Systematic analysis of Mendelian disease-associated gene variants reveals new classes of cancer-predisposing genes
ConclusionsOur findings suggest a possible cancer progression mechanism through metabolic profile alterations. Overall, our data indicates that pathogenic OMIM gene variants contribute to cancer progression and introduces new CPG classifications potentially underpinning diverse tumorigenesis mechanisms. (Source: Genome Medicine)
Source: Genome Medicine - December 25, 2023 Category: Genetics & Stem Cells Source Type: research
Quantitative thresholds for variant enrichment in 13,845 cases: improving pathogenicity classification in genetic hearing loss
ConclusionsOur study quantified evidence strength thresholds for variant enrichment in genetic HL cases, highlighting the importance of defining disease/gene-specific thresholds to improve the precision and accuracy of clinical genetic testing. (Source: Genome Medicine)
Source: Genome Medicine - December 18, 2023 Category: Genetics & Stem Cells Source Type: research
De novo identification of expressed cancer somatic mutations from single-cell RNA sequencing data
AbstractIdentifying expressed somatic mutations from single-cell RNA sequencing data de novo is challenging but highly valuable. We propose RESA – Recurrently Expressed SNV Analysis, a computational framework to identify expressed somatic mutations from scRNA-seq data. RESA achieves an average precision of 0.77 on three in silico spike-in datasets. In extensive benchmarking against existing methods using 19 datasets, RESA consistently outp erforms them. Furthermore, we applied RESA to analyze intratumor mutational heterogeneity in a melanoma drug resistance dataset. By enabling high precision detection of expressed somat...
Source: Genome Medicine - December 18, 2023 Category: Genetics & Stem Cells Source Type: research
Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases
ConclusionsOur data highlight the continued need to address the interpretation challenges in parallel with efforts to improve the sequencing technology itself. We propose a path forward for the implementation of lrWGS sequencing in the setting of autosomal recessive diseases in a way that maximizes its utility. (Source: Genome Medicine)
Source: Genome Medicine - December 14, 2023 Category: Genetics & Stem Cells Source Type: research
Comprehensive assessment of the genetic characteristics of small for gestational age newborns in NICU: from diagnosis of genetic disorders to prediction of prognosis
ConclusionSGA newborns in NICU presented with roughly equal proportions of monogenic and chromosomal abnormalities. Chromosomal disorders were associated with poorer prognosis. The rare-variant collapsing analyses studies have the ability to identify potential causative factors associated with growth and development. The SGA prognosis prediction model integrating genetic and clinical factors outperformed that relying solely on clinical factors. The application of genetic sequencing in hospitalized SGA newborns may improve early genetic diagnosis and prognosis prediction. (Source: Genome Medicine)
Source: Genome Medicine - December 13, 2023 Category: Genetics & Stem Cells Source Type: research
Publisher Correction: Analysis of transcriptomic features reveals molecular endotypes of SLE with clinical implications
(Source: Genome Medicine)
Source: Genome Medicine - December 13, 2023 Category: Genetics & Stem Cells Source Type: research
Pre-operative clonal hematopoiesis is related to adverse outcome in lung cancer after adjuvant therapy
ConclusionsIn resected NSCLC, existence of preoperative CH might amplify CH-related adverse outcomes through adjuvant treatments, resulting in poor survival results. (Source: Genome Medicine)
Source: Genome Medicine - December 12, 2023 Category: Genetics & Stem Cells Source Type: research
Evaluating the use of paralogous protein domains to increase data availability for missense variant classification
ConclusionsWe propose using structurally equivalent positions across related protein domains from different genes to augment evidence for variant co-localisation when classifying novel missense variants. Additionally, we advocate adopting a numerical evidence-based approach to integrating diverse data in variant interpretation. (Source: Genome Medicine)
Source: Genome Medicine - December 12, 2023 Category: Genetics & Stem Cells Source Type: research
Acute ischemia induces spatially and transcriptionally distinct microglial subclusters
ConclusionsICAM could induce excessive neuroinflammation, aggravating brain injury, whereas IPAM probably exhibit neuroprotective features, which could be essential for the homeostasis and survival of cells in the penumbra. Our findings provide a biological basis for targeting specific microglial subclusters as a potential therapeutic strategy for ischemic stroke. (Source: Genome Medicine)
Source: Genome Medicine - December 11, 2023 Category: Genetics & Stem Cells Source Type: research
Prenatal BRCA1 epimutations contribute significantly to triple-negative breast cancer development
ConclusionsOur findings suggest prenatalBRCA1 epimutations might be the underlying cause of around 20% of TNBC and low-ER expression breast cancers. Such constitutional mosaicBRCA1 methylation likely arise through gender-related mechanisms in utero, independent of Mendelian inheritance. (Source: Genome Medicine)
Source: Genome Medicine - December 6, 2023 Category: Genetics & Stem Cells Source Type: research
Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes
ConclusionsThe findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP’s effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans. (Source: Genome Medicine)
Source: Genome Medicine - December 4, 2023 Category: Genetics & Stem Cells Source Type: research
Personalized tumor combination therapy optimization using the single-cell transcriptome
ConclusionsOverall, comboSC provides a feasible and one-stop computational prototype and a proof-of-concept study to predict potential drug combinations for further experimental validation and clinical usage using the single-cell transcriptome, which will facilitate and accelerate personalized tumor treatment by reducing screening time from a large drug combination space and saving valuable treatment time for individual patients. A user-friendly web server of comboSC for both clinical and research users is available atwww.combosc.top. The source code is also available on GitHub athttps://github.com/bm2-lab/comboSC. (Source: Genome Medicine)
Source: Genome Medicine - December 1, 2023 Category: Genetics & Stem Cells Source Type: research
Mobilizable plasmids drive the spread of antimicrobial resistance genes and virulence genes in Klebsiella pneumoniae
ConclusionsOur work observed that a mobilizable MDR or virulence plasmid that carriesoriT but lacks the relaxase genes transferred with the helper CR conjugative plasmid and mobilizable plasmids escaped from CRISPR –Cas defence and remained stable in recipients. These results highlight the threats of mobilizable plasmids as vital vehicles in the dissemination of antibiotic resistance and virulence genes inK. pneumoniae. (Source: Genome Medicine)
Source: Genome Medicine - December 1, 2023 Category: Genetics & Stem Cells Source Type: research
Genome-wide prediction of pathogenic gain- and loss-of-function variants from ensemble learning of a diverse feature set
AbstractGain-of-function (GOF) variants give rise to increased/novel protein functions whereas loss-of-function (LOF) variants lead to diminished protein function. Experimental approaches for identifying GOF and LOF are generally slow and costly, whilst available computational methods have not been optimized to discriminate between GOF and LOF variants. We have developed LoGoFunc, a machine learning method for predicting pathogenic GOF, pathogenic LOF, and neutral genetic variants, trained on a broad range of gene-, protein-, and variant-level features describing diverse biological characteristics. LoGoFunc outperforms oth...
Source: Genome Medicine - November 30, 2023 Category: Genetics & Stem Cells Source Type: research
Evaluating the association of biallelic OGDHL variants with significant phenotypic heterogeneity
ConclusionsBased on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelicOGDHL variants lead to a highly variable monogenic disorder, variants inOGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous pheno...
Source: Genome Medicine - November 29, 2023 Category: Genetics & Stem Cells Source Type: research
