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PubMed1991

[The characteristics of the clinical course of lymphosarcomas in conformity with the morphological variants of the WHO and Working Formulation classifications].

Histological and cytological preparations of the lymph nodes, spleen, bone marrow and other tumors from 140 patients with different variants of lymphosarcomas were subjected to a comparative clinicomorphological analysis. The data obtained were correlated to the WHO classification and the working formulation of non-Hodgkin's lymphomas intended for clinical use. It has been found desirable that the working formulation may be used for predicting the disease course and elaboration of the programs of lymphosarcoma treatment.

Adolescent↗
PubMed1990

Chronic myeloproliferative disorders: prognostic importance of new working classification.

Variants of chronic myeloproliferative disorders (CMPD) were compared according to their clinical features and classified by bone marrow biopsy appearances. Subsequently, this classification was further evaluated using survival data and histological variables from iliac crest biopsy specimens of an additional 1391 patients, making a total of 2241 patients available for analysis of outcome. The patients were grouped again into three main classes: "typical"; "variant"; and "transformed". "Typical" comprised the "classic" groups. "Variant" included the less uniform myeloproliferative syndromes, distinguished also by more variable clinical features, a different prognosis, and a greater tendency to fibrotic and blastic transformation. "Transformed" defined the end stages of both "typical" and "variant" types. Ten subgroups were distinguished by different histology and prognosis. Particular prognostic importance was assigned to atypia and immaturity of haemopoiesis, predominance of individual haemopoietic cell line, number and anomalies of megakaryocytes and progressive fibrosis. It is suggested that the proposed subclassification would be helpful for studies of epidemiology and therapeutic trials by allowing more homogeneous groups to be recognised.

Bone Marrow↗
PubMed2004

Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation.

INTRODUCTION: Interpretation of results from mutation screening of tumour suppressor genes known to harbour high risk susceptibility mutations, such as APC, BRCA1, BRCA2, MLH1, MSH2, TP53, and PTEN, is becoming an increasingly important part of clinical practice. Interpretation of truncating mutations, gene rearrangements, and obvious splice junction mutations, is generally straightforward. However, classification of missense variants often presents a difficult problem. From a series of 20,000 full sequence tests of BRCA1 carried out at Myriad Genetic Laboratories, a total of 314 different missense changes and eight in-frame deletions were observed. Before this study, only 21 of these missense changes were classified as deleterious or suspected deleterious and 14 as neutral or of little clinical significance. METHODS: We have used a combination of a multiple sequence alignment of orthologous BRCA1 sequences and a measure of the chemical difference between the amino acids present at individual residues in the sequence alignment to classify missense variants and in-frame deletions detected during mutation screening of BRCA1. RESULTS: In the present analysis we were able to classify an additional 50 missense variants and two in-frame deletions as probably deleterious and 92 missense variants as probably neutral. Thus we have tentatively classified about 50% of the unclassified missense variants observed during clinical testing of BRCA1. DISCUSSION: An internal test of the analysis is consistent with our classification of the variants designated probably deleterious; however, we must stress that this classification is tentative and does not have sufficient independent confirmation to serve as a clinically applicable stand alone method.

Amino Acid Sequence↗
PubMed2006

Advances in molecular classification of renal neoplasms.

Kidney neoplasms are classified by light microscopy using the World Health Organization (WHO) system. The WHO system defines histopathologic tumor subtypes with distinct clinical behavior and underlying genetic mutations. In adults, the common malignant subtypes are variants of renal cell carcinoma (RCC). Histopathologic classification is critical for clinical management of RCC, but is becoming more complex with recognition of novel tumor subtypes, development of procedures yielding small diagnostic biopsies, and emergence of molecular therapies directed at tumor gene activity. Therefore, classification systems based on gene expression are likely to become essential for diagnosis, prognosis and treatment of kidney tumors. Recent DNA microarray studies have shown that clinically relevant renal tumor subtypes are characterized by distinct gene expression profiles, which are useful for discovery of novel diagnostic and prognostic biomarkers. In this review, we summarize the WHO classification system for renal tumors, general applications of microarray technology in cancer research, and specific microarray studies that have advanced knowledge of renal tumor diagnosis, prognosis, therapy and pathobiology.

Carcinoma, Renal Cell↗
PubMedDate not supplied

[The dependence of the progression of chronic glomerulonephritis on the clinical and morphological types of glomerulonephritis and on the tubulointerstitial changes].

Progression of chronic glomerulonephritis (CGN) is strongly associated with morphologic type of the disease, tubulointerstitial changes, some clinical syndromes. The aim of the study was to trace relations between the onset of chronic renal failure within 7 years since the diagnosis (fast progression of CGN--FP CGN), CGN clinical variant according to M. Ia. Ratner et al. classification (1987) and histomorphological changes in the renal biopsy. Unfavorable clinical types (active nephritic types and nephrotic-hypertensive type) proved dominating predictor of FP CGN not only because of close relationship between these type and FP CGN but also due to FP CGN occurrence in morphologically unfavorable morphological types and tubulointerstitial changes in line with concomitant unfavorable clinical types.

Adolescent↗
PubMed2024

Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK).

PURPOSE: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network. METHODS: A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group working group. RESULTS: CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants in which (A) active evidence suggests a reduced-penetrance effect size (eg, from case-control or segregation data) and (B) reduced penetrance effect is inferred from weaker/potentially inconsistent observed data. CONCLUSION: CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, although developed for cancer susceptibility genes, are potentially applicable to other clinical contexts.

Humans↗
PubMed2000

Childhood epilepsy with occipital paroxysms: clinical variants in 134 patients.

PURPOSE: In its recent proposal, the Commission on Classification and Terminology of the International League Against Epilepsy classified childhood epilepsy with occipital paroxysms (CEOP) into two syndromes with different predominant seizure types: early onset (Panayiotopoulos type) with eye deviation and ictal vomiting and late onset (Gastaut type) with initial ictal visual symptoms. We documented the clinical features of a large group of patients with CEOP to confirm whether the classification is justified. METHODS: A file review of all patients with partial-onset seizure and interictal occipital spikes referred to our pediatric seizure unit between January 1975 and May 1997 yielded 134 who met the criteria for CEOP. Data were collected with a specially developed protocol and classified according to the two International League Against Epilepsy systems: (a) seizure classification, to test age-specific differences associated with the predominant seizure type, and (b) syndrome classification, to determine whether the clusters of signs and symptoms are sufficiently delineated. RESULTS: Three groups were defined according to the predominant ictal manifestations. Group 1 (visual) consisted of 24 patients (17.9%) with ictal visual symptoms; 19 (14%) of these patients also had overlapping adversive manifestations, either as a separate seizure or as part of the same event (median age at first and last seizure, 7 years 11 months and 10 years). Group 2 (adversive) consisted of 72 patients (53.7%) with tonic eye deviation (median age at first and last seizure, 5 years 2 months and 7 years 2 months). Group 3 (nonvisual, nonadversive) consisted of 38 patients (28.4%) with various seizure spread patterns (median age at first and last seizure, 6 and 7 years 2 months). Two syndromes were identified. The Gastaut type included all 24 patients in the visual group (group 1); seizures were brief and frequent and were diurnal in 83%. The Panayiotopoulos type included all 72 patients in group 2; ictal eye deviation occurred in 100% of the patients and ictal vomiting in 44%; prolonged seizures were observed in 35% and were more frequent in patients who had ictal vomiting than in those who did not (46.8% versus 25%, respectively; p < 0.027). Seizures were infrequent; 24% of patients had a single seizure and 58% had nocturnal seizures. Onset was earlier than for the Gastaut type (p < 0.002). The 38 patients with nonoccipital manifestations did not satisfy the criteria for the complete form of either syndrome. CONCLUSIONS: The most common type of CEOP, the Panayiotopoulos type, is characterized by a cluster of signs and symptoms sufficiently delineated to justify their separate classification from Gastaut-type CEOP, despite the absence of ictal vomiting in more than 50% of the patients.

Age of Onset↗
PubMed1996

[The importance of the clinical classification of chronic glomerulonephritis for the prognosis of its progression and of the efficacy of therapy].

A significant correlation exists between clinical types of chronic glomerulonephritis (CGN) in a new clinical classification and morphological CGN types according to classification of WHO experts. Rapid progression is significantly correlated with clinicomorphological variants of CGN represented by unfavorable clinical types and unfavorable morphological types. No rapid progression occurred in combination of clinically favourable types and morphologically favourable and unfavorable types. The above classification is recommended for practice.

Adolescent↗
PubMed2026

'Truthsets' for clinical validation of large-scale functional assays: Practice recommendations from Cancer Variant Interpretation Group UK (CanVIG-UK).

BACKGROUND: Large-scale functional assays, including multiplex assays of variant effect, have substantial potential to resolve variants of uncertain significance (VUS), particularly for rare missense variants where clinical and population evidence are limited. The ClinGen assay-level clinical validation framework described by Brnich et al provided baseline guidance for the use of functional data for variant classification. However, clear consensus regarding construction of variant 'truthsets' by which to clinically validate functional data remains lacking. METHODS: CanVIG-UK developed consensus recommendations for truthset construction through an iterative national consultation process involving the CanVIG Steering Advisory Group (CStAG), wider CanVIG-UK membership, and engagement with international functional genomics experts. Consultation was based on previous analyses of 2,120 truthset constructions examining the impact of truthset composition on evidence point allocation within the ClinGen assay-level clinical validation framework. RESULTS: Across several consultations, CanVIG-UK established nine guiding principles and seven best-practice recommendations for assay-level clinical validation, using the assumed context of an assay for a cancer susceptibility gene where loss-of-function is the mechanism of pathogenicity. The principal recommendation stipulates, where assays are intended for use in interpretation of largely missense variants, the truthset used to validate should comprise only missense variants. Rather than mixtures of different variant types which may serve to over-estimate assay performance. Additional recommendations support option for relaxation of truthset stringency to improve power, augmentation of benign missense truthsets with systematically derived 'proxy-clinical' benign variants, independent clinical validation separate from assayist-defined validation, and careful evaluation of missense score distributions against that of protein-truncating and synonymous variants. Guidance is also provided for scenarios with limited pathogenic truthset availability and for assays reporting multiple deleterious zones or readouts. CONCLUSIONS: The CanVIG-UK principles and recommendations for truthset construction upon the ClinGen assay-level clinical validation framework, while aiming to form a baseline for future discussion regarding other functional and disease contexts and helping to address the gap between publication of new data and routine clinical implementation.

Journal Article↗
PubMed1988

Ocular palsy preceding chronic relapsing idiopathic polyneuropathy. Poor response to plasma exchange.

We report a case of chronic relapsing idiopathic polyneuropathy developing six weeks after the onset of extraocular palsy. As in the other four published cases, the patient failed to respond to steroids and also in this case to plasma exchange, thus confirming the poor prognosis. The electrophysiological features and poor response to plasma exchange are at variance with a demyelinating pathogenesis and suggest classification of this form as a distinct clinical variant.

Adult↗
PubMed1996

Sulcus vocalis: a rational analytical approach to diagnosis and management.

The term sulcus vocalis has been applied to a spectrum of disorders ranging from minor vocal fold indentations to destructive lesions causing severe dysphonia. To clarify the pathophysiology and to develop a more rational approach to treatment, we report a series of sulcus patients including 20 surgical cases. Clinical and histopathologic analysis produced a clinically useful classification: type 1 is a physiologic variant accentuated by atrophy but with intact lamina propria; types 2 (sulcus vergeture) and 3 (sulcus vocalis) are characterized by severe dysphonia, loss of vibratory activity, and destruction of the functional superficial lamina propria. These latter cases respond favorably to microsurgery designed to remove destroyed tissue, release scar contracture, and promote mucosal redraping by regional undermining. Further study of the extracellular matrix of the superficial lamina propria (Reinke's space) might indicate a common pathway in the pathogenesis of sulcus deformities and other related benign vocal fold lesions.

Adult↗
PubMedDate not supplied

[A case of GM-Gangliosidosis (atypical form of the AB variant)].

A case of GM-gangliosidosis, variant AB, with some atypical feautres is reported in a male child, who died at the age of 4 years and 3 months. When he was 2 and a half years old, he showed signs of progressive cerebral disease with increasing motor and mental impairment. The clinical signs suggested a form of neurolipidosis; however the data of the enzymatic activities of the peripheral blood leucocytes did not show any deficit related to these forms. More specifically the values of the exosaminides A and B were normal, although the component A was near the lowest limit of the range. The anatomical, histological, histochemical, ultrastructural and chemical studies showed that it was a form of GM-gangliosidosis with visceral involvement. In the crude lipid extracts of various organs there was not only GM-ganglioside, but also a compound not previously demonstrated in these forms of neurolipidosis. Chemically this compound may be considered a phosphoglyco-lipid-and protein complex. From the enzymatic data in the peripheral blood leucocytes, the case may be a variant AB of the Sandhoff and al. classification (1971). However some clinical signs make our case closer to the 3th type of the O'Brien and al, classification while some histopathological aspects are similar to Tay-Sachs disease (i.e. to the variant B of the Sandhoff et al. classification; i.e. to the 1th type of the O'Brien et al. classification). These data, and the presence of an 'unknown compound', not yet demonstrated in the known forms of GM-gangliosidosis, support the hypothesis that our case may be considered as an 'atypical' form of the variant AB of the gangliosidosis GM and that further studies are necessary to reach a final nosography of these entities.

Brain Chemistry↗
PubMed2026

Comprehensive evaluation of ACMG/AMP-based variant classification tools.

MOTIVATION: The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines represent the gold standard for clinical variant interpretation. Despite the widespread adoption of ACMG/AMP guidelines, a comprehensive comparison of the software tools designed to implement them has been lacking. This represents a significant gap, as clinicians require evidence-based guidance on which tools to use in their practice. RESULTS: We benchmarked four ACMG/AMP-based tools (Franklin, InterVar, TAPES, Genebe) selected from 22 tools, and compared their performance with LIRICAL, a top-performing phenotype-driven tool, using 151 expert-curated datasets from Mendelian disorders. Selection criteria included free availability, VCF compatibility, operational reliability, and not being disease-specific. Our evaluation framework assessed top-N accuracy (N&#x2009;=&#x2009;1, 5, 10, 20, 50), retention rates, precision, recall, F1 scores, and area under the curve (AUC). Statistical validation employed bootstrap confidence intervals (n&#x2009;=&#x2009;1000) and Friedman tests. LIRICAL (68.21%) and Franklin (61.59%) demonstrated superior top-10 variant prioritization accuracy in Mendelian disorders, significantly outperforming other tools (P&#x2009;=&#x2009;.0000). Results demonstrate that tools with advanced phenotypic integration significantly outperform those relying primarily on genomic features. AVAILABILITY AND IMPLEMENTATION: All data and source code required to reproduce the findings of this study are openly available in the Code Ocean repository at https://doi.org/10.24433/CO.6562438.v1.

Software↗
PubMed2026

CanVar-UK: A collaborative platform for germline interpretation in cancer susceptibility genes.

Germline variants in cancer susceptibility genes (CSGs) are typically inherited rather than arising de novo. Hence, wide cascade testing of families across geographies is common, meaning consistency in variant classification is particularly critical. Variant interpretation requires collation of variant-level data from diverse sources, as well as assembly of comprehensive clinical data, often necessitating sharing of information between genomic testing centers. Here, we describe CanVar-UK, a freely accessible web platform bespoke designed to support interpretation of germline CSG variants. CanVar-UK contains variant-level data for over 1.1 million single-nucleotide variants (SNVs), comprising all possible coding SNVs in 116 established CSGs. The data sources with which variants are annotated include in silico scores from 11 clinically relevant tools, population allele frequencies from gnomAD v4.1, case counts from multiple cohorts, including National Health Service (NHS) clinical laboratory testing, variant-level readouts from 47 selected functional and splicing datasets across 19 CSGs, genetic epidemiology studies, and live linkage to existing consensus classifications in the ClinVar database. The diagnostic discussion forum is only available to registered diagnostic scientist users. Through this, a variant-tagged email message can be dispatched in real time across the diagnostic forum community of >1,500 users, with all exchanges and classifications captured and stored in the platform. Already widely used by NHS diagnostic clinical scientists in the UK, CanVar-UK has a rapidly growing international diagnostic user base (>800 UK and >600 non-UK registered users). Survey of the NHS diagnostic user community illustrates the wide-ranging utility of CanVar-UK within their clinical workflows for interpretation of germline CSG variants.

Journal Article↗
PubMed1998

Dominant expression of sex-hormone-binding-globulin exon-7 splicing variant over wild-type mRNA in human ovarian cancers.

The intracellular expression of sex-hormone-binding-globulin(SHBG) exon-7-splicing-variant mRNA in human ovarian cancers was demonstrated by reverse-transcription/polymerase-chain-reaction, Southern-blot and DNA-sequencing analyses. Analysis of the missing base pairs proved that they corresponded to the entire exon 7, which is considered to encode a portion of the steroid-binding site, suggesting that the steroid-binding affinity of this variant might be different from that of the SHBG wild type. SHBG wild-type and variant mRNA was detected in all normal ovaries and in benign and malignant ovarian tumors analyzed. There were no significant differences in mean SHBG wild-type and variant mRNA levels among the 3 types of tissue, but the ratio of SHBG exon-7-splicing-variant to wild-type mRNA level in ovarian cancers was significantly higher (p < 0.05) than that in normal ovaries, with over-expression in some benign tumors. SHBG mRNA levels and the ratio of SHBG variant to wild-type mRNA was not associated with histological classification or clinical stages of ovarian cancers. These results suggest that over-expression of SHBG-exon 7-splicing-variant mRNA to the wild type might indicate the potential for neoplastic transformation.

Blotting, Southern↗
PubMed1998

World Health Organization Classification of lymphomas: a work in progress.

The World Health Organization (WHO) publishes classification handbooks for all neoplastic diseases. The last WHO Classification of leukemias and lymphomas was published in 1976. Since that time, through cytogenetics and molecular biology, it has been shown that many hematopoietic neoplasms are associated with a unique genetic profile. Similarly, the development of widely available and routinely applied monoclonal antibodies has allowed the identification of a unique immunophenotypic profile for most leukemias and lymphomas. These techniques have permitted the recognition of a number of distinct disease entities, and also enhance both diagnostic accuracy and reproducibility. The WHO Classification has been developed under the joint auspices of the European Association for Hematopathology (EAHP) and the Society for Hematopathology (SH). First organized in 1995, the Steering Committee appointed 10 committees covering T-cell and B-cell lymphomas and leukemias, myeloid and histiocytic tumors. The committees were asked to develop a list of diseases within their topic area, and to establish definitions of each disease according to established criteria. The WHO Classification uses the principles of the R.E.A.L. Classification, which defines each disease according to its morphology, immunophenotype, genetic features, postulated normal counterpart, and clinical features. Morphologic and clinical variants of individual diseases are discussed in the text, and their use is optional. The proposed classification was presented at the USCAP meeting in 1997, the site of the first joint meeting of the EAHP and SH. The presentation was followed by an open forum attended by EAHP and SH members. The Steering Committee also appointed a Clinical Advisory Committee to ensure that the classification meets clinical needs, and to resolve questions of clinical significance. The proposed WHO Classification for lymphomas is similar to the R.E.A.L. Classification for lymphomas, with minor modifications and reassessment of provisional categories based on new data since 1994.

B-Lymphocytes↗
PubMed1984

[Glucose-6-phosphate dehydrogenase deficiency and other erythrocyte enzyme abnormalities].

Normal values of glucose-6-phosphate dehydrogenase (G6PD), 6-phosphogluconate dehydrogenase (6PGD), glutathione reductase (GR), glucosephosphate isomerase (GPI), pyruvate kinase (PK) and pyrimidine 5'-nucleotidase (P5N) have been determined in normocytes, reticulocytes, newborn cord erythrocytes, and leucocytes. Metabolic and clinical aspects of G6PD and the classification of its genetic variants are reviewed. Enzyme determinations and their variation in drug-induced haemolysis are critically presented. Extensive tables are published listing the drugs and compounds that can cause haemolysis in G6PD-deficient patients, as well as those preparations which may, probably, be administered safely. Clinical and biochemical data in patients with the inherited enzyme defects GR, GPI, PK, and P5N, as well as acquired deficiency of the last-mentioned in chronic lead intoxication, are reviewed in the light of our personal experience in this field.

5'-Nucleotidase↗