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Results for “Variant interpretation”

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At least 127 records · Page 7Linked to original sources

PubMed1992

Molecular basis of human hypertension: role of angiotensinogen.

Essential hypertension is a common human disease believed to result from the interplay of multiple genetic and environmental determinants. In genetic studies of two large panels of hypertensive sibships from widely separated geographical areas, we obtained evidence of genetic linkage between the angiotensinogen gene (AGT) and hypertension, demonstrated association of AGT molecular variants with the disease, and found significant differences in plasma concentrations of angiotensinogen among hypertensive subjects with different AGT genotypes. The corroboration and replication afforded by these results support the interpretation that molecular variants of AGT constitute inherited predispositions to essential hypertension in humans.

Adult↗

PubMed2026

Swimming Upstream to Understand Congenital Anomalies of the Kidney and Urinary Tract: Zebrafish Models for Developmental Biology, Disease Mechanisms, and Functional Interpretation of Genetic Variation.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of pediatric chronic kidney disease (CKD) and comprise a heterogeneous group of developmental disorders with a substantial genetic contribution. Advances in next-generation sequencing have facilitated the identification of numerous candidate genes and rare variants associated with CAKUT. However, establishing causality and defining the biological functions of implicated genes remain major challenges. Functional validation is therefore essential to bridge the gap between gene discovery and mechanistic understanding, enabling the interpretation of genetic variation within the context of kidney development and disease. The zebrafish (Danio rerio) has emerged as a powerful in vivo model for studying renal development and interrogating the function of CAKUT-associated genes. Its utility stems from a high degree of genetic and developmental conservation with humans, conserved nephrogenic pathways, optical transparency during embryogenesis, and the relative ease of genetic manipulation. In this review, we provide an overview of zebrafish kidney development within the broader context of vertebrate nephrogenesis, highlighting the key genetic programs governing intermediate mesoderm specification, nephron segmentation, and pronephric morphogenesis. We then systematically examine CAKUT-associated genes that have been modeled in zebrafish, focusing on studies that have linked genetic perturbations to renal development and structural phenotypes. Finally, we discuss the strengths and limitations of zebrafish models for functional genomics and variant interpretation and consider their emerging role in bridging genetic discovery with mechanistic insights into CAKUT pathogenesis.

Animals↗

PubMed1983

Repolarization variant vs acute pericarditis. A prospective electrocardiographic and echocardiographic evaluation.

Patients with ECG nonischemic ST segment elevation were prospectively studied to determine the accuracy of the initial ECG diagnoses. Evaluations were made of 131 consecutive patients by serial clinical, ECG, and echocardiography to establish a diagnosis. Eighty-six (66 percent) had an initial ECG interpretation of repolarization variant. Only three of the 86 (3 percent) subsequently met clinical criteria for acute pericarditis. Analysis of the mean frontal ST segment vector and PR segment depression revealed no significant differences between the 119 patients with final clinical diagnosis of repolarization variant and the 12 with clinical acute pericarditis. The diagnostic reliability of the initial ECG alone as a means of confirming acute pericarditis is low (9/45, 20 percent) but in the detection of repolarization variant is extremely high (83/86, 97 percent).

Acute Disease↗

PubMed1985

[Acoasmatic hallucinosis in tardive schizophrenia].

A study of late schizophrenia manifested in the syndrome of involutional paranoid has allowed the identification of the clinical variant of such psychoses (44 observations) differing from the classical forms in that the clinical picture was predominated by elementary acoustic hallucinations (acoasms). The phenomenological analysis has established that the formation of the clinical picture is determined by acoasms and also the resulting delirium of imagination and delirious interpretations. Two major variants of such psychoses have been specified and described ("the syndrome of acoasmatic hallucinosis" and "the hallucinational-delirious syndrome with the predominance of acoasms"). It has been established that each of these syndromal variants may determine the picture of the disease throughout its course or be one of the sequential stages of its development.

Aged↗

PubMed1983

Two cases of prenatal diagnosis of a satellited Yq chromosome.

Accurate interpretation of chromosomal variants is essential in prenatal diagnosis in order to distinguish polymorphisms from potential pathology in the fetus. This paper reports intra-uterine diagnosis of a satellited Yq in two unrelated families. The 29-year-old consultant in Case A sought prenatal diagnosis because of a maternal family history of Down syndrome. Case B was studied because of maternal age of 37. GTG banded chromosome analysis of cultured amniotic fluid cells from both cases revealed a 46,XY chromosome constitution with extra material present on the Yqter. This was interpreted to be satellite material. QFQ, CBG and AgNOR staining were performed. The material in question proved to be AgNOR positive, indicating that it was transcriptionally active for ribosomal RNA production during the last cell cycle. In addition, frequent satellite association between the Yqter and other acrocentric chromosomes was noted. These findings confirmed the initial interpretation. Other family members were studied and an AgNOR positive Yqs chromosome was confirmed in normal males in three generations of both families. The Yqs chromosome observed in the fetal cells was therefore considered a normal variant. The outcome of pregnancy in Case A was a phenotypically normal male. Case B had not delivered at the time of this writing. The origin of this satellite material on the Y chromosome is considered.

Adult↗

PubMed1985

Preferential localization of variant nucleosomes near the 5'-end of the mouse dihydrofolate reductase gene.

We have probed the structure of nucleosomes within the 31-kilobase pair long, transcriptionally active gene for dihydrofolate reductase (DHFR) in mouse cells which contain multiple copies of the DHFR gene. We found that the distribution of electrophoretically variant nucleosomes within the DHFR gene is highly nonuniform: variant DHFR nucleosomes are abundant within and in the immediate vicinity of the approximately 200-base pair (bp) long first DHFR exon, and decrease by at least 10-fold within two nucleosomes upstream and downstream from this region. The nonuniformly distributed variant DHFR mononucleosomes are of two electrophoretically distinguishable discrete types. One corresponds to a mononucleosome containing a approximately 180-bp DNA fragment and possibly also histone H1 and high mobility group proteins. The other type of variant DHFR mononucleosome contains a approximately 146-bp DNA fragment, and its changes in relative content within the DHFR gene closely parallel those of the 180-bp variant mononucleosome. Several lines of evidence are consistent with the interpretation that the electrophoretically variant approximately 146-bp (core) mononucleosome species corresponds to diubiquitinated DHFR nucleosomes. We discuss possible causal relationships between the observed nonuniform distribution of variant nucleosomes within the DHFR gene and the DHFR gene transcription.

Animals↗

PubMed2025

BRCA1 Exon 11 Mutations in Breast Cancer: A Study From Pakistan.

Breast cancer ranks among the top causes of cancer-related deaths in women around the globe, with genetic mutations in the BRCA1 gene being a frequent cause of breast or ovarian cancer. This study investigates hotspot mutations in exon 11 of the BRCA1 gene among Pakistani women diagnosed with breast cancer. Thirty clinically diagnosed breast cancer patients, all women, were enrolled in the current study, and high-quality DNA was extracted from peripheral blood samples. Two of the twenty-five successfully sequenced samples had a homozygous missense variant (c.2312T > C: p.Leu771Ser) detected by Sanger sequencing after PCR amplification. Upon investigation in the ClinVar database, the identified variant showed conflicting interpretations of pathogenicity. Demographic data highlighted an early disease onset, showing that 56% of patients were under 50 years of age. The need for genetic screening was further supported by the fact that 24% of the patients had a positive family history of cancer. Our study emphasizes the necessity of screening BRCA1 gene mutations to better understand the pathogenic potential of the identified variants in the Pakistani population.

Humans↗

PubMed1981

Nucleotide sequence variants of Rattus norvegicus mitochondrial DNA.

The mitochondrial DNA (mtDNA) molecules of different albino, domesticated rats (Rattus norvegicus) of the SASCO colony are of two kinds (SASCO-1 and SASCO-2) in regard to their sensitivity at certain sites to a number of restriction enzymes. MtDNA molecules from Utah wild R. norvegicus (Wild-UT) have sensitivities to restriction enzymes which differ at some sites from either SASCO-1 or SASCO-2 mtDNA molecules. Four single nucleotide differences were found among the HindIII F fragments (169 nucleotides) of SASCO-1, SASCO-2, and Wild-UT mtDNAs. Arguments are presented in favor of the interpretation that each variant nucleotide is the third nucleotide of the codon containing it, and that none of the four differences would result in a difference in the respective amino acid translated.

Animals↗

PubMed1981

A variant of the Wiedemann-Beckwith syndrome.

The following combination of findings were established by histological examination of biopsy or autopsy material in an 11-day-old male baby: congenital mesoblastic nephroma, nodular renal blastema, dysgenetic pancreatic cyst, "cytomegaly" of the adrenal cortex, hyperplasia and hypertrophy of the islets of Langerhans, hypoplasia of the thymus and the lymphatic tissue. Since some of these changes constitute the characteristic histological findings in the Wiedemann-Beckwith syndrome and the remainder can be readily reconciled with it, the assignment of this case to this syndrome is discussed. Although the three cardinal symptoms are lacking, the combination of findings are interpreted as a variant of the wiedemann-Beckwith syndrome.

Adrenal Glands↗

PubMed1991

Tertiary and quaternary structural differences between two genetic variants of bovine casein by small-angle X-ray scattering.

The casein complexes of bovine milk consist of four major protein fractions, alpha s1, alpha s2, beta, and kappa. Colloidal particles of casein (termed micelles) contain inorganic calcium and phosphate; they are very roughly spherical with an average radius of 650 A. Removal of Ca2+ leads to the formation of smaller protein aggregates (submicelles) with an average radius of 94 A. Two genetic variants, A and B, of the predominant fraction, alpha s1-casein, result in milks with markedly different physical properties, such as solubility and heat stability. To investigate the molecular basis for these differences, small-angle X-ray scattering was performed on the respective colloidal micelles and submicelles. Scattering curves for submicelles of both variants showed multiple Gaussian character; data for the B variant were previously interpreted in terms of two concentric regions of different electron density, i.e., a "compact" core and a relatively "loose" shell. For the submicelle of A, there was a third Gaussian, reflecting a negative contribution due to interparticle interference. Molecular parameters for submicelles of both A and B are in agreement with hydrodynamic data in the literature. Data for the micelles, for which scattering yields cross-sectional information, were fitted by a sum of three Gaussians for both variants; for these, the corresponding two lower radii of gyration represent the two concentric regions of the submicelles, while the third reflects the average packing of submicelles within the micellar cross section. Most of the molecular parameters obtained showed small but consistent differences between A and B, but for submicelles within the micelle several differences were particularly notable: A has a greater molecular weight for the "compact" region of the constituent submicelle (82,000 vs 60,000) and a much greater submicellar packing number (6:1 vs 3:1). Reasons for these and other differences are to be sought in sequence differences and in differences in calcium-binding sites and charge distribution.

Animals↗

PubMed2026

Molecular Landscape and Advanced Diagnostic Technologies for BRAF Mutations in Cancer: From Quantitative PCR and ddPCR to CRISPR-Based Platforms.

BRAF mutations are key oncogenic alterations across multiple malignancies, including melanoma, thyroid carcinoma, colorectal cancer, non-small cell lung cancer, glioma, and hairy cell leukemia. The most prevalent variant, BRAF-V600E, induces constitutive activation of the MAPK signaling pathway, promoting tumor progression and influencing therapeutic responsiveness. Accurate detection of BRAF alterations is therefore essential for molecular classification, prognostic assessment, treatment selection, and resistance surveillance. This review summarizes the molecular heterogeneity of BRAF mutations and critically evaluates current diagnostic methodologies. Conventional approaches such as allele-specific PCR and Sanger sequencing are compared with advanced quantitative platforms, including high-resolution melting analysis, droplet digital PCR, and next-generation sequencing, with emphasis on analytical sensitivity, mutation coverage, and clinical applicability. Emerging technologies such as CRISPR-based assays, rolling circle amplification systems, and nanoparticle-based biosensors and point-of-care diagnostic platforms are also discussed for their potential to enhance ultra-sensitive detection, particularly in liquid biopsy settings. These emerging tools are highlighted for their potential to enable ultra-sensitive, rapid, and decentralized mutation detection, particularly in liquid biopsy settings. Key challenges, including intratumoral heterogeneity, low allele-frequency variants, FFPE-associated artifacts, and clonal evolution under therapeutic pressure, are examined within a translational framework. In addition, we examine critical barriers to clinical implementation, including standardization, cost, and global accessibility of molecular diagnostics, and outline potential solutions through scalable technologies and decentralized testing strategies. We propose that optimal BRAF testing requires a mutation subclass-informed and clinically integrated strategy combining comprehensive baseline profiling with longitudinal molecular monitoring. Future diagnostic paradigms will likely integrate multi-omics data and artificial intelligence (AI)-assisted interpretation to refine precision oncology implementation. Looking forward, we propose that optimal BRAF testing will require integration of multi-omics profiling with AI-assisted interpretation, enabling automated variant classification, real-time clinical decision support, and improved prediction of therapeutic response and resistance.

Humans↗

PubMed1977

Stem cell (immunoblastic) lymphoma. A variant of B lymphocytic lymphoma.

From a histologic review of cases coded as Hodgkin's disease and reticulum cell sarcoma, 12 cases were selected as examples of stem cell lymphoma in which the preponderant cell has characteristics of the B immunoblast. Clinically, these lesions affect the elderly (average age 57.3 years), disseminate early, and, with a few exceptions, progress rapidly to a fatal termination. Morphologically, the neoplastic stem cells, which have pyroninophilic cytoplasm, form diffuse infiltrates with an admixture of acidophilic cells. As a regional variation, the pattern in these lesions overlaps histologically with that seen in angioimmunoblastic lymphadenopathy. The overlap in patterns is presumptive evidence that the angioimmunoblastic pattern at times may be a precursory expression of the stem cell lymphoma. On the basis of morphologic features, these tumors are interpreted as a variant of B cell lymphomas.

Adult↗

PubMed2026

Bayesian Integration of Tumor Mutational Signatures and Somatic Features Refines Pathogenicity Assessment of Germline Mismatch Repair Variants.

Variants of uncertain significance (VUS) in mismatch repair (MMR) genes represent a persistent bottleneck in germline interpretation for Lynch syndrome, creating a critical opportunity to leverage tumor biology to refine pathogenicity assessment. Although tumor features such as microsatellite instability (MSI) and immunohistochemistry (IHC) are routinely evaluated, they are typically interpreted separately from germline classification, and their quantitative contribution within ACMG/AMP frameworks remains poorly defined. We therefore analyzed paired germline and tumor sequencing data from 1110 tumors across 1073 patients with colorectal or endometrial cancer to determine whether mismatch repair-deficient (MMR-d) mutational signatures can be quantitatively integrated into Bayesian germline variant interpretation. Using COSMIC single-base substitution signatures, tumors were classified as MMR-d or MMR proficient, and an empirically derived likelihood ratio (LR) quantified the association between MMR-d signatures and pathogenic germline MMR variants. The presence of an MMR-d signature increased the likelihood of an underlying pathogenic germline MMR variant approximately eightfold (LR ≈ 8; log10 LR ≈ 0.90), whereas its absence provided moderate-to-strong benign evidence (LR ≈ 0.156; log10 LR ≈ -0.81). Applying this integrative framework to 45 germline MMR VUS, joint modeling of tumor mutational signatures with additional somatic and variant-level evidence resulted in clinically significant reclassification of 38 (84.4%) variants, including three reclassified as pathogenic or likely pathogenic and 35 as likely benign. A total of 16 downgraded variants were independently downgraded by Invitae. These findings demonstrate that tumor mutational signatures can be formally incorporated into Bayesian germline interpretation, transforming tumor data into quantitative pathogenicity evidence and offering a principled strategy to reduce VUS burden in hereditary cancer genetics.

Humans↗

PubMed2026

Integrating germline and tumor sequencing to improve hereditary cancer diagnosis and care.

A subset of cancers arises due to inherited germline pathogenic variants in specific genes, known as hereditary cancers. These genes typically include tumor suppressors, DNA repair and replication fidelity genes, and occasionally oncogenes. In most hereditary cancer syndromes, Knudson's two-hit hypothesis applies, where a second somatic event inactivates the remaining allele of a tumor suppressor or DNA repair gene, leading to tumorigenesis. Advancements in genome-wide sequencing have significantly enhanced our understanding of the mutational processes involved in hereditary cancers. In particular, the assessment of microsatellite instability (MSI), tumor mutational burden (TMB), and mutational signatures has emerged as a powerful tool for the identification of hereditary tumors. Tumors with high or ultra-high TMB often reflect underlying DNA repair deficiencies, while specific mutational signatures can pinpoint the defective pathway. These tumor mutational features are especially informative in syndromes involving mismatch repair (MMR), homologous recombination (HR), base excision repair (BER), nucleotide excision repair (NER), and polymerase proofreading. Moreover, tumor sequencing aids in the interpretation of germline variants, identifies somatic mosaicism, and helps differentiate hereditary from sporadic cancers. Additionally, tumor molecular features associated with DNA repair deficiencies offer insights into personalized therapies, such as the use of PARP inhibitors for BRCA1/2-deficient tumors and immune checkpoint inhibitors for MMR- and polymerase proofreading-deficient cancers. Tumor profiling also uncovers actionable mutations in oncogenes like RET and VHL, which can be targeted with specific therapies. This review explores the integration of tumor molecular features with germline genetic data to refine diagnosis, risk assessment, and therapeutic strategies in hereditary cancer.

Humans↗

PubMed1988

Significance of duct-acinar dysplasia in prostatic carcinogenesis.

Duct-acinar dysplasia of the prostate is defined as a premalignant lesion characterized by cytologic, and especially nuclear, abnormalities that resemble those of carcinoma and affect the lining epithelial cells of preexisting ducts and acini. A progressive continuum of cytologic abnormality is divided into three grades, with grade III identified by the presence of numerous large nucleoli. Foci of carcinoma have been identified at their point of origin from dysplastic ducts, which confirms the malignant potential of this lesion. Foci of dysplasia are found in roughly 80% of prostates with invasive carcinoma and 40% of glands without cancer. It is concluded that the majority of prostate cancers probably arise within dysplasia foci. Foci of grade III dysplasia occasionally evolve by proliferation of cells to fill duct lumens. The intraluminal cell masses display a cribriform pattern, which has previously been interpreted as a variant of invasive Gleason grade 3 carcinoma. Dysplasia is further linked biologically to malignant transformation by the immunohistochemical demonstration of progressive loss of cytoplasmic differentiation markers and inappropriate overexpression of some markers during the evolution of dysplasia.

Humans↗

PubMed1993

Kinetic models for unfolding and refolding of ribonuclease T1 with substitution of cis-proline 39 by alanine.

The replacement of cis proline 39 of ribonuclease T1 by an alanine residue leads to a decrease in stability by about 20 kJ/mol and to major changes in the folding kinetics that are not easily explained by the proline model for protein folding. In particular, a novel very slow reaction is observed in the refolding of the Pro39Ala variant. Here the unfolding and refolding kinetics of this protein are further investigated. We show that the very slow reaction is not a prolyl isomerization. It is not created by a slow isomerization of the unfolded protein, nor is it catalyzed by prolyl isomerase, and all molecules have to undergo this reaction during refolding. Most of the unfolded Pro39Ala molecules contain an incorrect trans isomer at the remaining cis Pro55. They use a sequential pathway for refolding, in which trans to cis isomerization at Pro55 precedes the very slow reaction. The refolding of the minor fraction of unfolded Pro39Ala molecules with a correct cis isomer at proline 55 is a single first-order reaction that is limited in rate by the very slow step. The folding mechanism of wild-type ribonuclease T1 cannot be used to explain these results and independent mechanisms are proposed to model the unfolding and refolding of the Pro39Ala variant. The molecular interpretation of the changes in the folding mechanism is tied to the question, as to whether the cis character of the peptide bond at position 38-39 is maintained after the substitution of Pro39 by alanine. A possible explanation could be that the novel very slow folding reaction involves the trans to cis isomerization of the Tyr38-Ala39 bond. Such a reaction is probably slow, since the activation energy is high and since tight coupling with the formation of structure is required to stabilize the cis form of a non-prolyl peptide bond. Alternatively, the strong decrease in folding rate could be correlated with the general destabilization of ribonuclease T1 by the Pro39Ala mutation.

Alanine↗

PubMed1976

[Sphingolipid storage disease as an example of a molecular neuropathology (author's transl)].

A short survey on the sphingolipid storage diseases is presented. The chemical nature of the accumulated substances is related to the genetically induced enzymic blocks on their biodegradation. Two disorders are stressed with alter the nervous system: metachromatic leukodystrophy and familiar infantile amaurotic idiocy (GM2-gangliosidosis). The difficulties in the causal interpretation of three variants of the latter disease due to the involvement of isoenzymes are dealt with. The relationship between the enzyme defect in these disorders and their time of clinical onset is discussed. Finally, the diagnostic possibilities are presented which are a prerequisite for preventing a further dissemination of these therapy-resistent inborn errors of metabolism.

Child, Preschool↗

PubMed1979

Studies on 1-beta-D-arabinofuranosyl cytosine-resistant mutants of Chinese hamster fibroblasts: III. Joint resistance to arabinofuranosyl cytosine and to excess thymidine--a semidominant manifestation of deoxycytidine triphosphate pool expansion.

Variants isolated from mutagenized Chinese hamster fibroblasts by a single cycle of exposure to ara-C distributed into two classes: (1) deoxycytidine (dC) kinase deficient clones with a high level of resistance, this phenotype was recessive in hybrids; and (2) clones exhibiting joint resistance to thymidine (dT) and to "low" ara-C concentration, this phenotype was accounted for by an increased dCTP pool. The incorporation of exogenous dC into macromolecules was markedly altered in these variants. In hybrids, the phenotype of joint resistance to dT and ara-C was semidominant. Through a second selection step, variants cumulating recessive high resistance to ara-C and semidominant dT resistance were recovered. The identification of these two classes of ara-C-resistant variants suggests an interpretation of the known phenotypes of ara-C resistance as manifestations of chromosomal gene mutations. Dominant resistance mutations might contribute to the survival of cancer cells during prolonged ara-C chemotherapy.

Animals↗