL-4 and IL-4delta2, and their relationship to treatment and clinical parameters, in cells from lung lavage and blood from patients with pulmonary tuberculosis. METHODS: IL-4delta2, IFN-gamma, IL-4, and soluble CD30 (sCD30) levels were measured by polymerase chain reaction and relevant immunoassays in 29 patients and matched control subjects lacking responses to tuberculosis-specific antigens. RESULTS: mRNA levels for IL-4 and IL-4delta2 were elevated in unstimulated cells from blood and lung lavage of patients versus control subjects (p < 0.005). In control subjects, there were low basal levels of IL-4 and IL-4delta2 mRNA expressed mainly by non-T cells (p < 0.05). However, in patients, there were greater levels of mRNA for both cytokines in both T- and non-T-cell populations (p < 0.05 compared with control subjects). Radiologic disease correlated with the IL-4/IFN-gamma ratio and sCD30 (p < 0.005). After chemotherapy, IL-4 mRNA levels remained unchanged, whereas IL-4delta2 increased in parallel with IFN-gamma (p < 0.05). Sonicates of Mycobacterium tuberculosis upregulated expression of IL-4 relative to IL-4delta2 in mononuclear cell cultures from patients (p < 0.05). CONCLUSIONS: A Th2-like response, prominent in T cells and driven by tuberculosis antigen, is present in tuberculosis and modulated by treatment, suggesting a role for IL-4 and IL-4delta2 in the pathogenesis of tuberculosis and their ratio as a possible marker of disease activity. The specific antigens inducing the IL-4 response require identification to facilitate future vaccine development strategies.

Adult↗

PubMed2000

A unique parotid adenocarcinoma.

A large number of different types of benign and malignant tumours of the salivary glands are recognized, and rare and unusual variants arise from time to time that can be difficult to interpret. We report an apparently unique parotid neoplasm that does not fit any of the currently recognized diagnostic groups and can best be termed lymphadenocarcinoma. Clinical and pathological features are described, and its possible relationship to recognized tumour types is examined.

Adenocarcinoma↗

PubMed2004

Mutation screening of the phosducin gene PDC in patients with retinitis pigmentosa and allied diseases.

PURPOSE: To search for a phenotype associated with mutations in the phosducin gene PDC. METHODS: We screened 853 patients with retinitis pigmentosa or an allied disease diseases, including groups of 61 to 212 patients, each with dominant retinitis pigmentosa (RP), recessive RP, Leber congenital amaurosis, or cone-rod degeneration, for mutations in the PDC gene using direct genomic sequencing of the three coding exons and their flanking intron splice sites. RESULTS: We found one polymorphism in the 5' untranslated region (minor allele frequency of 0.149) and three rare single-base sequence variants (one missense change, one isocoding change, and one in the 3' untranslated region). The rare variants were found in one heterozygous patient each and none was interpreted as pathogenic. CONCLUSIONS: Phosducin mutations are not a major cause of dominant or recessive RP, Leber congenital amaurosis, or cone-rod degeneration. The human phenotype associated with phosducin defects remains unknown.

DNA Mutational Analysis↗

PubMed1991

[The pathogenetic, clinical and treatment problems of the mental disorders in brain trauma].

Authors examine the questions of pathogenesis and clinic of mental disorders caused by cerebrum traumata, as well as the peculiarities of its diagnosis and treatment. There is a principle scheme of systematized post-aggressive reaction after cerebrum injury which emphasises the necessity to study the pathophysiological process from the point of view of norm in pathology, development of protective mechanisms and individual peculiarities (sanagenetical approach). The structural and syndromological method is proposed to appreciate mental disorders and distinguish the variants of psychopathological syndromes. Therapy aspects of some mental disorders are interpreted from the point of view of sanagenetical position.

Brain Injuries↗

PubMed1990

Vestibular papillae of the vulva. Lack of evidence for human papillomavirus etiology.

Vestibular papillae of the vulva are usually considered as anatomical variants of the vestibular mucosa. Clinically, however, they are quite often interpreted as condylomata acuminata and recent studies have suggested that they could be related to human papillomavirus infection. This prompted us to search for human papillomavirus DNA using the Southern blot hybridization technique, by analyzing biopsy specimens taken from 29 patients who presented with papillae of the vestibular mucosa. Human papillomavirus sequences were detected only in two (6.9%) cases. By the same technique, human papillomavirus sequences were detected in 24 (96%) of 25 vulvar warts used as the control specimens. Thus, it appears unlikely that vestibular papillae are related to human papillomavirus infection. They are usually distinguishable from condylomata acuminata by clinical examination alone.

Adult↗

PubMed1989

[The problems of odontogenic kinship analysis in prehistoric anthropology in the example of aplasia/hypodontia].

Prehistorians have been seeking information about kinship in burial complexes for decades. During the last few years paleoanthropologists have once again applied themselves to the resolution of that problem. Many of them favour epigenetic variants as the basis for their kinship analyses. Teeth and maxillary bones seem well suited to be investigated in view to this question. The author discusses whether hypodontia and numerical variants of teeth still meet the criteria demanded of epigenetic variants today. Using the complex odontological feature of hypodontia and its variants as a model, the article shows that by including and interpreting new and little-known facts the amount of information gained from this feature can be increased considerably, as can its value towards kinship analysis. More odontological features have to be added and suitable methods have to be developed. The employment of odontological features for kinship analyses is then likely to be a success.

Anodontia↗

PubMed1985

[Correlation between the electron microscopic picture of small cell cancer of the lung and treatment results].

Electronmicroscopic study of 35 small-cell lung carcinomas showed these to be a group of lung carcinomas having different histogenesis (cytogenesis). Apart from carcinoma without signs of differentiation, this group also includes squamous-cell carcinoma, adenocarcinoma, apudoma and mixed carcinoma with various differentiation of tumour cells. A certain correlation between the ultrastructural features of the tumour and its susceptibility to the treatment is established. Small-cell carcinomas consisting of undifferentiated cells are most susceptible. A relatively good prognosis can be expected when a variant with the endocrine differentiation of tumour cells is treated. Tumours interpreted light microscopically as small-cell carcinoma but ultrastructurally identified as having squamous-cell differentiation, or as adenocarcinoma and mixed carcinoma have the least favourable prognosis after treatment.

Adult↗

PubMed1996

Sinonasal imaging.

Recent changes in sinonasal imaging are a direct result of the development of functional endoscopic sinus surgery. Because of this technique, radiologists have noted an increased volume of sinus imaging, developed new imaging techniques, and are interpreting films in a different manner. This article covers the common variants seen on coronal computed tomography, discusses the complications of functional endoscopic sinus surgery, reviews the radiographic criteria for sinusitis, and addresses the role of computed tomography and magnetic resonance imaging in evaluating the sinonasal cavity.

Aged↗

PubMed1995

["Blue" variant of naevus spilus].

We report on a 29-year-old female patient with an unusual pigmented lesion of the face. Clinically the lesion looked like a pigment patch of the naevus spilus type, while histological examination revealed the presence of dermal melanocytosis and multiple common blue naevi with a discrete lentiginous component in addition. The melanocytic nature of the infiltrate was ascertained by immunohistochemistry analysis using S 100 protein and HMB 45 antibodies. We interpret this lesion as agminated blue naevi in association with lentigo simplex, an unusual variant of speckled lentiginous naevus.

Adult↗

PubMed1986

Occult medullary thyroid carcinoma. Unusual histologic variant presenting with metastatic disease.

A 66-year-old man presented with an enlarged cervical lymph node, interpreted on fine-needle aspiration as squamous cell carcinoma. Histologic assessment of the excised mass demonstrated a mucin-positive glandular neoplasm that, by immunohistochemistry, was positive for carcinoembryonic antigen, calcitonin, and neuron-specific enolase. A subsequent total thyroidectomy revealed a grossly normal organ with a 2-mm microscopic focus of medullary carcinoma and foci of C-cell hyperplasia in the immediate vicinity of the tumor. No amyloid could be demonstrated in either lesion. The diagnostic difficulty encountered in this case is related to the presence of a rare morphologic variant (devoid of amyloid and forming mucin-positive glands) occurring as an occult primary but presenting as a metastasis. Although an occult primary in medullary carcinoma is recognized in familial cases, such a phenomenon is rare in sporadic cases.

Aged↗

PubMed2026

Unlocking the molecular engineering of Geobacillus glycoside hydrolases as a source of industrial biocatalysts.

This review examines Geobacillus sensu stricto as a source of thermostable glycoside hydrolases (GH) for biomass conversion, food processing, and enzyme engineering. Recent peer-reviewed literature was assessed with emphasis on taxonomy, genome-based Carbohydrate-Active Enzymes (CAZyme) prediction, biochemical validation, structural data, and engineering case studies. Taxonomic boundaries were interpreted using current Anoxybacillaceae frameworks, with Parageobacillus treated as a related comparator rather than as Geobacillus. The strongest evidence supports GH13 alpha-amylases, xylan-active systems, beta-xylosidases, and selected accessory enzymes. Recent studies also show that genome mining must be coupled with enzymatic assays and product profiling because CAZyme annotation alone does not prove industrial function. Molecular engineering has improved relevant traits, including the longer thermal half-life of engineered G. stearothermophilus alpha-amylase variants, the increased catalytic efficiency of oligo-alpha-1,6-glucosidase variants, and improved AmyS expression in Bacillus subtilis. Geobacillus glycoside hydrolases are best interpreted as process-specific, engineerable biocatalytic templates. Their translation requires reliable taxonomy, functional validation, structural interpretation, scalable expression and testing on realistic substrates. This synthesis also recognises current limitations: many predicted CAZymes still lack biochemical validation, complete cellulolytic systems remain less mature than xylan- and starch-active systems, and scale-up data remain scarce.

Geobacillus↗

PubMed2026

SeqQC-former: A sequence-quality fusion framework for QC-aware review prioritization of candidate somatic SNVs in cancer genomics.

The accurate prioritization of candidate somatic single-nucleotide variants (SNVs) remains a challenge due to the substantial variability in sequencing quality across genomic loci. SeqQC-Former is a sequence-quality fusion framework that integrates the local nucleotide context with read-level quality-control (QC) covariates derived from matched tumor-normal sequencing data. This integration generates QC-aware prioritization scores for the downstream review of candidate variants. Unlike conventional variant callers, SeqQC-Former is designed not to infer biological truth but to support post-calling review and prioritization under heterogeneous sequencing conditions. The framework was trained and evaluated on a SEQC2-derived dataset comprising 89,447 candidate loci, including 1378 positive and 88,069 negative loci. In chromosome-held-out validation, which aims to reduce potential genomic-position leakage, SeqQC-Former demonstrated strong discrimination (AUROC = 0.9479; AUPRC = 0.9448), indicating good generalization to previously unseen chromosomes. Given that the SEQC2-derived labels contain QC-associated information; these results should be interpreted as an evaluation of QC-aware prioritization capability rather than an independent validation of biological variant correctness. Ablation analyses revealed that structured QC covariates provided the dominant predictive signal under the current SEQC2-derived labeling regime. SeqQC-Former achieved a significantly higher AUROC than classical machine-learning baselines, as determined by DeLong's test (p < 0.01). Application to 53,164 glioblastoma variants demonstrated that external predictions were sensitive to QC scaling and threshold selection, underscoring that model outputs should be interpreted as QC-dependent prioritization scores rather than calibrated probabilities or definitive biological classifications. Overall, SeqQC-Former offers a reproducible post-calling QC-aware prioritization framework for large-scale somatic SNV review and underscores the importance of explicitly modeling sequencing-quality information when interpreting structured cancer genomics datasets.

Humans↗

PubMed2026

Whole-exome Sequencing Identifies Novel Candidate PCNT Variants in a Child With Overlapping MOPD II Features: A Case Report.

A 7-year-old Chinese boy presented with severe postnatal growth failure (height <3rd percentile at age 7 years), global developmental delay, moderate intellectual disability, and characteristic dysmorphic features including hypertelorism, short palpebral fissures, low-set ears, and a broad nasal bridge. A single electrocardiogram demonstrated a borderline corrected QT interval (QTc = 450 ms). No arrhythmias, QT-prolonging medications, electrolyte abnormalities, or relevant family cardiac history were identified. This finding warrants longitudinal cardiology follow-up and should not be interpreted as definitive Long QT syndrome. Whole-exome sequencing identified two novel missense variants in the PCNT gene (NM_006031.5): c.5675A>G (p.Glu1892Gly) in exon 28 and c.9734G>T (p.Arg3245Ile) in exon 45. Both variants were absent from gnomAD, ExAC, the 1000 Genomes Project database, and Chinese population databases, fulfilling ACMG criterion PM2. Although classified as variants of uncertain significance (VUS) because of limited functional evidence and conflicting in silico predictions, the variants occur in a gene associated with primordial dwarfism and are accompanied by partial phenotypic overlap with Microcephalic Osteodysplastic Primordial Dwarfism Type II (MOPD II). However, parental segregation analysis was unavailable; therefore, the variant phase could not be confirmed, and a recessive disease mechanism could not be established. These findings support the presence of candidate PCNT variants in an atypical primordial dwarfism phenotype and illustrate the utility of whole-exome sequencing for generating testable molecular hypotheses in genetically heterogeneous growth disorders. A definitive molecular diagnosis cannot be established at present, and the isolated borderline QTc finding requires further clinical evaluation.

Humans↗

PubMed2025

Genetic study of von Willebrand factor antigen levels ≤ 50 IU/dL identifies variants associated with increased risk of von Willebrand disease and bleeding.

BACKGROUND: von Willebrand disease (VWD) is a common inherited bleeding disorder caused by low levels or activity of circulating von Willebrand factor (VWF). Genetic susceptibility to VWF antigen (VWF:Ag) below normal (≤ 50 IU/dL) in the general population is underexplored. OBJECTIVES: To identify genetic variants influencing VWF:Ag levels ≤ 50 IU/dL. METHODS: We performed a genome-wide association study in 926 cases with VWF:Ag levels ≤ 50 IU/dL and 12 846 controls from 7 studies from the Trans-Omics for Precision Medicine program. We then examined whether significant genome-wide findings were also associated with clinical diagnosis of VWD in 5 biobanks with 708 VWD cases and 1 286 069 controls, and with 6 bleeding and thrombotic disorders in FinnGen. RESULTS: Variants at 2 loci were associated (P < 5 × 10-9) with VWF:Ag levels ≤ 50 IU/dL: ABO and VWF. The VWF index variant, p.Tyr1584Cys, is a rare (0.22%) missense variant with odds ratio (OR) of 78.58, while the ABO index variant is a common intronic variant with a smaller effect (OR = 2.52). Notably, both VWF (OR = 7.16) and ABO (OR = 1.57) variants were also associated (P < .025) with diagnosed VWD. Among p.Tyr1584Cys heterozygotes, the penetrance of VWF:Ag levels ≤ 50 IU/dL was 24.2% and the penetrance of diagnosed VWD was 0.3%. p.Tyr1584Cys was associated (P < .0042) with increased odds of heavy menstrual bleeding (OR = 1.27), iron deficiency anemia (OR = 1.55), and intrapartum hemorrhage (OR = 2.20), but decreased odds of deep vein thrombosis (OR = 0.54). CONCLUSIONS: Although there are currently conflicting interpretations of pathogenicity p.Tyr1584Cys, our results suggest that it is a low penetrance pathogenic variant that contributes to VWF:Ag levels ≤ 50 IU/dL, bleeding, and VWD.

Humans↗

PubMed1999

A consanguineous family with Hirschsprung disease, microcephaly, and mental retardation (Goldberg-Shprintzen syndrome).

Hirschsprung disease, mental retardation, microcephaly, and specific craniofacial dysmorphism were observed in three children from a large, consanguineous, Moroccan family. A fourth child showed similar clinical features, with the exception of Hirschsprung disease. The association of these abnormalities in these children represents the Goldberg-Shprintzen syndrome (OMIM 235730). Mutation scanning of genes potentially involved in Hirschsprung disease, RET, GDNF, EDN3, and EDNRB, showed a sequence variant, Ser305Asn, in exon 4 of the EDNRB gene in the index patient of this family. The Ser305Asn substitution present in two of the four patients and four healthy relatives and absent in one of the remaining two patients illustrates the difficulties in interpreting the presence of mutations in families with Hirschsprung disease. It is unlikely that the EDNRB variant contributes to the phenotype. This consanguineous family might be useful for the identification of a Goldberg-Shprintzen locus.

Amino Acid Substitution↗

PubMed2026

AI-enabled viral genomics: from virus discovery to host prediction and emerging variant forecasting.

The rapid expansion of metagenomic sequencing has generated vast repositories of viral sequence data that far outpace our capacity to interpret them using conventional approaches. Highly divergent sequences, sparse functional annotation, and taxonomically uneven sampling present fundamental challenges for reference-dependent methods, which lose sensitivity precisely for novel and understudied viruses with high public health relevance. Artificial intelligence (AI) provides a new avenue to address these challenges by enabling predictive inference from viral genomes and proteins while reducing dependence on sequence similarity. In this Review, we discuss representative advances in AI for virus discovery, taxonomic classification and functional annotation, prediction of host range and zoonotic potential, and efforts toward forecasting emerging variants. These advances are transforming viral genomics from a largely descriptive discipline into one with increasing predictive capability. We also critically assess the major challenges that constrain current approaches, including the availability of high-quality and representative datasets, rigorous model evaluation, biological interpretability and responsible governance for increasingly capable AI models.

Artificial Intelligence↗

PubMed2004

Automated quantification of 99mTc sestamibi myocardial perfusion compared with visual analysis.

OBJECTIVES: The visual interpretation of 99mTc sestamibi single photon emission computed tomography (SPECT) myocardial perfusion images can be challenging due to the quantity of scan information generated, the large number of normal variants, attenuation artifacts and gender differences. The development of automated, computer derived, quantitative indices of perfusion can assist in this interpretation by providing an objective measure. It is important to verify that similar results can be obtained when the software is used in centres outside those where the algorithms were initially developed. Our objective was to assess the degree of concordance between the visual and automated diagnostic assessments of 99mTc sestamibi SPECT. METHODS: We studied 718 patients referred for 99mTc sestamibi SPECT myocardial perfusion imaging. The SPECT studies were initially interpreted visually without benefit of computer based analysis, and were then subjected to blinded reprocessing to extract quantitative indices of perfusion. RESULTS: There was very good agreement between the visual and quantitative diagnostic classifications. When a visual abnormality was taken to be the reference standard, the automated summed stress score (SSS) showed agreement (SSS>3) in 80% (kappa 0.60, P<0.0001). The area under the receiver operating characteristic (ROC) curve was 0.89 (95% confidence interval (CI), 0.86-0.91). Concordance was greater in those with previous myocardial infarction or severe perfusion defects, but was not affected by age, prior revascularization, stress procedure or heart rate. Concordance over the presence or absence of visual reversibility and the summed difference score (SDS) in abnormal scans was slightly lower (overall agreement 73% (kappa 0.36, P<0.00001) and ROC area 0.84 (95% CI, 0.77-0.90)). CONCLUSION: Automated quantification of 99mTc sestamibi SPECT myocardial perfusion with the SSS and SDS provides objective diagnostic information and concordance when compared with conventional visual image interpretation.

Algorithms↗

PubMed1985

Benign fibrous histiocytoma of the skin. An immunohistochemical analysis of 30 cases.

In this study the immunohistochemical analysis of distinct morphologic variants of benign fibrous histiocytoma (BFH) of the skin was performed with immunoperoxidase technique for both lysozyme and alpha-1-antitrypsin (A1AT). Thirty cases including cellular, fibrous and xanthomatous variants of BFH were selected. Out of the total 6 cases (20%) showed positive staining only for A1AT, 3 cases (10%) only for lysozyme and 10 (33.3%) for both markers. Thus, 19 cases (63.3%) showed positive staining for one of both markers. Positive staining was higher in the cellular variant than the fibrous and xanthomatous types. Negative staining of tumors of definite histiocytic morphology may be interpreted as a variable enzymatic expression of different histiocytic activation and/or undetectable enzymatic content by the current techniques. These results are in accordance with our previous evolutional hypothesis of BFH which considered the cellular tumors as functionally more active variants evolving to less cellular, more fibrous and less active types. Current histogenetic concepts about this controversial group of skin neoplasms are discussed.

Aged↗