Frontiers in Genetics最新文献

Balanced chromosomal rearrangements (BCRs) refer to a type of chromosomal structural variations without chromosomal gains or losses. BCR carriers may experience fertility issues, including a higher risk of infertility, recurrent miscarriages, or having offspring with chromosomal abnormalities. Since there are no apparent gains or losses of genetic materials in BCR carriers, their detection has long been a focal and challenging issue in the field of chromosomal structural variation analysis. Karyotyping cannot detect submicroscopic rearrangements because of restricted resolution and the application of fluorescence in situ hybridization (FISH) is limited by the necessity of a known loci. Chromosomal microarray analysis and standard short-read sequencing, widely used in clinical practice, cannot detect BCRs. In summary, the clinical detection techniques are unable to accurately identify the breakpoints of BCRs. The improved short-read sequencing such as mate-pair sequencing has been found to detect balanced rearrangements. Emerging advanced technologies such as long-read sequencing, and optical genome mapping, have already shown their potential in detecting BCRs. This review primarily elucidates the principles, applicability, advantages, and limitations of the detection techniques for BCRs, aiming to assist in the early identification and appropriate advice of patients with BCRs in genetic counseling.

Background: Schizophrenia (SCZ) and post-traumatic stress disorder (PTSD) are severe psychiatric conditions with overlapping yet distinct symptomatology and pathophysiology.

Methods: We conducted a differential genome-wide association study (GWAS) to directly compare the genetic architectures of SCZ and PTSD using publicly available GWAS summary statistics from the Psychiatric Genomics Consortium (PGC).

Results: We identified four independent loci reaching genome-wide significance (P < 5 × 10^-8) for differential associations between SCZ and PTSD in individuals of European ancestry. These loci (rs62062288, rs58120505, rs12536395, and rs11057189) showed genome-wide significant associations with SCZ and nominal associations with PTSD (all Ps < 0.05) but with opposite directions of effect. Among these, only rs62062288 retained genome-wide significance for PTSD in trans-ancestry meta-analysis, whereas the other three loci showed markedly attenuated PTSD associations (all Ps > 0.001). rs62062288 maps to the 17q21.31 MAPT/CRHR1 locus, exhibiting a risk effect for PTSD and a protective effect for SCZ. GTEx analyses revealed that MAPT and CRHR1 are highly expressed across multiple brain tissues and that rs62062288 shows opposite regulatory effects on MAPT and CRHR1 expression in the brain tissue caudate basal ganglia, with the PTSD risk allele associated with increased MAPT expression and decreased CRHR1 expression. Additional brain-region-specific expression quantitative trait locus (eQTL) effects on CRHR1 were observed in frontal cortex BA9, hippocampus, and spinal cord, indicating tissue-dependent regulation.

Conclusion: These findings provide evidence for distinct and opposing genetic contributions to SCZ and PTSD. The identification of the MAPT/CRHR1 locus with brain-region-specific and gene-specific regulatory effects highlights divergent neurodevelopmental and stress-related pathways underlying these disorders.

Background: Children with complex genetic diseases increasingly survive to adulthood, but adult health is poorly understood. Using a genetics-first approach we investigated the incidence and accrual of cardiovascular and other outcomes in people with molecularly confirmed 22q11.2 microdeletion (22q-cases) compared with general population controls (population-comparators).

Methods: Using a retrospective matched cohort study design, we linked 365 adult 22q-cases (median age 32 years; 51% female) to health administrative data for ∼15 million individuals with universal healthcare, identifying 3,650 well-matched population-comparators. We used Poisson regression to estimate incidence rate ratios (IRRs) and 95% CI for five cardiovascular/risk conditions and other outcomes, and recurrent event modelling to assess their relative rate (RR) of accrual over a median 28 years of retrospective and prospective health data.

Results: Accrual of cardiovascular conditions occurred at a significantly greater relative rate (RR) in 22q-cases than population-comparators (RR 3.8, 95% CI 2.9-4.8; median ages 32, 31), even when restricting to 22q-cases with neither major congenital heart disease (CHD) nor schizophrenia (RR 3.6, 95% CI 2.4-5.4). Incidence was significantly greater in 22q-cases for hypertension and diabetes by age 18-24 (IRR 2.98, 95% CI 1.45-6.14; IRR 3.21, 95% CI 1.42-7.24, respectively), and by age 35-44 for heart failure. Other outcomes also showed increasing trajectories over young adult years in the 22q-case group, e.g., kidney disease, chronic obstructive pulmonary disease, healthcare resource use, and hospitalizations, including for individuals with neither CHD nor schizophrenia.

Conclusion: A population-based approach provided new evidence for accumulating illnesses over young adulthood, supporting the need for novel models of anticipatory care for adults with 22q11.2 microdeletion. A similar genetics-first strategy, defining cohorts with shared genetic changes, may facilitate understanding of premature aging mechanisms relevant to the general population.

Background: ctDNA is a promising biomarker in oncology. However, its prognostic and predictive value in HCC remains underexplored. This meta-analysis aims to evaluate the prognostic impact of ctDNA in HCC and its predictive value for recurrence.

Methods: A systematic review and meta-analysis were performed following PRISMA guidelines. PubMed, Embase, Web of Science, and CNKI were searched up to 1 June 2025, for studies assessing ctDNA in HCC patients with reported survival outcomes or predictive accuracy. Studies reporting hazard ratios for overall or disease-free survival, or AUCs for prediction, were included. Two reviewers independently screened studies and assessed quality using the Newcastle-Ottawa Scale (NOS). Meta-analyses used random- or fixed-effects models depending on heterogeneity, with sensitivity analyses performed to assess robustness.

Results: A total of 219 records were screened from PubMed, Embase, Web of Science, and CNKI, and 8 studies comprising 1,907 patients were included. ctDNA positivity was significantly associated with poorer OS, with a pooled HR of 2.34 (95% CI 1.96-2.78; p < 0.0001). Moderate heterogeneity was observed (I² = 32.2%). Sensitivity analyses confirmed the robustness of this finding. Two studies assessed the predictive value of ctDNA for RFS, yielding a pooled AUC of 0.66 (95% CI 0.47-0.86; I² = 65.7%). Discriminative accuracy was higher when ctDNA was detected postoperatively (AUC range: 0.57-0.77), suggesting its potential role in identifying minimal residual disease.

Conclusion: ctDNA is associated with adverse prognosis in HCC and may offer moderate predictive accuracy for recurrence. Standardized protocols for sampling and analysis are required to facilitate broader clinical translation.

Introduction: Pharmacogenomics enables the interpretation of how genetic variation influences drug response, offering a route toward precision oncology. Oral squamous cell carcinoma (OSCC) is a highly aggressive malignancy characterized by marked inter-individual variability in response to chemotherapy and radiotherapy, particularly in South Asian populations. However, the mechanism through which OSCC-associated genetic variants alter protein structure and drug interactions remains poorly understood.

Methods: To address this, we integrated OSCC-specific variants from a Southern Indian patient cohort with pharmacogenomic annotations from ClinPGx. First, OSCC variants were mapped to drug-associated single-nucleotide proteins, yielding 22 protein-altering variants. Second, structural availability and functional relevance were used to prioritize eight variants for detailed analysis. Third, homology modeling and molecular docking were applied to evaluate how these variants influence protein conformation and drug binding.

Result: This multistep pipeline identified variants in FLT3, ATM, MUTYH, XRCC1, XPC, and MSH3 that affect DNA repair, signaling, and drug interaction interfaces. The highly prevalent FLT3 T227M (rs1933437) variant was predicted to alter receptor dimerization and potentially modulate sunitinib binding. The MUTYH Q310H (rs3219489) variant, which is located near a zinc-binding motif in the interdomain connector, was predicted to perturb metal coordination and enzyme architecture, which indicates impaired base-excision repair.

Conclusion: These findings demonstrate how pharmacogenomics-guided structural analysis can reveal mechanistic links between OSCC-associated variants and therapeutic response. While our results are based on in silico modeling, they provide a biologically grounded framework for prioritizing variants for experimental validation and for advancing population-specific precision oncology in OSCC.

Background: Cell division cycle 27 (CDC27) gene expression is closely associated with the cell cycle and has been implicated in the pathogenesis of congenital heart disease (CHD) in animal models. This study focuses on investigating whether single-nucleotide polymorphisms (SNPs) in the CDC27 gene are associated with CHD and the cardiac remodeling process in the population of Xinjiang, China.

Methods: This study conducted a case-control study including 689 controls and 575 patients with CHD. SNPs of the CDC27 gene were genotyped using an improved multiple ligase detection reaction.

Results: Our study found that the CDC27 rs11570579 polymorphism was significantly associated with CHD susceptibility in the Uyghur population (additive model: aOR = 0.66, p = 0.029; dominant model: aOR = 0.80, p = 0.038), but not in the Han population. The rs11570488 GA genotype was associated with higher pulmonary artery systolic pressure (PASP), more severe cardiac remodeling, and increased long-term mortality in both ethnic groups (all p < 0.001), with the mortality difference being significant only in patients with pulmonary hypertension. Haplotype analysis identified ethnic-specific haplotypes associated with CHD susceptibility and elevated PASP.

Conclusion: The CDC27 rs11570579 polymorphism is associated with susceptibility to CHD in the Uyghur population of Xinjiang. The rs11570488 polymorphism is associated with PASP, cardiac remodeling, and long-term mortality in patients with CHD.

Background: The circRNA-miRNA axis is critically implicated in the pathogenesis of recurrent spontaneous abortion (RSA) by modulating trophoblast and decidual stromal cell functions. This study investigates the role of the miR-133a/circ-104792 network in RSA.

Methods: Using qRT-PCR, we measured miR-133a and circ-104792 expression in chorion and decidua from 10 RSA patients and 10 controls. The functional effects on proliferation (CCK-8, EdU) and apoptosis (flow cytometry, TUNEL) were assessed in HTR-8/SVneo and HESC cells following transfection with miR-133a mimics/inhibitor or circ-104792. Direct targeting of Bcl-xL by miR-133a and its interaction with circ-104792 were validated via dual-luciferase reporter and RNA pull-down assays. Bcl-xL expression was evaluated by qRT-PCR and western blot.

Results: miR-133a expression was (in chorion: p = 0.0008, 95% CI [2.85, 6.41]; in decidua: p = 0.0009, 95% CI [2.67, 6.03]) increased, while circ-104792 was significantly downregulated (in chorion: p = 0.0008, 95% CI [0.15, 0.34]; in decidua: p = 0.0007, 95% CI [0.13, 0.31]) in RSA tissues. In vitro, miR-133a overexpression inhibited cell proliferation, promoted apoptosis, and reduced Bcl-xL levels (in HTR-8/SVneo: 0.46-fold vs. 1.00 in NC group, p = 0.0045; in HESCs: 0.49-fold vs. 1.00 in NC group, p = 0.0003). Conversely, circ-104792 overexpression enhanced proliferation, suppressed apoptosis, and increased Bcl-xL expression (in HTR-8/SVneo: 2.17-fold vs. 1.00 in vector group, p = 0.0018; in HESCs: 1.94-fold vs. 1.00 in vector group, p = 0.0015). The dual-luciferase assay confirmed Bcl-xL as a direct target of miR-133a, and the RNA pull-down confirmed the miR-133a/circ-104792 interaction. Critically, circ-104792 overexpression rescued the suppressive effects of miR-133a on proliferation and Bcl-xL expression.

Conclusion: Our findings demonstrate that miR-133a promotes RSA-associated cellular dysfunction by targeting Bcl-xL, while circ-104792 acts as a ceRNA to sponge miR-133a, thereby antagonizing its effects. The miR-133a/circ-104792/Bcl-xL axis represents a potential key regulatory network in RSA, presenting potential novel targets for diagnosis and therapy.