Genetics research最新文献

Purpose: The genetic spectrum and early clinical indicators of familial exudative vitreoretinopathy (FEVR) remain incompletely defined, and few studies have investigated the genetic variants and clinical phenotypes associated with eoHM-FEVR and anisometropia-FEVR patients. The purpose of this study was to screen the pathogenic variations in 11 FEVR families and analyze the refractive status and pathogenic genes in patients with irregular dominantly inherited FEVR.

Methods: The patients with clinical diagnoses of eoHM-FEVR or anisometropia-FEVR were evaluated from October 2019 to August 2022. Comprehensive ophthalmic tests were performed on participants to confirm the phenotype. The genotype was identified using whole-exon sequencing and further verified the results among other family members by Sanger sequencing. Normal protein structures were modeled with AlphaFold, whereas mutant variants were analyzed via PyMOL. Variant pathogenicity followed the American College of Medical Genetics and Genomics (ACMG) guidelines. The protein-protein interaction (PPI) network analysis with STRING and k-means clustering was applied for detecting the interaction of genes in the candidate genes, and the ClusPro Server was used for protein-protein docking.

Results: A total of 11 FEVR families were included in the study, and all the probands were found to have high myopia in both eyes or one eye before the age of 7 years. The pathogenic variants were identified in the genes TSPAN12, LRP5, and FZD4 known to be associated with FEVR in six probands. Among 13 eoHM-related genes, FZD4 and LRP2 encode proteins that can dock together as analyzed by ClusPro software.

Conclusion: This study observed dominant inheritance of an irregular pattern in FEVR families, with asymmetric FEVR presenting as severe anisometropia. The eye with higher myopia often had more advanced FEVR and pronounced fundus changes. PPI network analysis revealed important modules of gene interaction, and the FZD4-LRP2 complex protein was potentially related to high myopia development. For patients with high myopia or with obvious anisometropia in both eyes, more attention should be paid clinically to the comprehensive examination of the peripheral fundus and early genetic testing.

Background: Optic nerve injury, as a neurodegenerative disorder, leads to irreversible visual impairment. Although the underlying mechanisms linking physical activity to optic nerve injury remain unclear, this study aimed to establish a causal relationship between physical activity and optic nerve injury using a Mendelian randomization (MR) framework.

Methods: This MR study utilized genome-wide significant variants as instrumental variables (IVs) for assessing the relationship between physical activity and optic nerve injury, focusing on individuals of European descent. The approach was supported by comprehensive sensitivity analyses and augmented by bioinformatics tools including differential gene expression, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses.

Results: Our study demonstrated that after adjustment for MVPA, alcohol intake, BMI, blood glucose, blood lipids, and smoking, LST was positively associated with glaucoma risk (β = 0.016, 95% CI: 0.004 to 0.027, p = 0.014), indicating its role as an independent risk factor. Conversely, MVPA was negatively associated with glaucoma risk (β = -0.012, 95% CI: -0.022 to -0.002, p = 0.026), supporting a protective effect, while smoking also showed a significant association (β = -0.020, 95% CI: -0.039 to -0.002, p = 0.037). Sensitivity analyses confirmed the robustness of these findings, and bioinformatic analyses implicated cholesterol metabolism and fibrosis pathways in optic nerve injury.

Conclusion: These findings underscore the potential of lifestyle modifications, including increased physical activity and reduced sedentary behavior, as a cost-effective strategy to prevent and manage optic nerve injury.

Background: Cockayne syndrome (CS) is a rare, autosomal-recessive, multisystem disorder characterized by microcephaly, failure to thrive, photosensitivity, leukodystrophy, muscle contracture, and intellectual disability. It is caused by deleterious variant in the ERCC6 and ERCC8 genes, which are involved in the transcription-coupled nucleotide excision repair system. According to severity and age of onset, CS is categorized into four types: I, II, III, and cerebrooculofacioskeletal syndrome (COFS). However, some researchers consider COFS to be a distinct disease from CS, while others describe COFS as a severe form of CS.

Methods: Whole-exome sequencing (WES) and Sanger sequencing were used to identify potential pathogenic causative variant.

Results: WES data analysis revealed a nonsense variant (NM_000124: c.3862C>T, p.R1288X) in the ERCC6 gene, which was co-segregated using Sanger sequencing. Although this variant has been reported previously in association with both CS and COFS separately, this study's patient manifested intermediate symptoms.

Conclusion: This study's findings expand the clinical spectrum of the variant (NM_000124: c.3862C>T, p.R1288X) and provide more supporting evidence that CS and COFS are phenotypic spectrums rather than different clinical conditions in which genetic and epigenetic factors probably play a pivotal role in the severity of symptoms.

Objective: To develop a prognostic nomogram for Wilms' tumor (WT) integrating genetic and clinical factors to improve evaluation accuracy and clinical utility.

Methods: RNA sequencing (RNA-seq) data from 125 WT patients and single-cell RNA (scRNA-seq) data from 2437 samples were analyzed using bioinformatics tools for data processing, including normalization and scaling with SCTransform, and cell clustering with Seurat. Principal component analysis (PCA) and Uniform Manifold Approximation and Projection (UMAP) were utilized for data visualization. Differential gene expression analysis identified pivotal genes for the Genetic Feature Prognostic Model for WT (GPM-WT). Univariate Cox regression analysis refined this model by incorporating clinical prognostic indicators. Survival analysis, Cox regression, and ROC curve assessments evaluated these models' prognostic capabilities. Immune cell infiltration and drug sensitivity were quantified, linking these to patient risk categories.

Results: Six prognostic lymphocyte genes (KLRC1, APOC2, GBP2, SLA, MLLT3, and SIGLEC5) were identified for GPM-WT. Clinical factors, age and sex, were integrated to refine the model. The Lymphocyte Gene and Clinical Features Prognostic Nomogram (LGCPN-WT) effectively distinguished high from low-risk groups, predicting 2-5-year survival rates with area under the curve (AUC) values of 0.771, 0.774, 0.751, and 0.785. Elevated immune cell infiltration and enhanced drug sensitivity characterized the high-risk group, exhibiting significant responsiveness to chemotherapy, targeted, and immunotherapy treatments (p < 0.05).

Conclusions: The study developed an integrated LGCPN-WT model, significantly enhancing survival prediction accuracy and clinical utility for WT, thus supporting personalized treatment approaches.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with high heritability. Nevertheless, the involvement of genetic variants in ASDs is not fully understood. One gene of interest is TRIO, which encodes a large protein that aids in GDP-to-GTP exchange as a Ras homologous (Rho) guanine nucleotide exchange factor (GEF), facilitating cytoskeleton reorganization. Thus, it plays crucial roles in neuronal migration, neurite outgrowth, and synaptic transmission. De novo mutations in TRIO have been extensively reported in the pathogenesis of ASDs. However, no evidence currently supports the genetic association between common variants in TRIO and ASDs. To investigate the role of common genetic variations in autism risk, we analyzed 12 tagging single-nucleotide polymorphisms (SNPs) in the TRIO gene. These tagging SNPs captured an average of 75% of all common variations in TRIO with a minor allele frequency (MAF) > 5%. Using the family-based association study in 239 Chinese Han autism trios, we identified the significant association of three SNPs (rs32593, rs33005, and rs27479) with autism. To confirm the association, the sample size was expanded to 427 trios by recruiting 188 additional trios. Our findings across all 427 trios confirmed that A allele of rs32593, G allele of rs33005, and C allele of rs27479 showed a preferential transmission to the affected offspring (rs32593: A > G, Z = 2.600, p = 0.0093; rs33005: G > T, Z = 2.978, p = 0.0029; rs27479: C > A, Z = 3.214, p = 0.0013) after Bonferroni's correction (p < 0.0042). Haplotype analyses showed that one haplotype (A-G) constructed from rs32593 and rs33005 was significantly associated with autism (p = 0.0064; Global p = 0.022). These results suggested that the common variants in TRIO might be involved in the susceptibility to autism in the Chinese Han population.

Background: Previous studies on the causal relationship or shared genetic basis between major depression disorder (MDD) and gastrointestinal (GI) diseases covered either a limited range and not comprehensive enough.

Methods: We used linkage disequilibrium score regression (LDSC) to estimate the heritability for nine traits and the genetic correlation (r _g ) between MDD and eight GI diseases, respectively. We further conducted a two-sample Mendelian randomization (MR) analysis to identify the causal relationship between MDD and eight GI diseases. Finally, based on the result of MR, we performed stratified LDSC (S-LDSC) to estimate the partitioned heritability and significantly enriched tissues, transcriptome-wide association study (TWAS) to define shared genes, and colocalization analysis to define the pleiotropic single-nucleotide polymorphisms (SNPs) and genes.

Results: For the heritability, heritability of all nine traits was significant. For genetic correlation, six GI diseases showed significant correlations with MDD. For the result of MR, we revealed the causal relationship between MDD and acute appendicitis (OR = 1.09), irritable bowel syndrome (IBS) (OR = 1.14), and ulcer of esophagus (OR = 1.24). Additionally, we found no significant overlapping tissues after S-LDSC. Finally, we defined three shared genes: PRSS16, ZNF602P, and ZNF204P by TWAS and nine pleiotropic genes C4A, FLOT1, LINC00243, MICB, and PRSS16 by colocalization analysis between MDD and acute appendicitis.

Conclusions: Our findings provided the evidence of genetic association, causal relationship, and shared pleiotropic genes between MDD and GI diseases especially acute appendicitis, offering new insights into our understanding of their shared genetic basis.

This case study examines a preterm newborn with autosomal recessive ABCC8 gene-related diffuse congenital hyperinsulinism (CHI). The interdisciplinary management of the patient, including advanced genetic testing and long-read sequencing, finally led to the molecular diagnosis. These findings were relevant for the immediate decision on further treatment options highlighting the importance of differentiating between focal and diffuse CHI forms, and for providing the family with counseling on the recurrence risks and prenatal diagnostic options. In summary, this study illustrates the clinical and genetic intricacies of CHI, emphasizing the significance of comprehensive genetic analysis in diagnostics and tailored treatment. The case advocates for the integration of state-of-the-art genetic diagnostic technologies in combination with clinical interdisciplinary management to improve patient outcomes.

Glioma represents the most prevalent intracranial neoplasms. Lower-grade gliomas (LGGs) are an important subtype of glioma, but the risk stratification of LGG has not been fully elucidated. As a recently recognized form of programmed cell death, cuproptosis is intimately tied to mitochondrial metabolism. Moreover, investigations have revealed that cuproptosis has been implicated in tumor initiation and progression. Long noncoding RNAs (lncRNAs) are engaged in diverse biological processes and connected with the malignant phenotype of gliomas. However, the significance of cuproptosis-related lncRNAs (CRLs) in LGG development remains not fully elucidated. In this work, 963 CRLs were identified using correlation analysis, and a prognostic signature was constructed based on LASSO and multivariate Cox regression analyses. This signature comprised four CRLs: AC002456.1, tumor protein p63 regulated 1-antisense RNA 1 (TPRG1-AS1), AC098851.1, and LYR motif containing 4-antisense RNA 1 (LYRM4-AS1). According to the CRL-based signature, LGG patients were classified into distinct risk groups. To investigate the involvement of biological processes in each LGG sample, we performed gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA) comparing the different risk stratifications. Subsequently, the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression (ESTIMATE) data and the tumor immune dysfunction and exclusion (TIDE) were utilized to access the tumor immune landscape of LGG samples. The results demonstrated that the immune landscapes of different risk stratifications differed significantly. Furthermore, we explored the association between the CRL risk signature and immunotherapy effectiveness using the IMvigor210 dataset. Several prospective drugs targeting samples with high scores were predicted, namely, MG-132, PLX-4720, AZD6482, and BMS-536924. We verified the antiglioma effect of MG-132 in vitro. Moreover, experiments conducted in vitro demonstrated that knockdown of the expression of the CRLs TPRG1-AS1 and LYRM4-AS1 might impair the migration and proliferation capacity of glioma cells. Taken together, these results indicate that CRLs are linked to prognosis and immune characteristics in LGG and give innovative therapeutic methods for individuals with LGG across different risk stratifications.

Angelman syndrome (AS) is a severe neurodevelopmental disorder resulting from different molecular mechanisms. Investigating the correlation between genotypes and phenotypes is crucial to facilitate accurate diagnosis and effective prevention strategies for this disorder. However, determining the genotypes of patients to analyze genotype‒phenotype correlations is challenging when parental genetic information is lacking. Therefore, we proposed a genotyping strategy for use with 11 unrelated Chinese patients with AS who were recruited for this study. The strategy involved a combination of methylation-specific polymerase chain reaction (MS-PCR), exome sequencing (ES), Sanger sequencing, and MS multiplexed ligation probe amplification (MS-MLPA). The results revealed that the number of molecular deletions involving the critical 15q11. 2-q13 region (54.5%) was lower than that reported in other studies of Chinese patients. In addition, the prevalence of patients with imprinting defects (IDs) (27.3%) and variants (18.2%) was greater, whereas the proportion of patients with uniparental disomy (UPDs) was lower. We also summarized the characteristics of patients with different genotypes and analyzed the correlations between genotypes and phenotypes. Compared with the consensus for diagnostic criteria, our results showed that several features were less common, including the combination of frequent laughing/smiling, tremulous limb movements, ataxia of gait, and microcephaly. Conversely, the incidence of both epilepsy and abnormal electroencephalograms (EEGs) was greater. Notably, a novel mutation in the UBE3A gene that had not been previously reported was identified in a family.

Background: Temperature sensitivity has gained considerable attention in the era of precision medicine. This trait has long been used to identify cold-heat patterns (C-HPs), a diagnostic framework in Traditional Korean Medicine that categorizes individuals based on their thermal responses. C-HP helps understand an individual's inherent physical characteristics, which have been shown to be highly heritable and thus shaped by genetic factors. However, genetic markers that are significantly associated with this trait remain scarce. To address this gap, we aimed to identify candidate single-nucleotide polymorphisms (SNPs) based on previous genomewide association studies (GWASs) of related traits.

Methods: Given the limited research directly addressing C-HP, we incorporated genetic studies related to traits such as "Cold" or "Heat," as well as thyroid hormone, which plays a key role in thermogenesis through the activation of various metabolic pathways. After selecting the SNPs reported in previous GWAS from the GWAS Catalog (EMBL-EBI), we validated these findings using 90 Korean patients reporting C-HP, with statistical significance assessed through residual permutations. Gene set enrichment analysis (GSEA) was performed using the GO Biological Process 2023 dataset to identify the pathways associated with C-HP. Furthermore, we compared our findings with control traits in order to confirm that the observed associations were specific to C-HP-related traits rather than random correlations. Principal component analysis (PCA) was conducted on candidate SNPs from the 1000 Genomes reference dataset to illustrate the ethnic variation for C-HP across five populations.

Results: Of 63 GWAS, we selected 548 SNPs for validation. Ultimately, 20 candidate SNPs associated with heat patterns and 19 candidate SNPs associated with cold patterns were identified. Of the heat-pattern SNPs, 18 were linked to thyroid hormone traits, with key SNPs including rs12409301 (CAPZB) and rs12855 (CDKN2C). For the cold-pattern trait, 16 SNPs were associated with thyroid hormones such as rs622474 (PDE4B) and rs11204752 (GOLPH3L). GSEA confirmed notable enrichment in vascular processes for the heat pattern and mitochondrial organization for the cold pattern. The most significant pathway was vascular smooth muscle cell development (p value = 1.28 × 10^-5) in the heat pattern. The clear ethnic differences in C-HP were observed in the PCA of 1000 Genomes populations where East Asian and African populations formed distinct, well-separated clusters.

Conclusion: Our study suggested a total of 39 candidate SNPs as genetic markers for C-HP that are plausible in the context of temperature sensitivity. We hope that our findings will provide a valuable basis for further biological research and potential clinical applications of C-HP.