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At least 19 recordsLinked to original sources
PubMed1978

Teratocarcinoma cell variants rejected by syngeneic mice: protection of mice immunized with these variants against other variants and against the original malignant cell line.

We reported previously that, by mutagenesis of a malignant teratocarcinoma cell line, it is possible to obtain a number of variant clones that are incapable of forming progressive tumors. Each of these "tum-" variants is rejected in syngeneic mice and stimulates the production of immune memory cells (self-protection). We show here that four different tum- clones confer an immune protection against each other although this cross-protection is invariably weaker than the self-protection. Moreover, mice immunized with living tum- cells are partially protected against the original malignant teratocarcinoma cells, even though the latter cells are incapable of conferring any immune protection when injected after being killed by irradiation. These results indicate that each tum- variant carries at least one specific transplantation antigen that is absent from the original tumor cell line and from most other tum- variants. Other tumor-specific transplantation antigens are probably present on all the tum- variants and also on the malignant teratocarcinoma cell line.

Animals↗
PubMed2026

Phenotypic manifestations and variant reclassification of germline PTEN variants: a nationwide Danish study.

BACKGROUND: Classification of heterozygous germline PTEN variants in patients with, or suspected of having, PTEN hamartoma tumour syndrome (PHTS) remains challenging. Accurate classification is essential as these patients require lifelong cancer surveillance. METHODS: We identified all patients with a PTEN variant previously classified as a variant of uncertain significance (VUS), likely pathogenic (LP) or pathogenic (P), collected clinical data and reclassified all variants using the latest PTEN gene-specific American College of Medical Genetics (ACMG) guidelines. Moreover, genotype-phenotype correlations were assessed. RESULTS: 167 patients from 112 families were enrolled. Eighty-seven unique PTEN variants were identified, including 20 novel variants. After applying the PTEN gene-specific ACMG guidelines, 32 variants (36.8%) were reclassified, resulting in 60 PTEN variants classified as LP/P (69.0%), 18 variants classified as VUS (20.7%), while 9 variants were classified as LB/B (10.3%). Genotype-phenotype correlation was performed among 104 patients with LP/P variants: 51 cancer cases were recorded in 41 patients and a distinct PHTS phenotype was observed in 25% of patients, with macrocephaly being present in 99% of patients with a known head circumference. Twenty-three patients had neurodevelopmental delay and/or autism, and we observed an increased prevalence of missense variants in these patients. CONCLUSION: We identified 87 different PTEN variants, and application of PTEN gene-specific ACMG guidelines led to reclassification of 32 variants (36.8%), underscoring the importance of regular variant reassessment using the most recent gene-specific guidelines, ensuring optimal patient management and surveillance.

Genetic Predisposition to Disease↗
PubMed2025

VarPPUD: Pinpointing diagnostic variants from sets of prioritized, strong candidate variants.

Rare and ultra-rare genetic conditions are estimated to impact nearly 1 in 17 people worldwide, yet accurately pinpointing the diagnostic variants underlying each of these conditions remains a formidable challenge. Because comprehensive, in vivo functional assessment of all possible genetic variants is infeasible, clinicians instead consider in silico variant pathogenicity predictions to distinguish plausibly disease-causing from benign variants across the genome. However, in the most difficult undiagnosed cases, such as those accepted to the Undiagnosed Diseases Network (UDN), existing pathogenicity predictions cannot reliably discern true etiological variant(s) from other deleterious candidate variants that were prioritized through case- or family-level analyses. Pinpointing the disease-causing variant from a small pool of plausible candidates remains a largely manual effort requiring extensive clinical workups, functional and experimental assays, and eventual identification of genotype- and phenotype-matched individuals. Here, we introduce VarPPUD, a tool trained on prioritized variants from UDN cases, that leverages gene-, amino acid-, and nucleotide-level features to discern pathogenic (disease causative) variants from other damaging or deleterious variants that are unlikely to be confirmed as relevant to the disease. VarPPUD achieves a cross-validated accuracy of 79.3% and precision of 77.5% on a held-out subset of uniquely challenging UDN cases, respectively representing an average 18.6% and 23.4% improvement over nine existing state-of-the-art pathogenicity prediction tools on this task. We validate VarPPUD's ability to discriminate likely from unlikely pathogenic variants using both synthetic data generated via a GAN-based framework and a temporally held-out set of UDN patients evaluated between 2022 and 2024. The model was trained exclusively on data available through 2021 and applied without retraining to the post-2021 cohort, demonstrating strong generalizability to newly accrued cases. Finally, we show how VarPPUD can be probed to evaluate each input feature's importance and contribution toward prediction-an essential step toward understanding the distinct characteristics of newly-uncovered disease-causing variants.

Humans↗
PubMed2026

ATM Variants and Breast Cancer Risk in North Macedonia: Focus on the Regionally Enriched p.(Leu2492Arg) Variant.

BACKGROUND: Germline pathogenic variants (PVs) in the ataxia-telangiectasia mutated (ATM) gene are established moderate-risk factors for breast cancer (BC), however, population-specific variant spectra and the clinical significance of many missense variants remain incompletely characterized. AIMS: To evaluate the prevalence of ATM variants in a large cohort of patients with BC from North Macedonia and compare it with that in the general population, with a particular focus on the frequency of the p.(Leu2492Arg) variant and its distribution relative to global genomic datasets. STUDY DESIGN: Retrospective case–control study. METHODS: ATM variants were analyzed in 1,211 patients with BC from North Macedonia using a targeted hereditary cancer gene panel. These findings were compared with those from 1,303 population-based controls analyzed by clinical exome or whole-exome sequencing. RESULTS: Pathogenic ATM variants were identified in 1.9% of BC cases and 0.4% of controls, indicating a significantly increased risk of BC [odds ratio (OR) = 5.02, p = 0.0006]. Most PVs were protein-truncating, with six recurrent variants accounting for over 70% of detections, suggesting regional enrichment. Carriers showed a significantly higher prevalence of human epidermal growth factor receptor 2-positive tumors (OR = 2.92, p = 0.0189). Variants of uncertain significance were observed at comparable frequencies in cases and controls. The p.(Leu2492Arg) missense variant was more frequently detected in cases than in controls (1.9% vs. 1.1%; OR = 1.78, p = 0.086) and exhibited a markedly higher allele frequency in this population than in global databases. CONCLUSION: These findings confirm ATM as a clinically relevant BC susceptibility gene in North Macedonia and highlight the population-specific enrichment of both PVs and the p.(Leu2492Arg) missense variant. The results emphasize the importance of using population-matched controls and regional genomic data for accurate risk assessment and variant interpretation.

Humans↗
PubMed2024

Identification of a novel EYA4 likely pathogenic variant in a Chinese family with postlingual non-syndromic hearing loss and analysis of molecular epidemiology of EYA4 variants.

BACKGROUND: EYA4 variants are responsible for DFNA10 deafness. Due to its insidious onset and slow progression, hearing loss in autosomal dominant non-syndromic hearing loss (ADNSHL) is usually challenging to detect early in clinical settings, with limited intervention options. Genetic testing can aid in early detection of hearing loss, enabling timely intervention to reduce disability rates and improve the quality of life. METHODS: In this study, we report the case of a Chinese family with postlingual and progressive hearing loss that was passed down for four generations. Whole-exome sequencing (WES) was performed on DNA samples from the proband. Candidate variants identified in the proband and family members were confirmed via Sanger sequencing. In silico prediction tools and co-segregation analyses were used to assess the pathogenicity of identified variants. A literature review of known EYA4 variants was performed, analysing variant frequency, distribution characteristics across different populations, and genotype-phenotype correlations. RESULTS: We identified a novel EYA4 variant, c.1745_1748del (p.Glu582ValfsTer6), in a Chinese family with ADNSHL, and co-segregation with the family's phenotype was confirmed. The audiometry showed mid-to-high frequency downsloping hearing loss. To date, 52 pathogenic variants of EYA4 have been reported, with majority identified in Asian populations. Most observed are the missense and frameshift variants. CONCLUSIONS: A novel variant of EYA4 was identified in a Chinese family with postlingual hearing loss, contributing to the expanding spectrum of EYA4 variants. The audiological features of EYA4 variants are highly heterogeneous and often challenging to detect early in clinical settings. Our findings highlight the significance of genetic testing in patients presenting with postlingual hearing loss.

Humans↗
PubMed2026

Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation.

Gene-based therapies are being developed for retinal diseases, including RS1-related X-linked retinoschisis. Therefore it is essential to determine which variants are pathogenic and which are benign when enrolling patients. The Clinical Genome Resource (ClinGen) X-Linked Inherited Retinal Diseases (XLRD) Variant Curation Expert Panel (VCEP) brings together clinician scientists, molecular biologists, and geneticists to apply their expertise and review the clinical, genetic, population, and functional evidence for variants. American College of Medical Genetics (ACMG) guidelines have been modified for RS1 to develop a highly systematic and conservative framework for evaluating variants. The curation process involves applying 28 different codes, each with 4 strength levels (very strong, strong, moderate, supporting) across different domains of phenotype, population data, computational assessment, functional impact, and segregation. With RS1-specific rules, a total of 54 pilot variants were tested. These included 47 variants in ClinVar. Of these 21 variants were re-classified: 2 likely pathogenic variants and one likely benign were changed to variants of uncertain significance and 4 previously unclassified variants were changed to pathogenic, likely pathogenic and likely benign. Other changes resolved conflicts or multiple classifications.

Humans↗
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↗
PubMed2024

A novel variant in the SPTB gene underlying hereditary spherocytosis and a literature review of previous variants.

BACKGROUND: Hereditary spherocytosis (HS, MIM#612641) is one of the most common hereditary hemolytic disorders. This study aimed to confirm a novel variant's pathogenicity and reveal a patient's genetic etiology. METHODS: The clinical data of a patient with HS who underwent genetic sequencing at the Children's Hospital of Chongqing Medical University were reviewed retrospectively. In silico prediction and in vitro minigene splicing reporter system were then conducted on the detected variant to analyze its intramolecular impact. A summary of the literature related to HS due to SPTB gene variants was also presented. RESULTS: A novel variant (c.301-2 A > G) in the SPTB gene (NM_001024858.4) was identified in the proband. Using Sanger sequencing, we conclusively confirmed that the inheritance of the variant could not be traced to the biological parents. The in vitro minigene assay revealed three different transcripts derived from the c.301-2 A > G variant: r.301_474del, r.301_306delCCAAAG, and r.301-1_301-57ins. Through a literature review, patients with HS who had been genotypically validated were summarized and the SPTB gene variant profile was mapped. CONCLUSION: We identified a splicing variant of the SPTB gene, thus confirming its aberrant translation. The novel variant was the probable genetic etiology of the proband with HS. Our findings expanded the variant spectrum of the SPTB gene, thus improving the understanding of the associated hereditary hemolytic disorders from a clinical and molecular perspective and contributing to the foundation of genetic counseling and diagnosis.

Humans↗
PubMed2025

Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.

Cardiovascular diseases are leading global causes of death and disability, often presenting as interrelated phenotypes of atherosclerotic vascular disease, heart failure and arrhythmias. Cardiovascular diseases arise from interactions between environmental factors and predisposing genotypes and include common Mendelian lipid disorders, cardiomyopathies and arrhythmia syndromes. The identification of a pathogenic variant through genetic testing can inform disease diagnosis, risk prediction, treatment and family screening. However, a major roadblock in genomic medicine is that for many variants, especially missense variants, we lack sufficient evidence to enable a definitive classification, and therefore these variants are deemed as 'variants of uncertain significance'. In this Review, we describe how multiplexed assays of variant effects can enable the functional assessment of nearly all coding variants in a target sequence, potentially offering a proactive approach to identifying the functional significance of gene variants that are observed later in a patient. We discuss validation, including the role of in silico variant effect predictors, and how multiplexed experimental methods are informing cardiovascular disease biology and ultimately resolving the problem of variants of uncertain significance at scale.

Humans↗
PubMed2025

The ClinGen Severe Combined Immunodeficiency Disease Variant Curation Expert Panel: Specifications for classification of variants in ADA, DCLRE1C, IL2RG, IL7R, JAK3, RAG1, and RAG2.

PURPOSE: This collaborative study, led by the Clinical Genome Resource Severe Combined Immunodeficiency Disease Variant Curation Expert Panel (ClinGen SCID-VCEP), implemented and adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for interpreting germline variants in genes with established relationships to SCID. The effort focused on the 7 most common SCID-related genes identified by SCID newborn screening in North America: ADA, DCLRE1C, IL2RG, IL7R, JAK3, RAG1, and RAG2. METHODS: The SCID-VCEP conducted a rigorous review of variants that involved database analyses, literature review, and expert feedback to derive gene-specific modifications to the ACMG/AMP guidelines. These specifications were validated using a pilot set of 90 variants. RESULTS: Of these 90 variants, 25 were classified as pathogenic, 21 as likely pathogenic, 14 as variants of uncertain significance, 18 as likely benign, and 12 as benign. Seventeen variants with conflicting classifications in ClinVar were successfully resolved. The criteria included modifications to 20 of the 28 original ACMG/AMP criteria specific to SCID-related genes. CONCLUSION: The SCID-specific variant curation guidelines developed by the SCID-VCEP will enhance the precision of SCID genetic diagnosis and provide a robust framework for interpreting variants in SCID-related genes, contributing to appropriate treatment of SCID.

Humans↗
PubMed2026

Rare variant analysis of whole genome sequenced juvenile idiopathic arthritis multiplex pedigrees identifies rare variants in NOD2 and ACVR1.

Juvenile idiopathic arthritis is a complex rheumatic disease that is influenced by environmental and genetic factors. Linkage and genome-wide association studies have identified genes that contribute to the risk of developing juvenile idiopathic arthritis but are limited in their ability to identify disease-risk variants of large effect. Penetrant, heritable risk variants can be detected in high-risk families, but such cases are uncommon due to the low prevalence of juvenile idiopathic arthritis. This study utilizes whole-genome sequencing of 23 multiplex families, the largest such cohort to date, to discover variants and genes relevant to JIA pathogenesis. Pathogenic variants in NOD2 associated with Blau syndrome, an ultra-rare Mendelian inflammatory disorder, are the most recurrent variants in the cohort, consistent with previous reports that milder presentations of Blau syndrome are oftentimes misdiagnosed as juvenile idiopathic arthritis. For the first time, however, rare variants in ACVR1 and SMAD6, integral components of the Bone Morphogenic Protein pathway, are found to be associated with juvenile idiopathic arthritis. Identified ACVR1 variants map to critical protein domains. AlphaFold modeling predicts that the ACVR1 interaction with its inhibitor OGT is disrupted by these variants, indicating that the patient-mutated protein has a gain-of-function phenotype. Drosophila melanogaster expressing either a wild-type or patient-mutated version of ACVR1 exhibit embryonic lethality, with the mutant exhibiting 1.4-fold greater lethality than wild-type. The combination of family-based cohorts for gene discovery, AI-based computational tools, and animal model studies for tests of variant function underscores shared disease pathogenesis between JIA and monogenic disorders of immunity and connective tissue.

Arthritis, Juvenile↗
PubMed2019

Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE): a cloud-based platform for curating and classifying germline variants.

Variant interpretation in the era of massively parallel sequencing is challenging. Although many resources and guidelines are available to assist with this task, few integrated end-to-end tools exist. Here, we present the Pediatric Cancer Variant Pathogenicity Information Exchange (PeCanPIE), a web- and cloud-based platform for annotation, identification, and classification of variations in known or putative disease genes. Starting from a set of variants in variant call format (VCF), variants are annotated, ranked by putative pathogenicity, and presented for formal classification using a decision-support interface based on published guidelines from the American College of Medical Genetics and Genomics (ACMG). The system can accept files containing millions of variants and handle single-nucleotide variants (SNVs), simple insertions/deletions (indels), multiple-nucleotide variants (MNVs), and complex substitutions. PeCanPIE has been applied to classify variant pathogenicity in cancer predisposition genes in two large-scale investigations involving >4000 pediatric cancer patients and serves as a repository for the expert-reviewed results. PeCanPIE was originally developed for pediatric cancer but can be easily extended for use for nonpediatric cancers and noncancer genetic diseases. Although PeCanPIE's web-based interface was designed to be accessible to non-bioinformaticians, its back-end pipelines may also be run independently on the cloud, facilitating direct integration and broader adoption. PeCanPIE is publicly available and free for research use.

Child↗
PubMed2025

Polygenic variants in DNA repair genes are associated with neurodevelopmental disorders, regression and increased burdens of somatic variants and short tandem repeat expansions.

PURPOSE: Developmental regression, characterized by the loss of acquired milestones, occurs in some individuals with neurodevelopmental disorders (NDDs); yet, its molecular basis remains unclear. Studies suggest that DNA damage repair (DDR) genes, such as FAN1, may protect against neurological dysfunction by modulating the somatic stability of short tandem repeats (STRs). This study explores the contribution of DDR gene variants in NDD cases presenting with regression. METHODS: We analyzed 1087 NDD patients, focusing on those carrying variants in DDR genes and presenting regression. We assessed the sensitivity to DNA damage using mitomycin C on lymphoblastoid cells. Somatic variants and STR expansions were evaluated through high-depth short-read genome sequencing. To further investigate the pathogenetic role of STR expansions, we performed long-read genome sequencing on the most severely affected proband. RESULTS: Probands with regression carried multiple DDR gene variants, several within the Fanconi anemia pathway. Their lymphoblastoid cells showed increased sensitivity to mitomycin C-induced cytotoxicity compared with parental and control samples. Probands with severe phenotypes and regression exhibited an accumulation of somatic variants and STR instability, enriched in neurodevelopmental genes. CONCLUSION: Our findings suggest that polygenic DDR gene variants may contribute to developmental regression in NDDs by promoting the accumulation of somatic variants and STR expansions.

Humans↗
PubMed1977

Genetic variants of human erythrocyte glucose 6-phosphate dehydrogenase: new variants in West Africa characterized by column chromatography.

Five electrophoretically slow-moving genetic variants of glucose 6-phosphate dehydrogenase are described: four are from Nigeria and one is from Togo. All variants have normal or moderately reduced activity, and they are not associated with adverse clinical or haematological manifestations. Three variants have been fully characterized and are different from all previously described ones. Two variants have been partially characterized and at least one of them is also probably new. The overall population incidence of sporadic variants of G6PD in the Nigerian population is 0-3%. In the course of this study a previously described ion-exchange chromatographic technique for the characterization of G6PD variants has been extensively evaluated. Data are given on ten different variants to demonstrate the high resolving power of this technique.

Chromatography, Ion Exchange↗
PubMed1976

Genetic variants of human erythrocyte glucose-6-phosphate dehydrogenase. Kinetic and thermodynamic parameters of variants A, B, and A- in relation to quaternary structure.

The values of Vmax and Km for the three genetic variants A, B, and A- of erythrocyte glucose-6-phosphate dehydrogenase have been determined at 10 different pH values in the range from 5.5 to 9.5, and at four different temperatures in the range from 18.5-40.0 degrees. The log Vmax versus pH curve for each of the enzymes shows a monotonic increase between pH 5.5 and 7, and a plateau from pH 7.5 upwards. These curves, and their temperature dependence, are compatible with the presence of a single ionizable group which, in its conjugate acid form, renders the enzyme-substrate complex inactive. The pK of this group is 6.94 at 18.5 degrees, and its enthalpy of ionization is 7.0 kcal mol-1. The log Km versus pH curves show a broad plateau between pH 6.2 and 8.2, interrupted by a sharp minimum at pH 7.2 for variant B, while variants A and A- show sharp maxima at pH 7.2 and 7.45, respectively. It is proposed that this unusual behavior depends on the dissociation of the tetrameric enzyme to dimers in this pH region. Specifically, it is shown that a sharp maximum or minimum of Km can arise if cooperative uptake or release of protons is linked to dimer formation, and if the degree of cooperativity is different for the free enzyme compared to the enzyme-substrate complex. The pH dependence of the equilibrium between the tetrameric and the dimeric form of the enzyme has been determined by gel filtration for the same three genetic variants B, A, and A-. In agreement with previous ultracentrifugal data, the enzyme is a tetramer in acid solution and a dimer in alkaline solution. The pH at which half of the enzyme is in dimeric form, under our experimental conditions, is 7.15 +/- 0.05 for variants A and B, and 7.35 +/- 0.05 for variant A-. These pH values correspond closely, for all three variants, to the sharp extrema in the pH dependence of their Km values for glucose 6-phosphate. From the measured dissociation equilibria, it can be inferred that the tetramer-dimer transition entails cooperative release of protons. The degree of cooperativity estimated from these data agrees closely with the independent estimate based on the pH dependence of Km.

Erythrocytes↗
PubMed1977

LBA technique in the detection of chromosome variants. I. Chromosomes with known sites of Q variants.

A method is described (LBA method) which used DNA replication pattern in the detection of chromosome variants in man. In Part I, results on chromosomes with known sites of Q-variants, i.e., 5 pairs of acrocentrics, as well as 3 and 4, were presented. Fourty-one variants were detected in a total of 40 acrocentrics. Twenty-eight of them were detected only by the LBA technique; 11 of them being in short arms and 17 of them in centromeres. Seven variants, including 4 of those in satellites, were detected only in QFQ-stained metaphases. Six short-arm variants were observed by both methods. It appears that a sequential QFQ-LBA technique is very useful in the detection of variants in D- or G-group chromosomes.

Centromere↗
PubMed1979

Thymidine kinase enzyme variants in Physarum polycephalum. In vitro interconversion of the enzyme variants.

Isoelectric focusing of plasmodial extracts of Physarum polycephalum demonstrated the presence of several multiple enzyme variants of thymidine kinase, which appear sequentially during the nuclear division cycle. Variants (A) + (A1) are the only enzyme variants found in the late G2-phase, whereas the variants (C) + (C1) are only present at the time of mitosis and S-phase (1, 2). Evidence is presented that multiple forms of thymidine kinase (A) + (A1) with high pI arise by dephosphorylation of a primary translation product with low pI (C and/or C1). The thymidine kinase fractions (A) + (A1) and (C) + (C1) + (c1) were separated and partially purified by DEAE-cellulose chromatography. The enzyme variants (C) + (C1) are converted in vitro by an endogenous enzymatic factor as well as by bacterial alkaline phosphatase into the variants (A) + (A1).

4-Nitrophenylphosphatase↗