New evidence for a viral pathogenic mechanism for new variant inflammatory bowel disease and development disorder?
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Autistic Disorder↗
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Potential viral pathogenic mechanism for new variant inflammatory bowel disease.
AIMS: A new form of inflammatory bowel disease (ileocolonic lymphonodular hyperplasia) has been described in a cohort of children with developmental disorder. This study investigates the presence of persistent measles virus in the intestinal tissue of these patients (new variant inflammatory bowel disease) and a series of controls by molecular analysis. METHODS: Formalin fixed, paraffin wax embedded and fresh frozen biopsies from the terminal ileum were examined from affected children and histological normal controls. The measles virus Fusion (F) and Haemagglutinin (H) genes were detected by TaqMan reverse transcription polymerase chain reaction (RT-PCR) and the Nucleocapsid (N) gene by RT in situ PCR. Localisation of the mRNA signal was performed using a specific follicular dendritic cell antibody. RESULTS: Seventy five of 91 patients with a histologically confirmed diagnosis of ileal lymphonodular hyperplasia and enterocolitis were positive for measles virus in their intestinal tissue compared with five of 70 control patients. Measles virus was identified within the follicular dendritic cells and some lymphocytes in foci of reactive follicular hyperplasia. The copy number of measles virus ranged from one to 300,00 copies/ng total RNA. CONCLUSIONS: The data confirm an association between the presence of measles virus and gut pathology in children with developmental disorder.
Adolescent↗
Potential viral pathogenic mechanism for new variant inflammatory bowel disease.
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Case-Control Studies↗
[Pathogenic variation among colonial variants of the Smith strain of Staphylococcus aureus].
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Animals↗
Pathogenic human mitochondrial tRNA variants impair RNA processing by compromising 5' leader removal.
Human mitochondrial genome (mtDNA) encodes multiple proteins in the oxidative phosphorylation complexes as well as the ribosomal and transfer RNAs (tRNAs) needed for in situ translation. These genes are transcribed from only three promoters, producing polycistronic transcripts that are co-transcriptionally cleaved by mitochondrial RNase enzymes to release majority of individual gene products. tRNAs separate many of these genes and are thought to serve as "punctuation" marks that enable RNase recognition, binding, and hydrolysis of the 5' "leader" and 3' "trailer" sequences flanking the tRNA. Mutations in the tRNA genes dominate the mtDNA-linked mitochondrial pathologies; yet a systematic study of the impact of tRNA sequence variation on the RNase-catalyzed processing is lacking. Here, we employed human mitochondrial tRNATyr as a model system to dissect the effect of tRNA variants on the in vitro 5' leader and 3' trailer hydrolysis. We found that nucleotide variations located near the catalytic interfaces - particularly within or near the tRNA acceptor stem - showed the strongest defects in 5' processing and prevented release of the downstream tRNA in a tRNA cluster where multiple tRNAs are transcribed in tandem. This work provides mechanistic insight into how mutations disrupt coordinated mitochondrial tRNA processing and establish a framework for predicting variant effects based on their structural position relative to the processing enzymes.
Journal Article↗
9p subtelomere deletion: pathogenic mutation or normal variant?
We report an apparently benign familial 9p subtelomere deletion identified using chromosome-arm-specific subtelomere probes in a patient with multiple congenital anomalies. Our experience demonstrated that the discovery of a subtelomeric deletion and/or duplication does not always guarantee the identification of the etiology for the patients phenotype and a positive finding with subtelomere probes should always be followed by parental study with the same probe in order to distinguish a disease causing alteration from a benign familial polymorphism.
Chromosome Deletion↗
[Differences in the ultrastructure of colored variants of colonies of pathogenic Neisseria].
Electron-transparent zones (vacuoles) of different size and localization have been detected in the cytoplasm of meningococci forming orange colonies. These vacuoles have been detected in cells from meningococcal cultures of different age, grown both in liquid and solid culture media. This phenomenon requires further deeper study. The presence of a relationship between newly detected vacuoles and the pathogenicity of meningococci is suggested.
Color↗
[Non-sexual variant of Ceratocystis sp. pathogenic for hamsters and comparable to Sphorothrix schenckii].
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Animals↗
A study for minisatellitic markers of Conidiobolus coronatus' pathogenicity to Galleria mellonella larvae.
A selected panel of 13 colonies of entomopathogenic fungus Conidiobolus coronatus representing 6 variants of pathogenicity to Galleria mellonella larvae (ranged from 100 to 10% of efficiency), derived from single spores, were tested for the presence of hypervariable loci in their genomes by hybridization with Jeffreys' human minisatellite probe 33.6. The probe produced informative fingerprints and revealed slight differences among colonies analyzed. Up to 20 variable bands per colony were recognized in the size range of 2-20 kb. The band sharing within groups with the same pathogenicity ranged from 0.966 to 0.800. The genetic distance between different variants ranged from 0.026 to 0.282. A few characteristic bands for high and low pathogenicity to the larvae were found.
Animals↗
Prenatal SNP-array chromosomal microarray analysis in 3,549 pregnancies: indication-specific yields and clinical implications.
BACKGROUND: SNP-based chromosomal microarray analysis (CMA) is widely used in invasive prenatal diagnosis, yet real-world performance across contemporary referral pathways, especially in the NIPT era, remains incompletely characterized. METHODS: We retrospectively analyzed 3,549 prenatal invasive samples tested by SNP array, and evaluated diagnostic yield overall and by referral indication and ultrasound phenotype. RESULTS: In total, we identified 398 pathogenic or likely pathogenic (P/LP) variants across 386 fetuses, resulting in an overall diagnostic yield of 10.9% (386/3,549). These findings comprised 223 aneuploidies and 175 pathogenic CNVs. In contrast, variants of uncertain significance (VOUS) were detected in 12.0% (426/3,549) of cases. Diagnostic yields were heavily stratified by indication: yields peaked in NIPT high-risk referrals (38.9%) and were intermediate in ultrasound-based cases (~ 11%), but dropped significantly in the advanced maternal age (AMA; 4.2%) and serum screening (~ 5-6%) groups. Conversely, VOUS rates remained remarkably stable across all referral categories. Sub-analysis of ultrasound abnormalities revealed that multisystem anomalies conferred the highest risk (27.3%), driven predominantly by aneuploidies; among soft markers, increased nuchal translucency (NT) emerged as the strongest predictor of chromosomal pathology. CONCLUSIONS: In our cohort, SNP-array identified clinically actionable findings in 10.9% of cases. NIPT enriched diagnostic yields, particularly for aneuploidies, and NT thickness was strongly associated with pathogenic findings. These results support an indication-based approach to genomic testing, with NIPT as a triage tool for aneuploidy and CMA for high-risk populations, while improving VOUS counseling.
Humans↗
Strong evidence that the common variant S384F in BRCA2 has no pathogenic relevance in hereditary breast cancer.
INTRODUCTION: Unclassified variants (UVs) of unknown clinical significance are frequently detected in the BRCA2 gene. In this study, we have investigated the potential pathogenic relevance of the recurrent UV S384F (BRCA2, exon 10). METHODS: For co-segregation, four women from a large kindred (BN326) suffering from breast cancer were analysed. Moreover, paraffin-embedded tumours from two patients were analysed for loss of heterozygosity. Co-occurrence of the variant with a deleterious mutation was further determined in a large data set of 43,029 index cases. Nature and position of the UV and conservation among species were evaluated. RESULTS: We identified the unclassified variant S384F in three of the four breast cancer patients (the three were diagnosed at 41, 43 and 57 years of age). One woman with bilateral breast cancer (diagnosed at ages 32 and 50) did not carry the variant. Both tumours were heterozygous for the S384F variant, so loss of the wild-type allele could be excluded. Ser384 is not located in a region of functional importance and cross-species sequence comparison revealed incomplete conservation in the human, dog, rodent and chicken BRCA2 homologues. Overall, the variant was detected in 116 patients, five of which co-occurred with different deleterious mutations. The combined likelihood ratio of co-occurrence, co-segregation and loss of heterozygosity revealed a value of 1.4 x 10-8 in favour of neutrality of the variant. CONCLUSION: Our data provide conclusive evidence that the S384F variant is not a disease causing mutation.
Adult↗
Mortality of Individuals With PRNP Variants Associated With Prion Disease in the United States, 1998-2024.
BACKGROUND AND OBJECTIVES: To characterize the survival of individuals with pathogenic PRNP variants-including to estimate annual hazards, to judge the accuracy of previously reported survival data, and to evaluate the utility of public record searches in determining vital status. METHODS: In this single-center cohort study, we gathered data on individuals who received positive antemortem PRNP genetic tests at the US National Prion Disease Pathology Surveillance Center (NPDPSC), including both diagnostic tests in symptomatic individuals, and predictive tests in asymptomatic individuals. Genetic test and autopsy results were queried from the NPDPSC database, and public record searches were conducted using online tools. RESULTS: Four hundred four individuals received positive genetic test results. Of 206 cases symptomatic at the time of genetic testing, 188 are likely now deceased based on typical disease duration for their genetic variants. Combined autopsy and public record searches in combination confirmed 174 of these deaths, for an estimated 92.6% sensitivity. We evaluated the age-dependent penetrance of the reportedly highly penetrance variants D178N and E200K and the reportedly low-penetrance variant V210I. Among 99 initially asymptomatic individuals with the pathogenic E200K variant, more than 936 person-years of follow-up, 18 deaths were observed, significantly fewer than 27.4 expected according to life tables based on retrospective data. The age-dependent penetrance of E200K calculated from these longitudinal data was significantly lower than that from retrospective data, with 69% penetrance by age 80 and a median age at death of 75. For the pathogenic D178N variant, the median age at death was 57, which was numerically later, but not significantly different from, that seen in retrospective data. For V210I, just 2 deaths occurred, both after age 90, consistent with minimal penetrance. DISCUSSION: Our data support high penetrance of PRNP D178N and E200K variants and low penetrance of V210I. For E200K, the age at onset distribution appears to be shifted slightly later, and lifetime risk slightly lower, than previously reported. Autopsy data and public death records in combination were sensitive and concordant for determining long-term outcomes, but additional prospective data should be gathered to support future preventive trials.
Journal Article↗
Base editing for precision therapeutics.
Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, β-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.
Humans↗
Idiopathic neonatal arterial ischaemic stroke: a trio-based whole-exome sequencing study.
OBJECTIVE: To assess the contribution of rare coding genetic variants to idiopathic neonatal arterial ischaemic stroke (NAIS). DESIGN: Observational genetic study using trio-based whole-exome sequencing (WES). SETTING: Multicentre study. PATIENTS: 23 newborns diagnosed with idiopathic NAIS and their biological parents. INTERVENTIONS: WES-trio with a customised workflow for filtering and interpreting variants in de novo autosomal dominant and recessive inheritance models. MAIN OUTCOME MEASURES: Identification of pathogenic (P) or likely pathogenic (LP) variants potentially associated with NAIS. RESULTS: We identified 28 unique rare de novo variants in 28 genes across 23 newborns with NAIS. Under the autosomal recessive model, no candidate genes were identified. No common P/LP variant across the 23 newborns was detected. In-silico predictors and comprehensive knowledge-driven analysis highlighted PIK3CD (p.Gln431Arg) as a candidate gene in one patient with perforant stroke. However, no more cases were identified with PIK3CD variants, and functional studies are warranted to assess its pathogenicity impact. CONCLUSIONS: Trio-based WES did not identify a monogenic cause for idiopathic NAIS. Coding variants therefore appear unlikely to explain the underlying genetic base of the disease. Furthermore, PIK3CD (p.Gln431Arg) may contribute to perforant stroke, although it requires further association evidence. As the potential role of non-coding or structural variants in NAIS remains possible, genome-wide long-read sequencing approaches may provide further insights into the genetic architecture of this condition.
Humans↗
Reference-Free Variant Calling with Local Graph Construction with ska lo (SKA).
The study of genomic variants is increasingly important for public health surveillance of pathogens. Traditional variant-calling methods from whole-genome sequencing data rely on reference-based alignment, which can introduce biases and require significant computational resources. Alignment- and reference-free approaches offer an alternative by leveraging k-mer-based methods, but existing implementations often suffer from sensitivity limitations, particularly in high mutation density genomic regions. Here, we present ska lo, a graph-based algorithm that aims to identify within-strain variants in pathogen whole-genome sequencing data by traversing a colored De Bruijn graph and building variant groups (i.e. sets of variant combinations). Through in silico benchmarking and real-world dataset analyses, we demonstrate that ska lo achieves high sensitivity in single-nucleotide polymorphism (SNP) calls while also enabling the detection of insertions and deletions, as well as SNP positioning on a reference genome for recombination analyses. These findings highlight ska lo as a simple, fast, and effective tool for pathogen genomic epidemiology, extending the range of reference-free variant-calling approaches. ska lo is freely available as part of the SKA program (https://github.com/bacpop/ska.rust).
Polymorphism, Single Nucleotide↗
Evolutionary pattern of intra-host pathogen antigenic drift: effect of cross-reactivity in immune response.
Several viruses are known to change their surface antigen types after infecting a host, thereby escaping the immune defence and ensuring persistent infection. In this paper, we theoretically study the pattern of intra-host micro-evolution of pathogen antigen variants under the antigen specific immune response. We assume that the antigen types of the pathogen can be indexed in one-dimensional space, and that a mutation can produce a new antigen variant that is one step distant from the parental type. We also assume that antibodies directed to a specific antigen can also neutralize similar antigen types with a decreased efficiency (cross-reactivity). The model reveals that the pattern of intra-host antigen evolution critically depends on the width of cross-reactivity. If the width of cross-reactivity is narrower than a certain threshold, antigen variants gradually evolve in antigen space as a travelling wave with a constant wave speed, and the total pathogen density approaches a constant. In contrast, if the width of cross-reactivity exceeds the threshold, the travelling wave loses stability and the distribution of antigen variants fluctuates both in time and in genotype space. In the latter case, the expected episodes after infection are a series of intermittent outbreaks of pathogen density, caused by distantly separated antigen types. The implication of the model to intra-host evolution of equine infectious anaemia virus and human immunodeficiency virus is discussed.
Animals↗
Gene Specific Pathogenicity Predictor for Chromatin-Remodeling BAF Complex-Associated Neurodevelopmental Disorders.
Advancements in whole genome sequencing have increased the number of variants of uncertain significance (VUS) identified in patient genomes. This has created a diagnostic bottleneck for genetic counselors tasked with sifting through these variants and determining those most likely to be causative for a patient's clinical presentation. Machine learning (ML) tools can aid in identifying pathogenic variants from VUS, but there is a need for gene-specific algorithms that predict pathogenic variants with high accuracy. To address this need, we present a workflow for developing gene-specific, ensemble-learning ML tools, that leverage outputs from other algorithms, locations of variants within the gene, and evolutionary conservation data to make a prediction of pathogenicity. Variants in SMARCA2 and SMARCA4 that are associated with rare neurodevelopmental diseases were used to screen 15 ML algorithms. A random forest learner was tuned to yield a final accuracy of 0.93 on holdout data. Generalizing this predictor to other BAF complex proteins resulted in a sharp decline in performance. We trained a final predictor for all genes in the study to create a predictor that identifies pathogenic variants in these BAF subunits with an accuracy of 0.91 on holdout data. This predictor specific to BAF complex proteins performs with higher accuracy and AUROC than any other predictor. The decline in performance when generalized to other proteins emphasizes the need for the gene-specific calibration of predictors. Our workflow for the development of such models provides a quick, computationally inexpensive route for improving the ML tools available to genetic counselors.
Journal Article↗
Studies on the pathogenicity of thiamineless dwarf-colony variants of Staphylococcus aureus isolated from the bovine udder.
The pathogenic characteristics of thiamineless dwarf-colony variants of Staphylococcus aureus (D strains) were compared with those of normal S aureus isolated from the bovine udder. Intravenous injection of D strains into embryonated hen's eggs and intracranial inoculations into mice produced similar results to those with normal S aureus. Intramammary infusion of D strains into normal cows resulted in mastitis which was indistinguishable from the type produced by infusion of S aureus. Intramuscular injection of thiamine HCl into cows with chronic mastitis due to D strains did not alter the course of the disease, although normal sized S aureus colonies were isolated several days after thiamine injection.
Animals↗