Pathogenic classification of intersex.
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Animals↗
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Results for “pathogenicity classification”
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[Etio-pathogenic classification of chronic pharyngitis].
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Humans↗
H4C5 missense variant leads to a neurodevelopmental phenotype overlapping with Angelman syndrome.
Recurrent de novo missense variants in H4 histone genes have recently been associated with a novel neurodevelopmental syndrome that is characterized by intellectual disability and developmental delay as well as more variable findings that include short stature, microcephaly, and facial dysmorphisms. A 4-year-old male with autism, developmental delay, microcephaly, and a happy demeanor underwent evaluation through the Undiagnosed Disease Network. He was clinically suspected to have Angelman syndrome; however, molecular testing was negative. Genome sequencing identified the H4 histone gene variant H4C5 NM_003545.4: c.295T>C, p.Tyr99His, which parental testing confirmed to be de novo. The variant met criteria for a likely pathogenic classification and is one of the seven known disease-causing missense variants in H4C5. A comparison of our proband's findings to the initial description of the H4-associated neurodevelopmental syndrome demonstrates that his phenotype closely matches the spectrum of those reported among the 29 affected individuals. As such, this report corroborates the delineation of neurodevelopmental syndrome caused by de novo missense H4 gene variants. Moreover, it suggests that cases of clinically suspected Angelman syndrome without molecular confirmation should undergo exome or genome sequencing, as novel neurodevelopmental syndromes with phenotypes overlapping with Angelman continue to be discovered.
Male↗
Dual Aberrant Splicing Caused by an Apparently Missense CHD7 Variant, c.5273A>G (p.Asp1758Gly), in CHARGE Syndrome.
CHARGE syndrome is a rare congenital disorder primarily attributed to heterozygous pathogenic variants of the CHD7 gene. Most pathogenic CHD7 variants are loss-of-function (LoF) variants, whereas the interpretation of missense variants remains challenging in the absence of functional evidence for their pathogenicity. We report a female infant presenting with clinical features characteristic of CHARGE syndrome. Targeted sequencing identified a heterozygous CHD7 variant (NM_017780.4:c.5273A>G), initially annotated as a missense substitution p.Asp1758Gly. This variant has been previously reported and registered with conflicting pathogenicity classifications; however, its transcript-level consequences remain unclear. Long-PCR-based RNA sequencing of total RNA from peripheral blood mononuclear cells revealed two aberrant splicing patterns associated with the variant: a predominant transcript carrying a 28-bp deletion due to cryptic donor splice-site activation, and a minor transcript with partial intron 24 retention. Both transcripts were predicted to result in premature termination codons. These findings demonstrate that c.5273A>G functions as a LoF variant through dual aberrant splicing rather than a simple missense substitution. This case underscores the importance of RNA-level splicing analysis for the accurate interpretation and classification of CHD7 missense variants.
CHD7↗
Estimation of carrier frequencies of autosomal and X-linked recessive genetic conditions based on gnomAD v4.0 data in different ancestries.
PURPOSE: Monogenic rare diseases contribute significantly to infant deaths and pediatric hospitalizations and cause burden to the patients and their families. The American College of Medical Genetics and Genomics recommended in 2021 that carrier screening of autosomal recessive and X-linked conditions with a carrier frequency of ≥1/200 and a severe or moderate phenotype should be offered when planning or during pregnancy. In November 2023 gnomAD v4.0 was released. It contains in total 807,162 individuals, being nearly 5× larger than previous versions, which have been used to estimate gene carrier frequencies (GCF). METHODS: We utilized gnomAD v4.0 (GRCh38) to calculate the GCFs for available genetic ancestry groups for variants having pathogenic or likely pathogenic classification (>80% of submissions) in ClinVar. We calculated GCF separately for exomes and genomes, combined data, and at-risk couple frequencies (ACF) per genetic ancestry group. RESULTS: In total, 324 genes had a GCF ≥1/200 in at least 1 ancestry subgroup. The number of genes with GCF ≥1/200 varied greatly between subgroups. ACFs were more similar, Ashkenazi Jewish having the highest ACF of 6.11%. CONCLUSION: Improved understanding of carrier risks and updated carrier screening content would allow patients to make more informed reproductive decisions.
Humans↗
Unraveling a novel FBN1 variant in Marfan syndrome with dilated aortic root manifestation.
BACKGROUND: Marfan syndrome (MFS) is a genetic disorder affecting connective tissue, with variable incidence rates. A significant portion of cases stems from novel genetic variants, while others inherit it from affected parents. OBJECTIVE: This study focuses on identifying the genetic cause of MFS in a specific family, using whole-exome sequencing (WES). METHODS: A 15-year-old male with confirmed MFS was examined, showing symptoms of palpitations and severe mitral valve regurgitation. WES was performed, followed by confirmation with Sanger sequencing. Variants were assessed for pathogenicity using bioinformatics tools and the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: One potentially novel pathogenic variant was found in exon 14 of the FBN1 gene: c.1676delCinsAAT, p.Ala559GlufsTer21. In silico analysis suggested a deleterious impact on protein structure and function, supporting their pathogenic classification. CONCLUSION: The identification of this novel variant highlights the importance of the FBN1 gene in MFS, especially its cardiovascular manifestations. Early intervention can improve patient outcomes, while ongoing research holds promise for further advancements in treatment for Marfan syndrome.
Humans↗
Exploring the Melanoma and Pancreatic Cancer Phenotype of a Potential CDKN2A Founder Variant, I49T (c.146T>C; p.Ile49Thr), in Individuals of Predominantly Mexican Ancestry.
PURPOSE: Pathogenic/likely pathogenic variants (P/LPVs) in the CDKN2A gene cause an increased risk of melanoma (MEL) and pancreatic cancer (PANC). The CDKN2A variant I49T (c.146T>C), reported to be recurrent in Hispanics, has conflicting pathogenicity classifications at laboratories, affecting clinical care. Multiple genetics clinics collaborated to explore cancers associated with I49T. METHODS: Institutional clinical databases were queried for the CDKN2A variants, I49T, known P/LPVs, and c.-2G>A (a benign variant [BV]), and history of PANC and MEL was abstracted. A combination of statistical tests was used to investigate cancer history associations. RESULTS: Data on 203 individuals, with qualifying CDKN2A variants detected on multigene testing between 2012 and 2023, were analyzed (I49T, n = 101; known CDKN2A P/LPVs, n = 57; BV, n = 45). Those with I49T were 91% less likely to have MEL than known CDKN2A P/LPVs (odd ratio [OR] = 0.089 [95% CI, 0.031 to 0.025]; P < .001) and were also less likely to have PANC (OR = 0.45 [95% CI, 0.14 to 1.41]; P = .17). However, mean age at PANC diagnosis for I49T was 56.0 years, significantly younger than known CDKN2A P/LPVs (μ = 71.0 years; P = .026). CONCLUSION: In the largest I49T study to date to our knowledge, MEL was significantly less frequent compared with known CDKN2A P/LPVs. Although a nonsignificant trend was observed for less PANC in I49T than known P/LPVs, individuals with I49T presented with PANC at a significantly younger age than those with known CDKN2A P/LPVs. The presence of I49T in Hispanics of mostly Mexican ancestry supports that it is a founder variant, relevant to understanding cancer risk in a large proportion of Hispanics in the United States.
Humans↗
[Perforations of the dura mater during epidural anesthesia. The value of epidurography].
The authors propose a pathogenic classification of perforations of the dura mater occurring during continuous epidural anaesthesia: according to the flow through the communication with the subarochnoid space. Two clinical forms of anaesthesia affecting the cord itself may be distinguished on this basis, one frequent and of immediate onset, diagnosed by the "test dose" and the other rare, of delayed onset, where this safety measure does not suffice. Routine prior epidurography is suggested, in order to ensure the diagnosis of dura mater perforation. In the case of the latter, it show either a more or less typical appearance of radicolography only or, more rarely, a picture which combines opacification of the epidural space with the subarachnoid passage of the contrast medium. This "mixed" appearance, although rare, should be known since it makes it possible to prevent delayed total spinal anaesthesia.
Aged↗
Primary amoebic meningoencephalitis.
As a serendipitous by-product of polio virus research, a highly fatal amoebic meningoencephalitis was recognized in animals. The causative microorganisms, contaminants of the viral cultures, were identified as small soil amoebae. These organisms, previously considered non-pathogenic, are prevalent throughout the world. Based on animal studies, the original investigators suggested the possibility of a similar disease in humans. Seven years later, human cases of amoebic meningoencephalitis were reported from widely separated areas of the world. Since 1965, a total of 79 cases have been reported. The literature of primary amoebic meningoencephalitis is presented. The history of the discovery and elucidation of this disease is reviewed. The 79 cases reported in the world literature are divided into two groups, those diagnosed retrospectively after reviewing previous deaths from meningoencephalitis, and those diagnosed at the time of the illness. The classification, morphology, pathogenicity, virulence and distribution of pathogenic soil amoebae are reviewed. The presenting clinical findings, diagnostic procedures, pathology, and management of this recently recognized, highly fatal, human disease is presented along with a report of a new case. Otolaryngologists should become familiar with this serious disorder with a transnasal portal of entry.
Amebiasis↗
Large-scale functional annotation establishes a reference framework for human LRRK2 variants.
Pathogenic variants in leucine-rich repeat kinase 2 (LRRK2)1are among the most frequent monogenic causes of Parkinson's disease (PD)2 and act through a gain-of-function mechanism of increased kinase activity. LRRK2-targeted therapies are in clinical development, but interpretation of the rapidly expanding catalogue of rare LRRK2 variants remains a barrier to translation. Here, we present functionally annotated data on >350 LRRK2 coding variants using a standardized cellular assay with Rab10 phosphorylation as a readout of kinase activity and integrated these data with curated genetic and clinical annotations from the Movement Disorders Society Genetic Mutation Database (MDSGene). Variants differed in activation magnitude, ranging from modest increases (e.g., p.G2019S) to strongly activating substitutions such as p.Y1699C or p.L1795F. Activating variants occurred across the full length of LRRK2, although the largest effects clustered within the ROC-COR regulatory hub, where structural analysis identified subdomains forming an allosteric scaffold controlling kinase output. All known/established pathogenic variants showed increased activity, whereas benign and likely benign variants remained within the wild-type range. Functional effect sizes correlated with pathway activation in patient-derived immune cells, altogether providing a framework for ACMG-based variant interpretation in which kinase activation can support PS3 functional evidence for reclassification of variants.
Protein phosphorylation↗
X-ray microanalysis as applied to fungal tissues.
Analytical electron microscopy combines the techniques of high-resolution electron microscopy and high-sensitivity X-ray microanalysis of samples. Spectrometry of the elements (characteristic X-rays produced by a scanning electron microprobe) was employed to detect some elements of Mendeleev's classification in pathogenic fungi for humans. X-ray microanalysis applied in wavelength dispersive spectrometry was used to study Coccidioïdes immitis, Paracoccidioïdes brasiliensis and Trichosporum cutaneum.
Coccidioides↗
Pathogenicity assessment of genetic variants identified in patients with severe hypertriglyceridemia: Novel cases of familial chylomicronemia syndrome from the Dyslipidemia Registry of the Spanish Atherosclerosis Society.
PURPOSE: Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases. METHODS: 245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients. RESULTS: Twenty-four biallelic variants were analyzed. Evidence-based criteria allowed the reclassification of 8 likely pathogenic (LP) variants in the LPL, APOA5, and LMF1 genes into pathogenic (P) and the change of 2 variants of uncertain significance (VUS) to LP. Conversely, 2 variations in LMF1 remained as VUS. Additionally, 1 variant in LPL and 2 in GPIHBP1 were likely benign. Twenty FCS cases had biallelic P/LP variants and 1 patient, with an FCS phenotype, harbored biallelic VUS. FCS was excluded from 4 patients with pathogenic/likely benign combinations. CONCLUSION: The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases.
Humans↗
Numerical classification of Yersinia enterocolitica and relationship between its subdivision and pathogenicity.
A total of 102 strains of Yersinia enterocolitica were studied on their morphology, physiology and biochemistry at 25 degrees C. All data coded in binary notation and similarities between each pair of strains by simple matching coefficient were calculated using subsequent computation. Four clusters were distinguished within the 102 strains at a similarity level of 90--93%. Although some discrepancies were recognized on reactions of indole, xylose, esculin and salicin, it was evident that 3 of the 4 groups in the present study correspond to the DNA relatedness groups of Brenner et al., respectively. On the other hand, it was confirmed, using feeding tests with monkeys, that only the group 1 was enteropathogenic. These results support the suggestion of Brenner et al. that their DNA relatedness group 1 is true Y. enterocolitica.
Animals↗
Spatiotemporal patterns of Rift Valley fever virus in Africa: a retrospective genomic epidemiology and phylodynamic modelling study.
BACKGROUND: Rift Valley fever virus (RVFV) is a mosquito-borne zoonotic pathogen causing outbreaks in humans and ruminants across Africa and the Arabian Peninsula. Originally restricted to the Great Rift Valley, RVFV has expanded geographically, prompting its classification by WHO as a pathogen of pandemic potential. We investigated the evolutionary and spatial dynamics of RVFV across Africa. METHODS: We used genomic data generated at the International Livestock Research Institute Nairobi genomic laboratory (BioProject PRJNA1106221) and combined with publicly available datasets retrieved from the National Center for Biotechnology (NCBI) GenBank nucleotide database. In retrieving RVFV genome sequences from the NCBI GenBank, we applied the search terms "Rift Valley fever virus segment L AND 6404[SLEN]", "Rift Valley fever virus segment M AND 3885[SLEN]", and "Rift Valley fever virus segment S AND 1520:1690[SLEN]" for L (Large), M (Medium), and S (Small) segments, respectively. For sequences without additional spatiotemporal information, we searched PubMed to extract the associated sequence metadata. We performed molecular clock analysis, phylogenetic inference, phylodynamic modelling (continuous phylogeographic reconstruction), and landscape phylogeography on the three RVFV genome segments (L, M, and S). We aimed to assess evolutionary rates, dispersal patterns, and environmental drivers. Focus was placed on lineage C, the most widely distributed variant. FINDINGS: The global dataset used in this study consisted of large (n=236), medium (n=237), and small (n=247), which were further filtered to exclude potential reassortants and vaccine strains. Genome sequences retrieved from NCBI GenBank database comprised large (n=180), medium (n=184), and small (n=202). The genome sequences from retrospective human and livestock isolates comprised large (n=56), medium (n=53), and small (n=45) collected in Burundi (2018), Kenya (2007, 2018, 2019, 2021, and 2022), and Rwanda (2018 and 2022). Our dataset revealed that RVFV exhibited low overall genetic diversity. Lineage C, however, showed evidence of active evolution, with substitution rates ranging from 3·58 × 10-4 to 9·76 × 10-4 substitutions per site per year. This lineage probably originated in Zimbabwe in the mid-1970s and has since expanded across eastern and southern Africa. Phylogeographic reconstructions revealed rapid spread, with diffusion coefficients exceeding 50 000 km2 per year. INTERPRETATION: Lineage C appears capable of establishing endemic transmission in new regions, with ongoing diversification observed during interepidemic periods. These observations reinforce the value of continuous genomic surveillance, particularly during cryptic transmission phases when adaptive mutations might emerge. Although further evidence is needed, observed trends in climate variability and land-use change point to the potential benefit of targeted surveillance in settings that could be at increased risk, including urban centres and wetlands. FUNDING: This work was supported by the German Federal Ministry for Economic Cooperation and Development, the Rockefeller Foundation, and the Africa Centres for Disease Control and Prevention.
Rift Valley fever virus↗
The Animal Variant Classification Guidelines v2: An Update With New Criteria and Improved Clarifications.
The Animal Variant Classification Guidelines (AVCG) were developed to standardize and objectify the classification of putative disease-causing variants. These guidelines are sufficiently reproducible and are used to classify previously published and new disease-causing variants across species. Here, the guidelines are updated (AVCG.v2), based on a three-phase decision process. Overall, four new criteria and seven clarifying comments were added. The number of criteria has increased from 23 to 27, with three new criteria supporting pathogenicity and one new criterion supporting benign classification. Pharmacogenomic variants were determined to fall within the scope of the guidelines. These updated guidelines are being used by the Variant Pathogenicity Working Group (VPWG), part of the Animal Genetic Testing Standardization standing committee, which is a committee of elected members of the International Society for Animal Genetics (ISAG). Under the auspices of ISAG, the VPWG retrospectively classifies published putative disease-causing variants. The pathogenicity label for a variant will be presented in the variant tables of Online Mendelian Inheritance in Animals (OMIA; https://omia.org/). The AVCGv.2 criteria and recommendations were developed by the expertise of the animal genetics community and the ISAG Executive Committee through the Animal Genetics Testing Standardization Committee endorses and strongly encourages their use to evaluate the evidence supporting pathogenicity of putative disease-causing variants.
Animals↗
Exploring shotgun metagenomic data to detect microeukaryotic pathogens in wildlife.
BACKGROUND: Microeukaryotic parasites of the intestinal tract are an understudied group of organisms that infect humans and many other animals. Targeted sequencing methods focused on individual loci are usually employed for detection of these parasites, making comprehensive studies of microeukaryotic parasite diversity within hosts or other systems difficult. Exploratory approaches such as shotgun metagenomic sequencing to survey the diversity of microeukaryotic parasites in new and existing datasets are not well developed. RESULTS: Utilizing existing datasets from 12 goose fecal samples, we explored some of the benefits and challenges of using shotgun metagenome sequencing to detect microeukaryotic parasites. We demonstrated the importance of careful curation of read classification data to avoid erroneously linking pathogens to hosts or environments as unsupported classifications were common in the data and varied widely depending on analysis parameters. However, we were able to establish strong support for the presence of sequences of Eimeria and Enterocytozoon bieneusi. In addition, examination of trichomonad reads indicated that parasite reads mapping to human pathogens unlikely to colonize geese may in fact represent cryptic microeukaryotic species that are not included in existing curated databases opening new potential avenues of study. CONCLUSIONS: Taken together these findings support the idea that exploring microeukaryotic parasite diversity within shotgun metagenomic datasets can be beneficial to our understanding of the presence and diversity of these organisms in wildlife hosts.
Animals↗
RNA splicing evidence enables robust classification of BRCA1 exon 18 variants: Results from the ENIGMA consortium.
The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) research consortium conducted a comprehensive study to characterize spliceogenic variants in BRCA1 exon 18. The absence of systematic RNA-based assessment for these variants has led to inconsistent interpretation, limiting accurate classification and management of individuals and their families. The splicing profile of 166 variants was assessed using minigene assays; 32 were additionally analyzed in blood-derived RNA from 51 individuals and 18 in mouse embryonic stem cell (mESC)-based assays to evaluate homology-directed repair (HDR) capacity. mRNA assessment by RT-PCR in blood samples and minigene assays showed a significant positive correlation, with splicing analysis in mESCs displaying highly concordant results. The mESC-based HDR assay showed that the in-frame exon 18 skipping (Δ18) transcript encodes a non-functional protein lacking rescue activity. Linear regression analysis using mESC splicing and functional data indicated that ≥59% of full-length (FL) levels and <34% of Δ18 were associated with benign HDR activity. These thresholds differ from those recommended by the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) specifications for applying BP7_strong(RNA): >30% functional transcripts or <70% non-functional transcripts. Incorporation of RNA splicing evidence into variant interpretation increased pathogenic (28.6%-31.7%) and benign (3.7%-24.4%) classifications while reducing likely pathogenic (19.5%-17.7%), uncertain (18.9%-8.5%), and likely benign (29.3%-17.7%) categories. Experimental mRNA profiling impacted the interpretation of 34% of variants and resolved uncertainty in approximately 10% of cases. Exon 18 skipping was less tolerated, indicating that the degree of splice perturbation required to impair BRCA1 function may depend on the nature of the resulting non-functional transcript.
Humans↗
[Effectiveness of antibiotics in bovine staphylococcal and streptococcal mastitis].
The present knowledge of the efficiency of antibiotics against bovine mastitis has been reviewed. Criteria for the choice of papers are given, together with tabulated results of treatments with one antibiotic or two. Results are discussed in relation to the time of treatment and the pathogenic agent involved, and a classification of the antibiotics into three groups is proposed: recommended; not advised; not sufficiently studied.
Animals↗