搜索结果：HGG advances

The inevitable progression of high-grade gliomas has prompted a need for data-backed identification of compromised tissue prior to detection on traditional serial imaging. Whole-brain magnetic resonance spectroscopy (WB-MRS) can fill this role to classify glioma progression prior to contrast enhancement. Voxel-level data can differentiate areas of perilesional tissue under supervised machine learning (ML) and has been shown to predict the likelihood of tumor progression within six months. In this study, we aim to improve the spatial utility of WB-MRS ML through unsupervised ML clustering for utility in intraoperative integration with existing neuronavigation platforms. This analysis involved 16 adult patients that developed recurrence of high-grade glioma (HGG) on serial imaging, including 13 with glioblastoma (GBM) and three with anaplastic astrocytomas. Postoperative WB-MRS images were used as data inputs. We investigated two unsupervised clustering methods to optimize the identification of compromised perilesional tissue from a previously published supervised model. All voxels within the new region of interest (ROI) are reclassified as future progression regardless of their classification from the supervised model. After hyperparameter tuning, Density-Based Spatial Clustering of Applications with Noise (DBSCAN) shows an area under the curve (AUC) of 0.942, while K-Means Clustering shows an AUC of 0.874. DBSCAN also shows a superior accuracy, specificity, sensitivity, and F1-score to the original supervised model alone. The incorporation of unsupervised clustering enhances the utility of WB-MRS for identifying compromised perilesional tissue and predicting high-grade glioma progression. Unsupervised clustering incorporates critical geospatial data and offers a more surgically relevant approach to visualizing tumor progression. Early detection of high-grade glioma recurrence remains a major limitation of current imaging modalities, restricting the ability to guide timely and precise interventions. While prior work has demonstrated that WB-MRS combined with supervised ML can identify metabolically abnormal tissue at risk for progression, these approaches lack spatial coherence and clinical usability. In this study, we introduce a hybrid pipeline integrating supervised voxel-wise predictions with unsupervised spatial clustering (DBSCAN and K-means) to refine recurrence mapping. This approach significantly improves classification performance and generates spatially contiguous, clinically interpretable regions of interest. Importantly, these outputs can be exported as DICOM overlays, enabling direct integration into neuronavigation systems. While still in pilot phase, this work advances WB-MRS from a predictive tool toward a clinically integrable platform, with potential applications in surgical planning, biopsy targeting, and longitudinal disease monitoring in patients with high-grade glioma.

Reirradiation has re-emerged as a viable salvage modality for recurrent central nervous system (CNS) tumors in the modern era of precision radiotherapy. Advances in image guidance, biological understanding of normal-tissue repair, and integration of targeted systemic agents have expanded its therapeutic window. The 2025 ISRS meta-analysis (62 studies; n = 2640) established a median overall survival (OS) of ~ 10.2 months after re-irradiation (re-RT) of recurrent HGG, confirming that focal single-fraction SRS (16 Gy × 1) or hypofractionated SRS (25 Gy/5 fx) achieves optimal tumor control with acceptable neurologic toxicity (7% vs 4%). EQD₂ > 120-130 Gy markedly increases radionecrosis risk (p = 0.003). Integration of DNA-damage-repair (DDR) inhibitors, VEGF blockade, and tumor-treating fields (TTFields) is under active investigation. Re-RT in ependymoma, meningioma, and spinal tumors is also gaining renewed interest with proton and MR-guided adaptive techniques.

Inherited retinal diseases (IRDs) comprise a diverse group of disorders that frequently lead to progressive vision impairment and blindness. Despite advances in genetic testing, a significant number of IRD cases remain genetically unsolved, often due to unidentified disease-associated genes or variants. This study reports additional cases for the newly discovered IRD genes of the AP-5 complex. A comprehensive ophthalmological evaluation was performed for all patients, including retinal imaging (multimodal imaging), visual field testing, and electroretinogram (ERG) testing. Whole-genome and -exome sequencing (WGS and WES) were performed for clinically unsolved IRD patients, and data were analyzed to identify underlying causal variants. The identified variants were subsequently validated using Sanger sequencing. Five unrelated patients from Europe and Iran were identified with a distinctive macular degeneration associated with bi-allelic variants in AP5Z1 (HGNC: 22197) and AP5B1 (HGNC: 25104), subunits of the vesicular fifth adaptor protein (AP-5) complex. The AP-5 complex is the part of the intracellular trafficking machinery thought to be involved in cellular homeostasis and lysosomal functioning in the retinal pigment epithelium (RPE). The identification of bi-allelic variants in two proteins of the AP-5 complex expand the characterization of AP-5 genes in sustaining and preserving normal macular function.

Prosody perception is an often overlooked aspect of human language despite its importance in facilitating spoken language comprehension. Sensitivity to prosodic cues varies between individuals, and prosody perception skills are shown to be associated with various language- and reading-related outcomes. Despite the importance of prosody perception in human communication, its underlying biology is poorly understood. This study investigates the genetic architecture of prosody (speech rhythm) perception and explores its evolutionary roots. We conducted a GWAS of prosody (n = 1,501) as measured by scores on the Test of Prosody via Syllable Emphasis ("TOPsy"). GWAS results yielded 14 suggestive significant signals (p < 5.00 &#xd7; 10-6). Gene set enrichment analysis identified shared genetic architecture between human prosody perception and key vocal learning brain regions in songbirds, suggesting that human prosody perception may have evolutionary convergence in communication mechanisms in animal vocal learning. Additionally, cross-trait polygenic score analyses suggest shared genetic influences between prosody perception and both word reading and musical beat synchronization, emphasizing how genetics influence prosody perception and its associations with communication-, education-, and music-related traits. These initial efforts could inform advances in communication sciences and disorders as well as educational contexts.

Heterotaxy (HTX) is a congenital disorder characterized by abnormal left-right organ placement, often leading to severe congenital heart disease (CHD). Despite advances in sequencing, many CHD and HTX-associated genes remain functionally unvalidated, hindering effective clinical diagnosis and management. Here, we leveraged a high-throughput CRISPR-Cas9 screening approach in the Xenopus model to rapidly evaluate candidate genes identified from whole-exome sequencing of human CHD patients. Our screen identified Filamin B (FLNB), an actin-binding protein previously linked to skeletal disorders but not to ciliopathies or CHD. We identified 5 probands with CHD and HTX, 3 with recessive and 2 with damaging heterozygous variants in FLNB. Disrupting flnb in Xenopus reproduced key features of the human HTX phenotype, including defects in cardiac development and impaired motile cilia function. Rescue experiments confirmed the functional conservation of human FLNB, directly implicating actin cytoskeletal disruption in ciliogenesis and left-right patterning defects. Our results provide crucial evidence linking human FLNB dysfunction to ciliopathies and CHD and HTX.

Pathogenic missense variants in PRKACA cause craniofacial, skeletal, and cardiac defects similar to Ellis-van Creveld syndrome. We report an individual with a previously unreported, de novo 3-amino-acid deletion in PRKACA, identified on trio genome sequencing, and phenotypic features including severe neonatal hypotonia, appendicular skeletal abnormalities, osteopenia, aortic dilation, coronary dilation, and vascular tortuosity. To assess this variant's effects, we performed in vitro and in vivo studies, generated an in silico model, and assessed cell ciliation in induced pluripotent stem cells from the patient. Although the protein product of the PRKACA (Protein kinase A [PKA]-C&#x3b1;) 3-amino-acid-deletion variant is catalytically active, it shows reduced interaction with the regulatory subunits of PKA (particularly type II), resulting in overactivation of the PKA pathway and/or an inability to initiate Hedgehog signaling. The deletion affects a key portion of PKA-C important for substrate tethering. Patient-derived induced pluripotent stem cells (iPSCs) have reduced ciliation compared to controls. Collectively, this supports that the PRKACA variant is pathogenic, and we propose that it is causal for our patient's unique skeletal dysplasia and vasculopathy phenotypes. This expands the phenotypic spectrum of pathogenic variants in PRKACA and suggests that affected individuals may require periodic screening for aortic and coronary dilation as well as osteopenia.

Mitochondrial disorders show remarkable clinical and genetic heterogeneity and result from variants in either mitochondrion- or nucleus-encoded genes. CHCHD4 is a component of the mitochondrial import and assembly pathway that imports small cysteine-containing substrates. We report a pediatric patient with biallelic CHCHD4 variants who presented with severe neurological regression and early death. Western blot analysis showed decreased levels of CHCHD4 and diminished assembly of complexes I and IV in his fibroblasts. To demonstrate that CHCHD4 variants were responsible for the observed biochemical phenotype, we overexpressed wild-type CHCHD4 in control and subject fibroblasts, restoring levels of complex I and IV proteins and the associated assembly defects. Proteomic studies pointed to electron transport and complex I biogenesis as the main dysregulated pathways and showed a severe loss of several complex I and IV proteins and/or assembly factors rescued by overexpression of wild-type CHCHD4. CHCHD4 has numerous targets and interacting factors and is involved in the export of iron-sulfur clusters synthesized inside mitochondria. Surprisingly, few of these interacting factors or non-mitochondrial functions were impacted by the observed CHCHD4 defect. In conclusion, our work establishes CHCHD4 deficiency as a cause of dysregulated mitochondrial protein import resulting in a severe neurological condition.

Genetic relatives share long stretches of DNA they co-inherited from a common ancestor in identical-by-descent (IBD) segments. Because children inherit half their parents' genomes, the expected amount of DNA relatives share drops by 12 for each generation that separates them, being 2-d for d-degree relatives. Even so, there is substantial variance in sharing rates so that most distant relatives share zero IBD segments. I characterized IBD segment sharing between relatives by simulating 100,000 pairs for each of first through eighth cousins, including once-removed and half-cousins, while modeling both crossover interference and sex-specific genetic maps. My results show that 98.5% of third cousins share at least one IBD segment, while only 32.7% of fifth cousins and 0.96% of eighth cousins have such sharing. These sharing rates are slightly higher than those that arise from models that ignore the more elaborate crossover features and can be filtered by segment length. The resulting segment count distributions are available with an interactive segment length threshold online.

Differences in immune responses are observed between males and females, influenced by genetic, hormonal, and environmental factors. The sex-specific genetic effects on cytokine production, however, remain underexplored. This study aimed to identify sex-specific quantitative trait loci (QTLs) affecting cytokine production in response to diverse infectious antigens. We performed sex-stratified cytokine QTL (cQTLs) mapping in two population-based cohorts from Tanzania and the Netherlands. In the Tanzanian cohort, 12 genome-wide significant cytokine QTLs were identified, with 7 observed in males and 5 in females. In the Dutch cohort, 12 genome-wide significant cQTLs were identified, with 6 cQTLs each in males and females. Colocalization analysis confirmed that all 12 genome-wide cQTLs from the Tanzanian cohort are sex specific, while in the Dutch cohort 10 genome-wide cQTL variants are modulated in a sex-specific manner. Furthermore, pathway and phenotype enrichment analyses linked the identified cQTL variants to relevant immune functions and sex-biased traits. Our study highlights the importance of sex-stratified genetic analyses when investigating the genetic basis of cytokine production in humans. We show that sex-specific cQTLs may underlie observed phenotypic differences between males and females and that accounting for such effects can inform the development of personalized medical treatments for sex-biased diseases.

The genetic liability to a complex phenotype can be assessed using polygenic risk scores (PRSs) and is calculated as the sum of genotypes weighted by effect-size estimates derived from summary statistics of genome-wide association study (GWAS) data. Due to different allele frequencies (AFs) and linkage disequilibrium (LD) patterns across populations, PRSs developed in one population drop drastically in predictive performance when transferred to another. One of the major factors contributing to AF and LD heterogeneity is genetic drift, which acts strongly during population bottlenecks and is influenced by the dominance of certain alleles. In particular, because causal variants on empirical data are typically not known, the presence of population-specific LD patterns will strongly affect the transferability of PRS models. In this work, we therefore conducted demographic simulations to investigate the influence of the dominance coefficient on the transferability of PRSs among European, African, and Asian populations. By modifying the length and size of the bottleneck leading to the split of Eurasian and African populations, we gain a deeper understanding of the underlying dynamics. Finally, we illustrate that in our simulations, PRS models that are adapted to the underlying dominance coefficient can substantially increase the prediction performance in out-of-target populations.

The impact of clinical exome and genome sequencing (ES/GS) depends on the clinical setting. In the sequencing arm of a multifactor randomized clinical trial to evaluate broadening access, we assessed the diagnostic and inconclusive findings of ES as a "first-tier" test in 101 pediatric participants in whom suspicion of a genetic condition by primary care providers had prompted initial outpatient consultation in a pediatric genetics or neurology clinic. This implementation focused on the early stages of the diagnostic odyssey, capturing a clinically less-selected population with lower pre-test probability than traditional specialist cohorts. Variants were prioritized using phenotype-driven gene lists. After returning the results to participants, the clinical teams performed familial variant testing or additional phenotyping at their discretion, based on potential diagnostic benefit. We then implemented a multidisciplinary case conference in which the laboratory and clinical teams assessed additional clinical information. Initially, 57% of participants had non-negative reports: 5% had one or more variant findings considered explanatory for the presenting phenotype, with 52% having results initially classified as inconclusive. After family testing and/or phenotypic characterization, a total of 9% were considered positive/diagnostic, 10% were reclassified from inconclusive to negative, and 38% remained inconclusive. While ES, as a first-tier genetic test, can expedite some diagnoses, these results demonstrate challenges in early implementation. In this population, initial testing can leave substantial residual uncertainty, shifting the diagnostic odyssey rather than concluding it and necessitating factors such as parental testing, ongoing phenotyping, and reassessment of variants over time to resolve inconclusive results.

Dilated cardiomyopathy (DCM) results from systolic dysfunction, while restrictive cardiomyopathy (RCM) is due to diastolic dysfunction. The diverse pathophysiology of primary DCM and RCM suggests distinct underlying genetic mechanisms. A well-established disease gene for DCM and RCM is cardiac troponin I3 (TNNI3), which causes dominant and recessively inherited forms. In children, bi-allelic truncating TNNI3 variants have typically been associated with DCM, and heterozygous missense TNNI3 variants are associated with RCM. We report a 2-year-old female with severe RCM that is genetically caused by a homozygous TNNI3 nonsense variant, c.406C>T (p.Arg136&#x2217;), which results in a more distal (C-terminal) truncation than most previously reported disease-associated nonsense variants. In myocardial biopsies of the patient, TNNI3 protein abundance was diminished, suggesting that residual TNNI3 function may underlie RCM, while TNNI3 absence causes DCM. The RCM in this patient was treatment refractory and resulted in a heart transplant at the age of 28 months. Overall, recessive TNNI3 protein truncation causes severe pediatric RCM, suggesting that the allelic status, type of genetic alteration, and length of TNNI3 protein truncation determine cardiomyopathy onset and subtype manifestation.

Sphingolipids are integral components of cell membranes and modulate cell survival, proliferation, and apoptosis. ASAH2 is a brain- and gut-enriched gene encoding the neutral N-acylsphingosine amidohydrolase 2, a poorly characterized member of the human ceramidase family. This enzyme plays a pivotal role in maintaining the sphingolipid homeostasis, which is crucial for neurogenesis and synaptic function in the central and peripheral nervous systems. In fact, a dysregulated sphingolipid metabolism is associated with progressive neurological conditions, including Alzheimer disease and Parkinson disease. Here, we report the identification of biallelic ASAH2 variants in an individual with a neurodevelopmental condition featuring cognitive impairment, neuropathy, ophthalmoplegia, and progressive cerebellar and extraocular muscles atrophy. Through exome sequencing, we identified very rare missense ASAH2 variants, predicted to be deleterious by in silico analyses. Muscle biopsy histopathologic evaluation revealed features suggestive of neuropathic damage. Lipidomic profiling revealed a hyper-accumulation of glucosylceramide in the subject's cells. Then, the functional investigation of the ASAH2 variants in Drosophila showed the production of an unstable protein and consistent loss-of-function neuromotor phenotypes. Our findings support ASAH2 as a candidate gene for a previously uncharacterized neurodevelopmental disorder with neuropathic features and progressive cerebellar atrophy, underscoring the important role of this ceramidase in human nervous systems.

Polygenic scores (PGSs) offer moderate to high prediction accuracy for complex traits, but most are developed in European ancestry cohorts, reducing their performance in populations of other ancestries. This study aimed to improve standing height prediction, a heritable and ancestry-influenced trait, in an admixed Latino cohort, the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), by modeling ancestry using principal components (PCs) alongside PGSs. SNPs were selected from a large European ancestry genome-wide association study (GWAS) using various p value thresholds, and weights were trained using traditional and penalized regression in the UK Biobank (UKB). PGSs with PCs were trained separately in the HCHS/SOL and UKB. Compared to PGSs alone, modeling PGSs with PCs moderately improved height prediction in the HCHS/SOL (squared correlation [R2] increase of &#x223c;0.05), while mild improvements were observed in the UKB (R2 increase of &#x223c;0.01). These results underscore the importance of incorporating genetic ancestry into predictive models for admixed populations, particularly when the trait exhibits ancestry-specific associations.

Index trait bias (also called index event bias) can occur in genetic studies due to conditioning on incident trait, which can bias genetic associations with subsequent traits. We propose the use of two Bayesian Mendelian randomization (MR) methods (Bayesian weighted MR [BWMR] and MR-HORSE) to correct index trait bias in genome-wide association studies (GWASs) of subsequent traits. We compare these Bayesian MR methods to previously proposed methods for index trait bias through a simulation study. We observe that BWMR has similar type I error compared to using an inverse variance weighted MR, weighted median MR, and Dudbridge but has an inflated type I error compared to SlopeHunter. MR-HORSE and SlopeHunter have similar type I errors for smaller correlations between incident and subsequent traits; however, MR-HORSE and SlopeHunter have better controlled type I error for a large negative correlation and large positive correlation, respectively. All methods have comparable power across correlations between incident and subsequent traits. We applied the methods to a GWAS of subsequent acute ischemic stroke (AIS) or 3-point major adverse cardiovascular event after an incident AIS event in the Million Veteran Program and for fasting insulin adjusted for body mass index, and we observed slight differences in the results between the correction methods. We observed that a single index trait bias correction method is not optimal across all scenarios; therefore, applying multiple methods and checking for consistency between the estimates could provide an approach to determine the presence of and correction for index trait bias.

Variants with intermediate functional effects-neither fully disruptive nor functionally neutral-represent an under-recognized source of genetic complexity and define a functional gray zone that complicates variant classification. Here, we address this issue using GT>GC (+2T>C) 5' splice-site variants as a tractable model, as approximately 15%-18% of such substitutions retain variable levels of residual wild-type (WT) transcript. Using residual WT transcript as a quantitative functional readout, we first revisited disease-associated GT>GC variants previously shown to retain substantial WT transcript, including SPINK1 c.194+2T>C, HBB c.315+2T>C, and BRCA2 c.8331+2T>C, illustrating how intermediate splicing effects complicate clinical interpretation across distinct genes and disease contexts. We then performed a locus-wide assessment of all 26 theoretically possible GT>GC substitutions in CFTR, integrating SpliceAI delta donor-loss scores with classifications from expert-curated databases. Minigene splicing analyses of four selected CFTR variants, together with full-length and minigene analyses of a BAP1 GT>GC variant with conflicting clinical interpretations, revealed heterogeneous and context-dependent splicing outcomes, underscoring both inter-assay variability and the inherent limitations of commonly used splicing assay systems. Collectively, our findings indicate that GT>GC variants capable of generating appreciable residual WT transcript exemplify a broader class of intermediate-effect alleles that expose the limitations of both computational prediction and experimental assessment. These observations highlight the need for classification frameworks that incorporate quantitative functional data and better capture the continuum of variant effects.

Autonomy is a leading indicator of well-being and a cornerstone principal of research ethics. Yet adults with intellectual disability are routinely denied autonomy in research settings, affecting participation and generalizability. To inform health research policy and practice, we conducted a national survey of 150 adults with intellectual disability to explore their views on autonomy and decision-making in precision medicine research (PMR), a leading area of health research. Participants expressed strong interest in participating in PMR and controlling their participation decisions, sometimes with support. Findings highlight the need for policies and practices that honor these interests and facilitate autonomy. Over time, such efforts can improve health outcomes for this underserved population.

The American College of Medical Genetics and Genomics (ACMG) recommends Tier-3 reproductive carrier screening for 97 genes associated with autosomal recessive (AR) conditions (AR genes). Gene selection for screening is based on a gene carrier frequency (GCF) of &#x2265;1/200 in the Genome Aggregation Database (gnomAD)v2 populations and disease severity. The utility of ACMG Tier 3 in the Middle Eastern population is unclear as this ancestral group was not represented in the gnomADv2. We utilized genome data from 14,392 individuals in the Qatar Genome Project to estimate the carrier frequency of AR conditions in the Middle Eastern population. The frequency of 136,624 pathogenic/likely pathogenic variants in 2,987 AR genes from ClinVar was analyzed to estimate the GCF in the Qatari cohort. Genes with GCF &#x2265; 1/200 were curated by an expert panel for the severity of corresponding conditions. We identified 69 genes with GCF &#x2265; 1/200 associated with moderate to profound clinical presentations, 53 of which were unique to the Middle Eastern population. Common variants were observed with high frequency for individual genes such as IL2RA that suggested the presence of founder effects not described previously. Simulation studies predicted that inclusion of the ancestry-specific genes increased the chance of detecting at-risk couples from 3.85% to 8.15% in the Middle Eastern population. This study highlights the limitations of relying on global datasets to accurately identify the candidate genes for carrier screening in different populations. Our findings provide a framework for targeted, population-specific carrier-screening programs in regions not represented in the large genome datasets.

Genetic summary statistics can be used in a variety of analyses, such as causal inference, genetic correlation, and risk scores, to provide insights into the genetic architecture of conditions and traits. However, complete statistics are often not reported limiting the utility of this data. Indeed, many post-hoc analyses of diseases require case and control allele frequencies (AFs), which are not always published. Here, we present methods and software to derive case and control AFs from genome-wide association study (GWAS) summary statistics using the odds ratio, case and control sample sizes, and either the total (case and control aggregated) AF or standard error (SE). In simulations and real data, derivations of case and control AFs using total AF are highly accurate while using SE underestimates AFs when covariates were included in the GWAS. While estimating case and control AFs using the total AF is preferred due to its high accuracy, SE is more commonly available. Thus, we developed a bias adjustment using gnomAD AFs as a proxy for true AFs reducing bias when using SE. The methods and software provided here expand the utility of publicly available genetic summary statistics and promote the reusability of genomic data. The R package Case-Control Allele Frequency Estimation (CCAFE) is freely available on Bioconductor and GitHub.