Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Variant classification”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 199 records · Page 11Linked to original sources
PubMed2026

The importance of integrating genetic testing into reproductive medicine: a retrospective observational study investigating the monogenic causes of human infertility in couples considering ICSI.

The genetic landscape of human infertility is complex with diverse etiologies. Identifying the underlying etiology is crucial for guiding reproductive decisions and improving management for infertile couples. Here, we aim to report on the molecular spectrum of monogenic genetic causes of reproductive failure. Over a 3-year period, we recruited all infertile couples considering assisted reproductive technologies (ART) for whom the underlying genetic cause had been identified, in either partner, using exome sequencing (ES). Clinical data of all participants along with their hormonal profiles, sonographic findings and spermograms were recorded. The study included 50 couples with primary infertility. Clinically, male factor infertility was documented in 26 patients, female factor infertility in 10, while reproductive failure was unexplained in the remaining 14 couples. All participating couples had potentially disease-causing variants in infertility genes. ES identified variants related to male infertility in 26 men, while variants in female infertility-related genes were detected in the remaining couples (n = 24). According to ACMG classification criteria, 78% (39/50) of couples harbored pathogenic/likely pathogenic (P/LP) variants, whereas 22% (11/50) carried variants of uncertain significance (VUS). In view of the identified genetic etiologies, the cohort was stratified into two groups based on the predicted reproductive outcome: (1) couples with significantly impaired reproductive potential, and (2) couples who can have biological children using appropriate medical interventions. However, classifications involving VUS were interpreted cautiously and considered exploratory. This study provides further evidence for the molecular heterogeneity of human infertility and highlights the usefulness of genetic testing for infertile couples pursuing ARTs.

Humans↗
PubMed1984

Polymorphism of erythrocyte galactose-1-phosphate uridyl-transferase in Italy: segregation analysis in 693 families.

In the course of a population study in Italy, blood samples collected from 802 unrelated newborns and both their parents (when possible) have been examined for galactose-1-phosphate uridyltransferase (GALT) polymorphism. Electrophoresis and quantitative assay of GALT activity were not always sufficient for an accurate identification of the different GALT genotypes; segregation analysis provided better criteria for classification. A parent-child correlation coefficient for GALT activity equal to 0.107-0.155 was found when only the transmission of the normal allele was concerned, but the correlation rose to 0.618-0.682 when the Duarte and Los Angeles alleles were segregating. This confirmed the existence of a low (Duarte) and high (Los Angeles) activity variant. The overall validity of our genotype classification is supported by the good agreement between observed and expected mating types and segregations. The following gene frequencies were found for the different alleles: N = 0.9192, G = 0.0036, D = 0.0372 and LA = 0.0400.

Adult↗
PubMedDate not supplied

[Geometry and algebra of branches of the middle cerebral artery].

A classification of the cortical branches of the middle cerebral artery (MCA) is suggested by means of which each branch in any hemisphere can be qualified and identified in any variant of MCA branching. The principle of the classification consists in grouping the branches into arteries and trunks of the second, third, etc. order. Branches supplying blood to a certain sector of the lateral surface of the hemisphere are designated arteries. Their number and zone of branching are constant. Branches giving rise to 2 and more arteries are named trunks. Branching of the trunks, the number of trunks of the second, third, etc. order, and the site and type of origin of the arteries are extremely variable. Each trunk can be designated by a formula stating its order and the name of the artery supplied by this trunk. The arrangement of the MCA branches on the surface of the gyri and deep in the sulci, represented on the map of the lateral surface of the hemisphere, is designated conditionally as geometry of MCA branches. The order of branching of the trunks and the type of origin of the arteries, represented on abstract maps of the lateral surface of the hemisphere, are designated conditionally as algebra of the MCA branches. The variability of the geometry and algebra of the MCA branches must be taken into consideration in operations for extra-intracranial microanastomosis and in endovasal intervention on the MCA.

Cerebral Arteries↗
PubMed1983

Adult non-Hodgkin's lymphoma. Correlation of cell surface marker phenotype with prognosis, the new working formulation, and the Rappaport and Lukes-Collins histomorphologic schemes.

The interrelationships between histomorphologic classification, cell surface marker phenotype and prognosis were prospectively studied in 130 adults with non-Hodgkin's lymphomas. Within each of the classification schemes used there were certain histologic variants that exhibited heterogeneity of cell lineage as well as those that were extremely uniform. Diffuse lymphomas with cell populations consisting of large cells, or mixtures of large and small cells were the most heterogeneous phenotypically and were most resistant to precise definition of immunologic cell lineage. The new Working Formulation for Clinical Usage likewise exhibited considerable heterogeneity of phenotype even within well defined histomorphologic categories. Two immunologic phenotypic variables that conferred a significant favorable prognosis were the expression of surface membrane immunoglobulin (B derivation) and the simultaneous expression of a membrane mu and delta immunoglobulin heavy chain. The results of this study suggest that cell surface marker phenotypic determinations have well defined and potentially useful correlations with histomorphologic classification schemes, and are useful in predicting biologic behavior and prognosis. It is suggested that a knowledge of both immunologic phenotype and histomorphologic characteristics is necessary in formulating therapeutic decisions.

Humans↗
PubMedDate not supplied

[Angiographic study of the colonic vessels with a view to esophagoplasty].

Variants of the colic vessels were studied angiographically in 34 cadavers, drawing up an original classification of the colic arteries arising from the lower mesenteric artery. Sixteen variants of the left colic artery were found, which were grouped into five main types, the classical type being encountered in only 22.6% of the cases. In one case the lower mesenteric artery was absent. In coloesophagoplasty better results were obtained with the isoperistaltic transverse colon than with the upper ileocolon in 64% of the cases and similar results in 20%; in 16% of the cases the latter operation was preferable.

Angiography↗
PubMed2026

Tackling non-canonical splicing in arrhythmogenic cardiomyopathy to reduce the uncertain significance variants burden.

BACKGROUND: Splice-altering variants (SAVs), particularly those outside canonical splice sites, are an underappreciated contributor to inherited cardiovascular diseases. In arrhythmogenic cardiomyopathy (ACM), these variants frequently remain classified as of uncertain significance (VUS) due to limited predictive power and lack of transcript-level evidence, constraining genetic yield and clinical management. Our study aimed to determine the functional impact of SAVs in ACM genes and refine their classification using ACMG/AMP and ClinGen SVI criteria. METHODS: SAVs identified in 200 ACM probands underwent SpliceAI prediction, GTEx cardiac exon-usage annotation, and functional assessment using pSPL3-based minigene assays. Aberrant transcripts were quantified using Percent Splicing Alteration (PSA). Segregation data and ACMG/AMP criteria refined by ClinGen SVI were applied to integrate functional and clinical evidence for classification. RESULTS: Aberrant splicing was confirmed in 9/20 variants (45%), including synonymous, missense, and non-canonical intronic changes. SpliceAI scores correlated strongly with PSA values (R²=0.86). Case-control burden testing revealed significant enrichment of splice-altering variants in DSP, DSG2, DSC2 and FLNC. Integrating predictive algorithms with experimental validation and segregation analysis markedly enhances reclassification of 16/20 variants (80%). CONCLUSION: Splicing defects beyond canonical sites significantly shape ACM genetic landscape. Integrating predictive models with experimental validation clarifies uncertain variants bridging the gap between genomic uncertainty and clinical decision-making.

Humans↗
PubMed1990

Diffuse sclerosing variant of papillary thyroid carcinoma. S-100 protein immunocytochemistry and prognosis.

The recently published second edition of the WHO classification of thyroid tumours describes the diffuse sclerosing papillary carcinoma (DSPC) as a specific variant of papillary thyroid cancer (PC). Besides several histological hallmarks, this rare tumour is characterized by its occurrence in young individuals and is thought to have a less favourable prognosis than PC in general. The observations on two examples of this tumour presented herein, however, are at variance at this assumption. The neoplasms occurred in a 10 year old girl and a 34 year old woman. Each time, diffuse involvement of both thyroid lobes and bilateral cervical lymphadenopathy were seen. In one case, the carcinoma extended into the cervical soft tissue. Follow-up disclosed both patients to be without evidence of disease 2 and 13 years, respectively, after thyroid surgery. Immunocytochemically, both thyroid primaries as well as 7 other cases of DSPC reported in the literature showed dense accumulations of S-100 protein positive dendritic/Langerhans cells. Such infiltrations have been demonstrated to be correlated with a benign clinical course of PC. It is thus suggested that DSPC behaves similarly or even less aggressively than PC in general, at least if prominent Langerhans cell infiltration is present.

Adult↗
PubMed1987

Pathology of nasopharyngeal carcinoma. Proposal of a new histologic classification correlated with prognosis.

To establish a new histologic classification with better correlation with patient prognosis, the histologic features of nasopharyngeal carcinoma (NPC) were correlated with prognosis and clinical stage among 494 patients who had been followed a minimum of 5 years after initial radiotherapy. A slight modification of World Health Organization (WHO) classification by the separation of spindle cell variant from the nonkeratinizing (NK) and undifferentiated carcinomas (UD) provided a better prognostic correlation: keratinizing squamous cell carcinoma (KS), spindle cell carcinoma (SP), round cell carcinoma (RC), and mixed cell carcinoma (Mix, or NK); 5-year survival rates were 21%, 41%, 51.8%, and 54%, respectively. This prognostic distinction was further improved by dividing the three nonkeratinizing carcinomas (SP, RC, and Mix) into two subtypes each, according to the degree of cell anaplasia and pleomorphism: Type A (with marked anaplasia and/or pleomorphism), and Type B (with moderate or little anaplasia). The three Type A carcinomas had very similar 5-year survival rates (33.3 to 38.6%), as did the three Type B carcinomas (60% to 71.8%). Therefore, a working formulation for the malignancy of NPC emerged: high-grade malignancy (KS; 5-year survival, 21%), intermediate malignancy (Type A carcinomas, 5-year survival, 30%-40%), and low-grade malignancy (Type B carcinomas, 5-year survival rate, 60%-72%). The prognostic distinction remained true after stratification by clinical stage. Therefore, the histologic condition of the tumor of NPC correlated with patient's prognosis.

Adolescent↗
PubMed1991

Sinonasal papillomas and human papillomavirus: human papillomavirus 11 detected in fungiform Schneiderian papillomas by in situ hybridization and the polymerase chain reaction.

A series of 19 paraffin-embedded sinonasal papillomas (four squamous papillomas, three fungiform papillomas, nine inverted papillomas, and three cylindrical cell papillomas) were investigated for evidence of human papillomavirus (HPV) infection using immunohistochemistry (polyclonal antibody to HPV capsid antigen), in situ hybridization (DNA probes for HPV 6/11, 16/18, and 31/33/35), and the polymerase chain reaction (primers and probes for HPV 6, 11, 16, 18, and 33). All three fungiform papillomas were positive by all three techniques: immunohistochemistry, in situ hybridization for HPV 6/11, and the polymerase chain reaction for HPV 11. None of the other lesions contained detectable HPV using the specific probes included in this study. These results support the continued classification of fungiform papilloma as a distinctive variant of schneiderian papilloma characterized by a predominantly exophytic growth pattern and an association with HPV 11.

Adult↗
PubMed1985

Cytogenetic study in six Spanish patients with Burkitt's lymphoma.

A cytogenetic study carried out on affected tissues of six children with Burkitt's lymphoma revealed five cases with a typical translocation (8q-; 14q+) and one with a variant t(2p-; 8q+). Additional cytogenetic variations were present in three cases. One had two acrocentric marker chromosomes comprised of material from chromosome #1 (1q21----q44) translocated to the Y gonosome. The other two cases had a cytogenetic alteration of chromosome #12. Cytogenetic studies carried out systematically in Burkitt's lymphoma could be a great help in possibly establishing differences in the biologic and clinical aspects of cases presenting with the t(8;14) versus cases with variant translocations, as this would allow for classification of these patients into groups which, at present, cannot be differentiated using other diagnostic methods.

Adolescent↗
PubMed2025

Optical Genome Mapping Is a Powerful Diagnostic Tool in Non-Hodgkin Lymphoma.

Non-Hodgkin lymphoma (NHL) is a diverse and heterogeneous group of hematological malignancies. These lymphomas arise from the clonal proliferation of either B/T or natural killer lymphocytes, and their correct classification relies partly on identifying characteristic structural variants and copy number alterations. Current standard-of-care technologies for detecting these genomic features, chromosome banding analysis (CBA) and fluorescent in situ hybridization (FISH), are labor intensive and have specific limitations. CBA has low resolution and relies on viable cell culture, whereas the targeted approach of FISH does not provide the whole genome view required for comprehensive disease characterization. This highlights the need for higher-resolution nontargeted genomic methods. Previous studies have evaluated optical genome mapping (OGM) as a whole genome alternative for cytogenomic characterization in NHL diagnostics but were restricted in number and to cases with peripheral blood and/or bone marrow invasion. Here, we selected a comprehensive cohort of 110 NHL cases (79 B-NHL and 31 T-NHL/natural killer-NHL) derived from different types of tissue biopsies, all with established histopathological diagnoses. Seventy-eight samples were genomically well characterized at diagnosis by CBA and FISH. The remaining 32 cases were included because of previous CBA failure, although FISH data were available for 20 cases. OGM provided informative results in 94% of the cohort, with a high concordance rate of 97.6% compared with CBA/FISH in detecting clinically relevant aberrations. The 2 variants that were missed were both present at the detection threshold of OGM. In contrast, OGM successfully resolved 26 samples with previous CBA failure and detected 3 additional disease-defining events, resulting in diagnostic reclassification of 1 patient. Finally, OGM identified novel recurrent aberrations that warrant further investigation into their pathogenetic implications. To conclude, OGM robustly detects clinically relevant structural variants and copy number alterations and presents a promising alternative to CBA and FISH in routine diagnostic evaluation of NHL.

Humans↗
PubMed1990

Episodic paroxysmal hemicrania: a further case and review of the literature.

Episodic paroxysmal hemicrania was delineated as a clinical entity only two years ago, separating patients whose attacks remained grouped in bouts lasting weeks, from those who started irregularly and lapsed into chronicity or began and continued in the chronic state. A further case of the episodic variety and a review of the nine previously recorded cases is reported. The division into episodic and chronic variants of paroxysmal hemicrania conforms with the classification of cluster headache. The similarity of the two conditions is emphasised although the response to indomethacin in paroxysmal hemicrania is a special feature.

Adult↗
PubMed1991

Histopathologic features of high-grade non-Hodgkin's lymphomas in acquired immunodeficiency syndrome. The French Study Group of Pathology for Human Immunodeficiency Virus-Associated Tumors.

High-grade B-cell non-Hodgkin's lymphomas are observed in 5% to 10% of patients with acquired immunodeficiency syndrome. To describe their histologic subtypes, a group of pathologists was formed. One hundred thirteen cases were reviewed and classified according to the Working Formulation, the updated Kiel classification, and a recent description of morphologic variants of high-grade B-cell non-Hodgkin's lymphoma. Three major types of intermediate- or high-grade lymphomas were observed: (1) large-cell or centroblastic mainly polymorphic lymphomas with a component of immunoblasts (35 cases); (2) immunoblastic lymphomas with plasmablastic and plasmacytic features in most cases (33 cases); and (3) small non-cleaved cell Burkitt's or non-Burkitt's lymphoma (41 cases), with 15 cases fitting typical criteria of Burkitt's lymphoma and 26 heterogeneous cases in which the size and shape of the cells and the presence of plasmablastic features varied. The most frequent pathologic sites of involvement at presentation were the lymph nodes, gastrointestinal tract, bone marrow, brain, oral cavity, and muscles. A comparison between the histologic type and the site of involvement showed that most cases involving lymph nodes, bone marrow, or muscles were small noncleaved cell Burkitt's or non-Burkitt's lymphomas, while those that affected the gastrointestinal tract, brain, and oral cavity were centroblastic or immunoblastic lymphomas with consistent plasmacytic differentiation. In 10 cases, previous persistent generalized lymphadenopathy syndrome was present. In 13 cases, the lymphomatous proliferation was associated with follicular or diffuse hyperplasia seen on the same lymph node biopsy specimen or in another lymph node.

Acquired Immunodeficiency Syndrome↗
PubMed1985

[Teratoma].

The current concepts of the histogenesis of teratoma and criteria for the morphological diagnostics of its histological variants recommended by the WHO International Histological Classification of Tumours are presented.

Adolescent↗
PubMed2026

Expert consensus on the reporting and clinical follow up of individuals with incidentally discovered germline RET variants in the UK.

Incidentally discovered pathogenic germline genetic variants refer to the finding of a pathogenic variant in a gene that is unrelated to the reason for the initial test and is not actively sought. Our clinical understanding of the risk of developing a particular medical condition and the required clinical action for a specific pathogenic gene variant is predominantly based on knowledge and information acquired from cases ascertained through a 'phenotype-first approach' rather than in clinically unselected individuals. Therefore, a modified approach is required for incidentally discovered gene variants. Data from large UK and US population-based cohorts have demonstrated that RET variants classified as moderate-risk RET variants as per the American Thyroid Association (ATA) classification have a low penetrance for medullary thyroid cancer and other RET-related conditions (e.g. phaeochromocytoma) and are not associated with excess mortality when identified incidentally in clinically unselected adult individuals. Here, we provide guidance based on multidisciplinary expert consensus opinion for the reporting and subsequent clinical surveillance and management of patients with incidentally discovered RET gene variants in the UK.

Humans↗
PubMed2026

Cytogenetic Diversity of Variant Philadelphia Translocations in Chronic Myeloid Leukemia.

INTRODUCTION: Chronic myeloid leukemia (CML) is a disease characterized by Philadelphia (Ph) translocations. These translocations can be classical or variant. The structural features and diagnostic implications of variant Philadelphia translocations remain incompletely defined, and they display considerable cytogenetic heterogeneity. METHODS: In this retrospective study, variant Ph translocations identified by conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) were systematically classified among 639 patients diagnosed with CML. A total of 35 patients with variant Ph translocations were included in the analysis. Molecular follow-up data, when available, were assessed using RT-qPCR analyses in a subset of patients. RESULTS: Chromosome analysis revealed 2 simple and 33 complex variant Ph translocations. FISH analysis, performed in 20 patients, identified deletions involving BCR, ABL1, or both in a limited number of cases. Additional chromosomal abnormalities and secondary translocations accompanied variant Ph translocations in four patients. The partner chromosomes involved in variant Ph translocations showed marked diversity, involving multiple chromosomal loci. CONCLUSION: Variant Philadelphia chromosome translocations in CML exhibit substantial cytogenetic diversity, reflecting the complexity of their underlying genomic architecture. The rarity and heterogeneity of these rearrangements complicate their classification and interpretation in routine diagnostic practice. Descriptive reporting of variant Ph translocations may contribute to a better understanding of their diagnostic complexity and support more accurate cytogenetic interpretation in CML.

Humans↗
PubMed2026

Mitochondrial DNA diversity in Ecuadorian populations: Recurrence of variant 16136 within haplogroup B2.

The identification of lineage-defining variants, frequently found in the coding region of mitochondrial DNA (mtDNA), is essential for refining haplogroup classification. Most mtDNA studies in South American populations have focused on the control region (CR), which has provided important insights into population structure and maternal lineage origins, although information needed for more robust phylogenetic resolution has been neglected. This study investigates the maternal genetic structure of Ecuadorian populations by combining CR and whole mitogenome analyses. Sequences from the mtDNA CR were obtained from 461 individuals (253 Mestizos and 208 Native Americans), while complete mitogenomes were sequenced for 127 individuals to improve phylogenetic resolution by identifying lineage-defining variants present in coding region. Most mtDNA haplogroups in the two population groups analyzed were of Native American origin (A2, B2, B4, C1, D1, D4), with significant differences in the distribution of specific lineages between them. Among Mestizos, African haplogroups (all within the L branches) and Eurasian haplogroups (H, K, R, U) were detected at low frequencies, whereas no African lineages were observed among Native Americans. The results obtained highlighted a heterogeneity within Ecuadorian populations that must be considered when developing mtDNA haplotype databases for forensic purposes. Whole mitogenome sequences enabled the identification of variants that refined haplogroup classifications, provided a more accurate reconstruction of the maternal genetic diversity, and improve the discrimination between Native American and Asian maternal lineages within haplogroup B4b.

Humans↗
PubMed2026

Biallelic pathogenic variants in FLNB are associated with paediatric steroid-resistant nephrotic syndrome via podocyte cytoskeletal dysfunction.

BACKGROUND: Steroid-resistant nephrotic syndrome (SRNS) is a severe paediatric kidney disease and a leading cause of end-stage kidney disease in children, with a high genetic contribution. While over 80 monogenic causes of SRNS have been identified, a significant proportion of affected patients still lack a clear genetic diagnosis, indicating that additional causative genes remain to be discovered. METHODS: Through whole-exome sequencing of a paediatric SRNS cohort, we identified three probands carrying biallelic FLNB pathogenic variants. Sanger sequencing was performed for familial cosegregation verification and ACMG classification. Expression of Filamin B, Nephrin and Synaptopodin in renal tissues was assessed by immunohistochemistry/immunofluorescence. Wild-type and patient-derived variant FLNB plasmids were constructed and transfected into HEK293T cells and immortalised human podocytes (HPCs). The effects of these variants on protein expression, localisation and cytoskeletal organisation were assessed by western blotting and immunofluorescence. FLNB expression in HPCs was silenced using shRNA to evaluate the impact on podocyte marker proteins, cytoskeletal integrity and migratory capacity. A zebrafish flnb knockdown model was employed to validate its effects on renal development. RESULTS: All three probands presented with isolated SRNS without skeletal developmental abnormalities, and renal tissues showed significantly reduced Filamin B protein expression. In vitro, p.L117P and p.M1803L variants led to markedly reduced protein expression, while p.R470L and p.K2586R induced perinuclear aggregation of Filamin B accompanied by F-actin rearrangement. FLNB silencing led to downregulation of Nephrin and Synaptopodin, cytoskeletal disorganisation and impaired cell migration. Zebrafish flnb knockdown exhibited pericardial oedema, defective nephron development and abnormal podocyte foot processes. CONCLUSION: We report for the first time that biallelic FLNB pathogenic variants are associated with paediatric SRNS by disrupting Filamin B expression, cytoskeletal integrity and podocyte function, providing evidence that FLNB is a novel monogenic cause of SRNS.

Humans↗