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Results for “Variant pathogenicity assessment”

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PubMed2025

Clinical Actionability of Genetic Findings in Cerebral Palsy: A Systematic Review and Meta-Analysis.

IMPORTANCE: Single gene variants can cause cerebral palsy (CP) phenotypes, yet the impact of genetic diagnosis on CP clinical management has not been systematically evaluated. OBJECTIVE: To evaluate how frequently genetic testing results would prompt changes in care for individuals with CP and the clinical utility of precision medicine therapies. DATA SOURCES: Published pathogenic or likely pathogenic variants in OMIM genes identified with exome sequencing in clinical (n = 1345) or research (n = 496) cohorts of CP were analyzed. A systematic literature review for evidence of effective therapies for specific genetic etiologies was performed. STUDY SELECTION: Nonstandard interventions that led to a detectable improvement in a defined outcome in individuals with variants in the gene of interest were included. DATA EXTRACTION AND SYNTHESIS: Literature was evaluated using PRISMA guidelines. A diverse, expert working group was established, scoring rubrics adapted, and scoring consensus built with a modified Delphi approach. MAIN OUTCOMES AND MEASURES: Overall clinical utility was calculated from metrics assessing outcome severity if left untreated, safety and practicality of the intervention, and anticipated intervention efficacy on a scale from 0 to 3. RESULTS: Of 1841 patients with CP who underwent exome sequencing, 502 (27%) had pathogenic or likely pathogenic variants related to their phenotype. A total of 243 different genes were identified. In 1841 patients with identified genetic etiologies of CP, 140 (8%) had a genetic etiology classified as actionable, defined as prompting a change in clinical management. Also identified were 58 of 243 genes with pathogenic or likely pathogenic variants with actionable treatment options: 16 targeting the primary disease mechanism, 16 with specific prevention strategies, and 26 with specific symptom management. The level of evidence was also graded according to ClinGen criteria; 45 of 101 interventions (44.6%) had evidence class D or below. The potential interventions have clinical utility with 98 of 101 outcomes (97%) being moderate-high severity if left untreated and 63 of 101 interventions (62%) predicted to be of moderate-high efficacy. Most interventions (72 of 101 [71%]) were considered moderate-high safety and practicality. CONCLUSIONS AND RELEVANCE: The findings indicate that actionable genetic findings occurred in 8% of individuals referred for genetic testing with CP. Evaluation of potential efficacy, outcome severity, and intervention safety and practicality indicates moderate-high clinical utility of these genetic findings. Genetic sequencing can identify precision medicine interventions that provide clinical benefit to individuals with CP. The relatively limited evidence base underscores the need for additional research.

Humans↗

PubMed2006

The application of high-throughput AFLP's in assessing genetic diversity in Fusarium oxysporum f. sp. cubense.

Fusarium oxysporum f. sp. cubense (Foc) is responsible for fusarium wilt of bananas. The pathogen consists of several variants that are divided into three races and 21 vegetative compatibility groups (VCGs). Several DNA-based techniques have previously been used to analyse the worldwide population of Foc, sometimes yielding results that were not always consistent. In this study, the high-resolution genotyping method of AFLP is introduced as a potentially effective molecular tool to investigate diversity in Foc at a genome-wide level. The population selected for this study included Foc isolates representing different VCGs and races, isolates of F. oxysporum f. sp. dianthi, a putatively non-pathogenic biological control strain F. oxysporum (Fo47), and F. circinatum. High-throughput AFLP analysis was attained using five different infrared dye-labelled primer combinations using a two-dye model 4200s LI-COR automated DNA analyser. An average of approx. 100 polymorphic loci were scored for each primer pair using the SAGA(MX) automated AFLP analysis software. Data generated from five primer pair combinations were combined and subjected to distance analysis, which included the use of neighbour-joining and a bootstrap of 1000 replicates. A tree inferred from AFLP distance analysis revealed the polyphyletic nature of the Foc isolates, and seven genotypic groups could be identified. The results indicate that AFLP is a powerful tool to perform detailed analysis of genetic diversity in the banana pathogen Foc.

DNA Fingerprinting↗

PubMed2025

Assessment of different promoters in lentiviral vectors for expression of the N-acetyl-galactosamine-6-sulfate sulfatase gene.

Mucopolysaccharidosis IVA (MPS IVA) is caused by pathogenic variants in the GALNS gene encoding N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme, leading to glycosaminoglycan (GAG) accumulation in multiple tissues, resulting in progressive skeletal dysplasia and poor quality of life. There is currently no effective treatment for this skeletal disease. This study proposes a novel lentiviral vector (LV)-based gene therapy that produces and secretes the active GALNS enzyme at supraphysiologic levels within the cells. LVs carrying the native GALNS encoding sequence (cDNA) were made under three different promoters: CBh, COL2A1, and CD11b. Moreover, we designed LVs carrying the native GALNS cDNA tagged with D8 octapeptide under the CD11b promoter and a human codon-optimized GALNS cDNA under the CBh promoter, respectively. Transduced HEK293 cells, HepG2 cells, and MPS IVA fibroblasts and chondrocytes were cultured for 8 and 30 days, and the media were collected every three days. The enzyme activity, GAG levels, and vector copy numbers (VCNs) in these cells and media were analyzed. LV with the COL2A1 promoter produced the highest enzyme activity in HEK293, HepG2, MPS IVA fibroblasts, and chondrocytes, followed by LV with the CBh promoter. VCNs were higher in MPS IVA fibroblasts treated with LV-CBh-hGALNS and in HepG2 cells treated with LV-CD11b-hGALNS than in HEK293 cells. Accumulated GAGs were normalized to wild-type levels by the LV gene therapy, especially with CBh and COL2A1 promoters. These findings, if further validated, could significantly impact the treatment of MPS IVA, offering a more effective and feasible treatment option.

Humans↗

PubMed2025

Developing a disease-specific accessible transcriptional signature as a biomarker for ataxia with oculomotor apraxia type 2.

BACKGROUND: Genetic ataxias are clinically heterogenous neurodegenerative conditions often involving rare or private mutations and it is often difficult to assign pathogenicity to rare gene variants solely based on DNA sequencing. An effective functional assay from an easy-to-obtain biospecimen would aid this assessment and be of high clinical value. SETX encodes a ubiquitous DNA/RNA helicase crucial for resolving R-loops and maintaining genome stability. Loss-of-function mutations cause a recessive disorder, Ataxia with Oculomotor Apraxia Type 2 (AOA2). METHODS: Here we utilize Weighted Gene Co-expression Network Analysis (WGCNA) from patient blood to construct an AOA2-specific transcriptomic signature as a biomarker to evaluate SETX variants in patients clinically suspected of having AOA2. RESULTS: WGCNA from peripheral blood RNA of 11 AOA2 patients from 7 families initially identified a single gene module that was modestly effective in distinguishing individuals with AOA2 from controls (sensitivity 73%, specificity 97%) and was able to robustly differentiate AOA2 patients from those with genetically distinct, yet phenotypically similar, neurological disorders (sensitivity 100%, specificity 100%). An independent derivation of the transcriptional biomarker identified a dual module model that was able to better distinguish individuals with AOA2 from controls (sensitivity 100%, specificity 97%). As validation, we examined a second cohort of 21 patients from 13 families and demonstrate that this dual module transcriptional biomarker could discriminate patients clinically suspected of AOA2 from controls (57%, 95%CI: 34%-78%). Overall, the transcriptional biomarker was able to separate AOA2 subjects (n = 32) from controls (n = 35) with 72% sensitivity and 97% specificity. Notably, this transcriptomic biomarker enabled verification of the first pathogenic SETX mutation found in a non-canonical transcript, expanding the spectrum of mutations that contribute to AOA2. CONCLUSIONS: Our study identified a transcriptional biomarker that was able to differentiate AOA2 from controls and from other related neurological disorders, consequently expanding the spectrum of known pathogenic mutations. This proof-of-concept study illustrates that transcriptional biomarkers may be used to validate variants of uncertain significance in known genetic diseases.

Humans↗

PubMed2003

Experiences and perspectives for the use of a Paenibacillus strain as a plant protectant.

A study on the microbial ecology in an active slow sand filter, used for disinfecting the circulating plant nutrient solutions, showed that spore-forming plant-associated bacteria belonging to the Bacillus-Paenibacillus complex are well adapted for transmission in the solutions and passage through the filter. Therefore, strains from this bacterial group were suitable candidates for biological control in irrigated and closed plant growth systems. The spore-forming Paenibacillus polymyxa strain PpDGB was selected in in vitro tests as a potent pathogen-antagonist and was tested as a prophylactic protection agent in the plant rhizosphere, especially for cultures stages that are highly susceptible to stress and disease. Plant cuttings, in vitro plants and seeds of different plant types were bacterized and planted in their typical disease-conducive environment where nutrient solutions or water irrigation was applied and further plant development was monitored. Observed plant parameters were plant survival, weight, chlorophyll concentration in the leaf mesophyl, root health and root hair formation. The PpDGB treatment initially induced stress in the plants, which was observed as a transient stop in plant transpiration. This effect caused some necrosis in the most stress-sensitive in vitro plant species. In the other plants this stress period was followed by a significant enhancement in plant growth. In case of seed treatment, more seeds germinated and seedling growth was faster. In the tested formulation, PpDGB enhanced growth but not disease resistance, probably due to simultaneous activation of the residual plant pathogens. Therefore variant formulations have to be tested. The influence of PpDGB on the composition of the bacterial communities in the rhizosphere was assessed by DGGE profiling. In soilless plant cultures, PpDGB-driven profile changes could be observed from the 5th day after the initial treatment. P. polymyxa bacteria were shown to be widely present in association with plants and specific PpDGB detection in plant and rhizosphere was only possible with newly developed strain-specific PCR primers based on Nif H gene sequences. Quantitative PCR based on SYBR Green fluorescence enabled detection of low PpDGB concentrations in the plant rhizosphere.

Araceae↗

PubMed2001

Safety and antigenicity of non-adjuvanted and MF59-adjuvanted influenza A/Duck/Singapore/97 (H5N3) vaccine: a randomised trial of two potential vaccines against H5N1 influenza.

BACKGROUND: In 1997, pathogenic avian influenza A/Hong Kong/97 (H5N1) viruses emerged as a pandemic threat to human beings. A non-pathogenic variant, influenza A/Duck/Singapore/97 (H5N3), was identified as a leading vaccine candidate. We did an observer-blind, phase I, randomised trial in healthy volunteers to assess safety, tolerability, and antigenicity of MF59-adjuvanted and non-adjuvanted vaccines. METHODS: 32 participants were randomly assigned MF59, and 33 non-adjuvanted vaccine. Two doses were given 3 weeks apart, of 7.5, 15, or 30 microg haemagglutinin surface-antigen influenza A H5N3 vaccine. Antibody responses were measured by haemagglutination inhibition, microneutralisation, and single radial haemolysis (SRH). The primary outcome was geometric mean antibody titre 21 days after vaccination. FINDINGS: The A/Duck/SIngapore vaccines were safe and well tolerated. Antibody response to non-adjuvanted vaccine was poor, the best response occurring after two 30 microgram doses: one, four, four, and one person of eleven seroconverted by haemagglutination inhibition, microneutralisation, H5N3 SRH, and H5N1 SRH, respectively. The geometric mean titres of antibody, and seroconversion rates, were significantly higher after MF59 adjuvanted vaccine. Two 7.5 microg doses of MF59 adjuvanted vaccine gave the highest seroconversion rates: haemagglutination inhibition, six of ten; microneutralisation, eight of ten; H5N3 SRH, ten of ten; H5N1 SRH, nine of ten. Geometric mean titre of antibody to the pathogenic virus, A/Hong Kong/489/97 (H5N1), was about half that to A/Duck/Singapore virus. INTERPRETATION: Non-adjuvanted A/Duck/Singapore/97 (H5N3) vaccines are poorly immunogenic and doses of 7.5-30 microg haemagglutinin alone are unlikely to give protection from A/Hong Kong/97 (H5N1) virus. Addition of MF59 to A/Duck/Singapore/97 vaccines boost the antibody response to protection levels. Our findings have implications for development and assessment of vaccines for future pandemics.

Adult↗

PubMed2026

Real-world clinical utility of exome sequencing in pediatric drug-resistant epilepsy: Experience from a tertiary center in Thailand.

BACKGROUND: Genomic testing has increasingly contributed to the diagnosis and management of pediatric drug-resistant epilepsy (DRE), particularly in patients with suspected genetic etiologies. This study evaluated the diagnostic yield and real- world clinical utility of whole-exome sequencing (WES) in children with DRE. METHODS: Children with DRE and seizure onset before 15 years of age were enrolled between January 2020 and December 2023. Clinical data, including demographics, seizure characteristics, developmental history, electroencephalography (EEG), brain magnetic resonance imaging (MRI), and prior investigations, were reviewed. WES was performed in all probands and, when available, their parents. Variants were interpreted according to standard guidelines. Clinical utility and 1-year seizure and developmental outcomes were assessed from follow-up records. RESULTS: Fifty-six patients (23 males, 33 females) were included. The median age at seizure onset was 1 year (interquartile range [IQR] 0.3-4 years), and 96.4% had developmental comorbidities. Pathogenic or likely pathogenic variants were identified in 39% (22/56), with the highest diagnostic yield in children with seizure onset before 3 years of age. Channelopathies accounted for most genetically solved cases (68%), predominantly involving sodium channel genes. Genetic diagnoses provided clinical utility in 73% (16/22) of solved cases by guiding treatment and precision management. At 1-year follow-up, genetically solved patients showed more favorable seizure and developmental outcomes than those with genetically unsolved patients. CONCLUSION: WES achieved a 39% diagnostic yield and substantial clinical utility in pediatric DRE, particularly in early-onset and channelopathy-related disorders. These findings support early molecular diagnosis to facilitate genotype-informed management in appropriately selected children. However, the more favorable developmental and seizure outcomes observed in genetically solved patients should be interpreted with caution, as they may have been influenced by multiple factors beyond genetic diagnosis. In resource-limited settings, careful clinical phenotyping remains essential for treatment decisions and for prioritizing children for genomic testing.

Clinical utility↗

PubMed2026

Parkinson Disease Pathogenic Variants: Cross-Ancestry Analysis and Microarray Data Validation.

BACKGROUND AND OBJECTIVES: Known pathogenic variants (PVs) in Parkinson disease (PD) contribute to disease development but have yet to be fully explored by arrays on a large scale. This study evaluated genotyping success of the NeuroBooster array (NBA) and determined the frequencies of PVs across ancestries. METHODS: We analyzed the presence and allele frequency of PVs in 28,710 PD cases, 9,614 other neurodegenerative disorder cases, and 15,821 controls across 11 ancestries within the Global Parkinson's Genetics Program (GP2) data set. Cluster plots were used to assess the quality of PVs genotyped on NBA. RESULTS: Genes previously predicted to have high or very high confidence of causing PD tend to have more PVs and are present across ancestry groups. Of 34 known PD gene PVs assessed, 25 were typed by NBA and classified as "good" (n = 12), "medium" (n = 4), or "bad" (n = 9) quality variants. DISCUSSION: Our results confirm the likelihood that established PD genes are pathogenic and highlight the importance of ancestrally diverse research in PD. We also show the usefulness of the NBA as a reliable tool for the genotyping of rare variants of PD.

Journal Article↗

PubMed2026

National genomic projects in Asia and Africa: a review.

National genome projects (NGPs) are increasingly shaping precision medicine by improving representation of population-specific genetic diversity. This review compiles findings from NGPs across Asia and Africa, regions that remain underrepresented in global genomic databases despite their extensive demographic and genetic diversity. A total of 53 studies from 24 countries were identified to understand (1) the genomic approach utilized, (2) novel findings that have emerged, and (3) strategies for improving research in these regions. The NGPs implement population-based variome databases (20 NGPs), linear reference genome assemblies (8 NGPs), and graph-based pangenome assemblies (1 NGP). Novel variants ranged between 0.28% (China) and 19.6% (Iran), whereas rare variants accounted for up to 88.9% of the detected variants in the Chinese population. Each NGP documents its country's evolutionary and migration history, which impacts disease frequency and pharmacogenomic variants. Clinically, NGPs revealed strong population stratification in disease-associated and pharmacogenomic variants. For example, the GJB2 rs72474224 hearing-loss variant ranged from 13% in Vietnam and 12% in Hong Kong to 0.0894% in Turkey, while the VKORC1 rs9923231 pharmacogenomic variant reached 89.2% in Taiwan but was 20%-25% in European-related Russian subpopulations. These findings demonstrate that clinically relevant allele frequencies, pathogenicity assessments, and drug-response markers differ substantially across ancestries. This review highlights ongoing efforts and strategies to enhance the representativeness of genomic data through NGPs in Asia and Africa. We also suggest future directions for national projects, including integrating family-based studies, multi-omic data, and standardized pipelines to accelerate discovery and support the equitable implementation of precision medicine.

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↗

PubMed2004

Intronic mutations in the L1CAM gene may cause X-linked hydrocephalus by aberrant splicing.

L1 disease is a clinically heterogeneous X-chromosomal neurodevelopmental disorder that is frequently associated with mental retardation and congenital hydrocephalus in males. It is caused by mutations in L1CAM that encodes a multifunctional transmembrane neuronal cell adhesion molecule. We report our findings on 6 novel intronic L1CAM sequence variants (c.523+5G>A, c.1123+1G>A, c.1547-13delC, c.3323-17dupG, c.3457+3A>T, and c.3457+18C>T), and a recurrent one (c.523+12C>T). While the pathogenic potential of nucleotide changes within the evolutionarily well-conserved splice consensus sequence (c.523+5G>A, c.1123+1G>A, and c.3457+3A>T) is widely accepted, it is not always straight forward to assess the disease relevance of intronic mutations, if they lie outside the consensus. The c.523+12C>T variant co-segregated with X-linked hydrocephalus in two unrelated families. In the mutated allele, a preferentially used novel splice donor site is generated that results in a frame shift due to insertion of the first 10 bp of intron 5 in the mature mRNA, a largely truncated protein, and most likely a functional null allele. The c.1547-13delC mutation creates a new acceptor site resulting in the insertion of 4 additional amino acids at the end of the immunoglobulin like domain 5. In contrast, c.3323-17dupG and c.3457+18C>T seem to be non-pathogenic L1CAM variants.

Base Sequence↗

PubMed2026

RBM20 Truncating Variants and Human Cardiomyopathy.

IMPORTANCE: Genetic diagnosis has become increasingly important to guide clinical decision-making for patients with dilated cardiomyopathy (DCM). Pathogenic or likely pathogenic (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic DCM, but the role of RBM20 truncating variants (RBM20tvs) is unclear. OBJECTIVE: To assess the contribution of RBM20 variants to arrhythmogenic DCM. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, participants in the genome-first UK Biobank (UKB) and All of Us populations were evaluated to assess the etiologic fraction, natural history and penetrance of RBM20 variants. Retrospective data were collected from an international cohort of patients with DCM and RBM20 variants identified at centers of excellence for genetic heart disease and compared based on time to event. Study dates are not disclosed because the institutional review board did not authorize the sharing of this information. EXPOSURES: RBM20 variants were compared to known P/LP variants and variants of uncertain significance in RBM20 as well as titin truncating variants (TTNtvs). MAIN OUTCOMES AND MEASURES: Major ventricular arrhythmias, end-stage heart failure, and heart failure hospitalization as measured by medical record review (retrospective cohort) and diagnostic codes (UKB). RESULTS: Two main cohorts were studied for this project. In UK Biobank, a cohort of participants with RBM20tvs, RBM20 synonymous variants, and TTNtvs was studied. Of these 4249 participants, 1869 (44%) were male. The mean (SD) age at enrollment was 56 (8.2) years. In the RBM20 registry, of 179 patients, 105 (58.6%) were male, and the mean (SD) age at enrollment was 43.8 (19.1) years. A validation cohort from the All of Us biobank was also used. This consisted of 7002 participants, 4342 of whom (62.0%) were male, and the mean (SD) age was 52.7 (16.7) years. The etiologic fraction of RBM20 variants in arrhythmogenic DCM was 0.53 (95% CI, 0.32-0.67; P < .001). In genome-first biobanks, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20 variants than in those with TTNtvs (hazard ratio, 0.55; 95% CI, 0.36-0.84; P < .001). Patients with RBM20tvs and DCM presented to referral centers later in life than those with P/LP RBM20 and DCM (mean [SD], 53 [10] vs 34 [18] years; P < .001) and were less likely to have a family history of sudden cardiac arrest (2 of 10 [20%] vs 11 of 17 [65%]; P = .046) or cardiomyopathy (2 of 10 [20%] vs 14 of 18 [78%]; P < .001). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between patients with RBM20tv and DCM or those with P/LP RBM20 and DCM, though sex-adjusted lifetime hazard was reduced in those with RBM20tv and DCM (hazard ratio, 0.13; 95% CI, 0.03-0.56; P = .01). CONCLUSIONS AND RELEVANCE: This study found that RBM20 variants contributed to arrhythmogenic DCM phenotypes but conferred reduced lifetime disease penetrance compared to TTNtvs and milder disease severity alone than P/LP RBM20 variants. Their potential for additive interactions with other damaging variants should be considered in patients with DCM and their families.

Humans↗

PubMed2026

Genomic and computational analysis of variants in telomere regulatory genes in subjects with bone marrow failure.

Telomere Biology Disorders (TBDs) are a genetically heterogeneous and often under-recognized cause of Bone Marrow Failure Syndromes (BMFS), driven by defective telomere maintenance and progressive telomere attrition. We performed an integrated genomic, telomeric and computational analysis in 118 subjects presenting clinical features of BMFS to delineate the contribution of Telomere Regulatory Genes (TRGs) variants to disease pathogenesis. Whole exome sequencing (WES) identified pathogenic (18.18%), likely pathogenic (27.27%) and rare variants of uncertain significance (54.54%) in 27 subjects (22.9%) across five TRGs: RTEL1, TERT, TINF2, NOP10, and WRAP53. Telomere Length (TL) assessment revealed significant telomere shortening in TRG variant-positive subjects compared with age-matched controls, with the most profound attrition observed in individuals harboring de novo TINF2 gene variants. RTEL1 emerged as the most frequently affected gene, with recurrent clustering of variants within its C-terminal regulatory region. A familial NOP10 variant, Asp12His, segregated with cutaneous pigmentation and hematological abnormalities consistent with the established role of NOP10 in dyskeratosis congenita, further broadening the known mutational spectrum of the gene. Structure-guided in-silico analyses predicted that both novel and recurrent variants disrupt protein stability, telomerase assembly or trafficking and shelterin complex integrity. Reduced TERT expression and a significant inverse correlation between telomere length and clinical severity further underscored the functional impact of TRG defects. Collectively, this study provides the first comprehensive characterization of TRG variants in the Indian BMFS cohort and highlights the utility of integrating genomic sequencing, telomere length measurement and computational modeling to improve diagnostic precision, variant interpretation and clinical stratification in TBDs.

Journal Article↗

PubMed2006

The P1812A and P25T BRCA1 and the 5164del4 BRCA2 mutations: occurrence in high-risk non-Ashkenazi Jews.

Founder mutations in the BRCA1 and BRCA2 genes have been discovered in the Ashkenazic Jewish population, but a founder mutation(s) has not been discovered among non-Ashkenazi Jews (NAJ). Two BRCA1 mutations (P1812A, P25T), and a BRCA2 mutation (5164del4) have been detected in NAJ high-risk families. We studied the prevalence of these three mutations in 270 high-risk NAJ families, including 85 from Iraq/Iran, 67 from North Africa, 27 from Yemen, 50 from the Balkan region, and 41 with mixed ancestry. The three mutations were detected only in individuals related to the original families. We conclude that the P1812A and P25T BRCA1 and 5164del4 BRCA2 mutations are not likely to be founder mutations in NAJ high-risk families. We also assessed the pathogenicity of the BRCA1 P1812A mutation in vitro using reporter gene assays in yeast and mammalian cells. We found that the BRCA1 P1812A variant activity assays yielded a slightly reduced reporter gene activity. Thus, there is some uncertainty as to the pathogenicity of BRCA1 P1812A.

Adult↗

PubMed1986

Selection of mutants of mumps virus with altered structure and pathogenicity by passage in vivo.

The neurotropic Kilham strain of mumps virus was serially passaged in newborn hamster brains in order to assess possible changes in viral characteristics. Two modes of passage were employed, one with a 4-5 day interval between inoculation and harvest and the other with a 10-12 day interval. After 10 and 8 passages, respectively, two viral variants were isolated which differed in antigen characteristics and in pathogenicity. In Vero cell cultures the variant derived from the short-term passage, designated as RK, showed much greater fusion capacity than the other, designated as SK. The highly fusing variant was highly lethal and caused much more extensive necrosis and grew to higher titers in the brain. With a series of monoclonal antibodies directed against the structural proteins of mumps virus marked differences between the variants could be detected in the nucleocapsid (NP) protein and also slight changes in the hemagglutinin-neuraminidase (HN) and phospho- (P) proteins. Differences were found in the preference of the viral variants to infect various regions of the brain. The RK variant heavily infected the caudate nucleus whereas the SK variant did not. This study demonstrates that different modes of passage can affect characteristics of virion components and disease pattern.

Animals↗

PubMed2004

A recombinant Newcastle disease virus (NDV) expressing VP2 protein of infectious bursal disease virus (IBDV) protects against NDV and IBDV.

Infectious bursal disease virus (IBDV) causes a highly immunosuppressive disease in chickens. Currently available, live IBDV vaccines can lead to generation of variant viruses. We have developed an alternative vaccine that will not create variant IBDV. By using the reverse genetics approach, we devised a recombinant Newcastle disease virus (NDV) vector from a commonly used vaccine strain LaSota to express the host-protective immunogen VP2 of a variant IBDV strain GLS-5. The gene encoding the VP2 protein of the IBDV was inserted into the most 3'-proximal locus of a full-length NDV cDNA for high-level expression. We successfully recovered the recombinant virus, rLaSota/VP2. The rLaSota/VP2 was genetically stable, at least up to 12 serial passages in chicken embryos, and was shown to express the VP2 protein. The VP2 protein was not incorporated into the virions of recombinant virus. Recombinant rLaSota/VP2 replicated to a titer similar to that of parental NDV strain LaSota in chicken embryos and cell cultures. To assess protective efficacy of the rLaSota/VP2, 2-day-old specific-pathogen-free chickens were vaccinated with the recombinant virus and challenged with a highly virulent NDV strain Texas GB or IBDV variant strain GLS-5 at 3 weeks postvaccination. Vaccination with rLaSota/VP2 generated antibody responses against both NDV and IBDV and provided 90% protection against NDV and IBDV. Booster immunization induced higher levels of antibody responses against both NDV and IBDV and conferred complete protection against both viruses. These results indicate that the recombinant NDV can be used as a vaccine vector for other avian pathogens.

Animals↗

PubMed2026

CHEK2 Germline Variants in Cancer Predisposition: Whole Genome Sequencing Results.

While pathogenic germline CHEK2 variants are known to increase cancer risk, there is currently insufficient evidence regarding the precise risk of developing malignant neoplasms associated with specific missense variants or variants of uncertain significance. As a result, no clear clinical guidelines exist regarding consultation, monitoring and specific treatment options for those patients. For the first time in Russia, clinical data and whole-genome sequencing (WGS) results were analyzed for 3150 patients with cancer and suspected hereditary cancer syndromes (HCS) and 5163 healthy individuals. This dataset formed the basis for assessing the role of germline CHEK2 variants in the development of different cancer types. The chromosomal coordinates and coding sequence coordinates are given in accordance with the GRCh38 (hg38) genome assembly and the NM_007194.4 transcript. Pathogenic (P) and likely pathogenic (LP) variants of CHEK2 significantly increased the risk of breast cancer (OR = 2.015 [95% CI: 1.27-3.21]; p = 0.0031), but the association with colorectal cancer was not statistically significant (OR = 1.354 [95% CI: 0.42-4.42]; p = 0.616). A moderate increase in cancer risk was identified for the c.1100del variant (OR = 2.263 [95% CI: 1.19-4.32]; p = 0.0132) and for the common P/LP variants c.1100del, c.444+1G>A and c.433C>T (OR = 2.219 [95% CI: 1.40-3.51]; p = 0.0007). Notably, our study confirmed that CHEK2 c.470T>C (p.Ile157Thr) is the most common variant in the patient group, identified in 3.8% of cases (120/3150), compared with 3.0% in the control group (155/5163). Although the association between the most common CHEK2 variant c.470T>C and cancer risk reached nominal statistical significance (OR = 1.279 [95% CI: 1.00-1.63]; p = 0.0463), the effect size was minimal, suggesting that the contribution of this variant to hereditary cancer risk in the Russian population is modest. Additional studies are required before this variant can be definitively excluded from clinical interpretation.

Humans↗

PubMed1999

Comparative analysis of Epstein-Barr virus gene polymorphisms in nasal T/NK-cell lymphomas and normal nasal tissues: implications on virus strain selection in malignancy.

Whether particular Epstein-Barr virus (EBV) strains are preferentially selected in malignant diseases remains controversial. Assessment of the importance of strain variation in the pathogenicity of EBV has been hampered principally by the lack of accurate data on the prevalence of virus variants in the normal population. To clarify this issue, a detailed comparative analysis of the EBV genomes contained in normal nasal and nasopharyngeal mucosal tissues and in nasal T/NK-cell lymphoma, which originates at these anatomic sites, was carried out by PCR amplification across the 30-bp deletion and the 33-bp repeat loci in the LMP1 gene and the type-specific polymorphic loci in the EBNA2 and EBNA3C genes and by sequence analysis of the 3' C-terminal region of the LMP1 gene. Whilst the majority of EBV strains in either normal or tumour tissues were type 1 viruses with similar numbers of LMP1 repeats, a marked predominance of LMP1 deletion (del-LMP1) over non-deleted/wild-type LMP1 (wt-LMP1) variants was observed in nasal T/NK-cell lymphoma. Although del-LMP1 variants were also prevalent in the normal carriers of our population, wt-LMP1 was detected at a significantly higher frequency in normal vs. tumour tissues (p = 0.036). More critically, wt-LMP1 variants were found frequently in mixed infection with del-LMP1 variants in the normal carriers. Sequence analysis identified 2 major del-LMP1 (and several wt-LMP1) variants containing signatory nucleotide changes in relation to the prototype B95-8 sequence in both normal and neoplastic nasal tissues. Together, our data provide strong evidence for a selection mechanism for del-LMP1 over the wt-LMP1 variants in tumours.

Antigens, Viral↗