Global Medical Genetics最新文献

Objective: To characterize the clinical features of a fetus with postaxial polydactyly caused by a de novo PRKACB gene variant and to perform a genetic analysis.

Methods: A pregnant woman who presented to Zhejiang Provincial People's Hospital on 4 December 2024 was enrolled in this study. Fetal clinical data were collected, and genomic DNA was extracted from the fetus and both parents. Clinical whole-exome sequencing (WES) was performed on the trio (fetus and both parents). Candidate variants were identified and validated by Sanger sequencing, followed by bioinformatics analysis. This study was approved by the Medical Ethics Committee of Zhejiang Provincial People's Hospital (approval number: QT2025076).

Results: Prenatal ultrasonography revealed bilateral postaxial polydactyly and several fetal biometric measurements that were inconsistent with gestational age. The clinical diagnoses were intrauterine growth restriction and polydactyly. WES identified a de novo heterozygous variant (c.802 G>A; p.Asp268Asn) in exon 8 of the fetal PRKACB gene (NM_182948.4). According to the ACMG variant-classification guidelines, this variant was interpreted as likely pathogenic (PS2_Moderate, PM1, PM2_Supporting and PP3). AlphaFold-based structural prediction indicated that the PRKACB p.Asp268Asn substitution resulted in the loss of two hydrogen bonds, thereby altering the protein's three-dimensional conformation and affecting structural stability.

Conclusion: The PRKACB gene c.802 G>A (p.Asp268Asn) variant is a potential genetic cause of bilateral postaxial polydactyly in the fetus. Identification of this variant expands the known mutational spectrum of PRKACB gene and provides an important reference for genetic counselling and prenatal diagnosis.

Objective: This study aimed to evaluate the association of single nucleotide polymorphisms (SNPs) in IKZF1, ARID5B, and CEBPE with acute lymphoblastic leukemia (ALL) susceptibility in Chinese children.

Methods: A case-control study was conducted involving 360 ALL patients and 398 healthy controls. Nine SNPs were genotyped, and their associations with ALL risk were analyzed using logistic regression under various genetic models. Multifactor dimensionality reduction (MDR) analysis was employed to investigate SNP-SNP interactions.

Results: Seven of the nine SNPs were significantly associated with ALL susceptibility. Specifically, IKZF1 SNPs (rs11980379, rs4132601, rs10272724) and a CEBPE SNP (rs4982731) were associated with an increased risk of ALL. In contrast, ARID5B SNPs (rs10994982, rs10821938) and another CEBPE SNP (rs2144827) were associated with a reduced risk. Stratified analyses revealed age- and sex-specific associations. MDR analysis identified significant SNP-SNP interactions, with a robust four-SNP model (rs10994982, rs2144827, rs10272724, rs10821938) showing the best predictive performance for ALL risk.

Conclusion: Specific SNPs in IKZF1, ARID5B, CEBPE and their interactions are associated with childhood ALL susceptibility in Chinese populations, providing references for ALL risk stratification.

Purpose: Persistent toe walking in children is often considered idiopathic; however, increasing evidence suggests that alterations in the PMP22 gene-implicated in Charcot-Marie-Tooth disease type 1 A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)-may contribute to its pathogenesis. This study investigates the association between PMP22 variants (duplications, deletions, and point mutations) and toe walking in children, aiming to delineate their clinical and genetic characteristics.

Methods: A retrospective analysis was performed on 22 pediatric patients (mean age: 7.7 years) with persistent toe walking and confirmed PMP22 variants identified through a 49-gene next-generation sequencing (NGS) panel. In selected cases, Multiplex Ligation-dependent Probe Amplification (MLPA) was applied to confirm copy number variations. Comprehensive clinical evaluations included musculoskeletal, neurological, and developmental assessments.

Results: All identified variants demonstrated dominant inheritance. Pathogenic variants were present in 54.5 % of patients, likely pathogenic in 31.8 %, and variants of uncertain significance (VUS) in 13.6 %. Among pathogenic cases, most carried PMP22 duplications, one had a deletion, and the remainder harbored the missense variant p.(Thr118Met). The three VUS carriers exhibited comparatively milder phenotypes, such as muscle cramps, lumbar hyperlordosis, mild dorsiflexion restriction, hyporeflexia, pes cavus, and clinodactyly/brachydactyly; only one presented with tremor. Lumbar hyperlordosis (90.9 %) and pes cavus (90.9 %) were the most consistent findings.

Conclusions: Persistent toe walking may represent an early sign of PMP22-related neuropathies rather than a benign idiopathic gait pattern. The predominance of PMP22 duplications and characteristic neuromuscular features highlight the clinical utility of integrating NGS and MLPA testing for accurate diagnosis, targeted management, and genetic counseling.

Background: Terminal erythroid differentiation (TED) is the maturation process of proerythroblasts into enucleated erythrocytes. Animal models are essential for studying red blood cell disorders.

Methods: We isolated erythroblasts at different TED stages from mouse bone marrow using FACS and performed integrated multi-omics analyses.

Results: We developed a stage-specific transcriptome and proteome profile, enhancing murine TED databases. The most significant changes occurred during the transition from proerythroblasts to basophilic erythroblasts, characterized by immune function suppression and activation of erythroid processes. Global gene and protein expression dynamics showed that orthochromatic erythroblasts exit the cell cycle, with transcription cofactors histone deacetylase 1(HDAC1), histone deacetylase 2(HDAC2), and cell division control protein 6 homolog (CDC6), playing key roles in cell cycle regulation. Additionally, autophagy was initiated at the basophilic stage, indicated by increased autophagy-related gene (ATG) mRNA levels and activation of autophagy marker proteins like microtubule associated protein 1 light chain 3 beta (LC3-I), optineurin (OPTN), and ATGs, including Atg7, Atg4b, Atg3, and Atg2b.

Conclusions: Overall, we have generated a foundational murine transcriptome and proteome dataset, providing insights into the functional dynamics and regulatory mechanisms of terminal erythroid differentiation.

Severely infected patients produce large amounts of inflammatory cytokines, such as interleukin-6 (IL-6) and interleukin-1β (IL-1β), leading to a "cytokine storm", which is a clinically refractory condition. Because IL-6 and IL-1β differ significantly in gene family, chromosomal location, protein structure, and signaling pathways, existing techniques are ineffective at simultaneously removing cytokines. This work developed a novel blood purification material by chemically grafting histidine onto a polyvinylidene fluoride (PVDF) membrane. ATR-FTIR and XPS analyses confirmed the successful grafting of histidine onto the PVDF membrane. Following histidine grafting, the membrane's adsorption capacity for IL-6 in aqueous solution increased with histidine concentration. The optimized histidine-grafted PVDF membrane achieved adsorption rates of (36 ± 4)% for IL-6 and (63 ± 5) % for IL-1β in plasma. Additionally, the histidine-grafted PVDF membrane demonstrated enhanced biocompatibility, exhibiting a low hemolysis rate, minimal adsorption of red blood cells and platelets, and anticoagulant properties without activating the coagulation cascade. This histidine-grafted PVDF membrane offers a promising new therapeutic strategy for treating severe infections and holds significant potential for clinical application.

Glioblastoma (GB) remains the most aggressive and treatment-resistant primary brain tumor, characterized by extensive heterogeneity, therapeutic resistance, and dismal prognosis. In this comprehensive review, we aimed to synthesize emerging insights into the roles of non-coding RNAs (ncRNAs)-including microRNAs, long non-coding RNAs, circular RNAs, and PIWI-interacting RNAs-in the regulation of glioblastoma progression, resistance mechanisms, and potential therapeutic strategies. We critically evaluated the molecular functions of ncRNAs in key oncogenic processes such as proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), and immune evasion. Additionally, we reviewed current detection methods, delivery technologies, and clinical trials targeting these ncRNAs. A central goal of this review was to bridge a notable gap in the literature by highlighting underrepresented ncRNA classes such as circRNAs and piRNAs, which exhibit regulatory complexity and potential as biomarkers and therapeutic agents in GB. We further discussed delivery challenges posed by the blood-brain barrier and explored promising nanocarrier and exosome-based approaches to enhance therapeutic targeting. Through curated case studies, we showcased the translational potential of targeting specific ncRNAs to reverse multiple resistance types and improve immunotherapy response. This review provides a consolidated framework for understanding the dynamic role of ncRNAs in glioblastoma and proposes an expanded toolkit for precision oncology approaches. Our findings not only underscore the therapeutic promise of ncRNAs but also call for future investigations into the lesser-known subclasses that could redefine the landscape of GB management.

Ovarian cancer (OC) is one among most significantly fatal gynecological cancers, with late-stage detection and an inadequate prognosis. Plasminogen activator inhibitor-1 ( PAI1 ) gene anticipates negative outcomes in many different kinds of malignancies. Several research investigations are currently being done to examine the biological role of PAI1 in OC and the possible benefits of targeted pharmacotherapies. The PAI1 gene has been linked to the emergence and development of cancer in the ovary. PAI1 , an inhibitor of serine protease, influences the fibrinolysis and extracellular matrix remodeling, both of which are crucial for tumor expansion and metastatic growth. PAI1 levels have been discovered to be subsequently more elevated in malignant ovarian tissues than in usual ovarian tissue, demonstrating a potential connection among PAI1 overexpression and OC development. PAI1 promotes tumor cell proliferation, movement, and an invasion by influencing the urokinase-plasminogen activators and through interactions with cell surface receptors. In addition, PAI1 gene contributes to angiogenesis and apoptotic cell death, which contribute to the more hostile phenotypes of OC. The prognostic and therapeutic consequences of focusing on PAI1 in OC are explored, demonstrating PAI1 's potential to be a biomarker and emphasizing for novel treatment approaches. The PAI1 gene possesses several functions in OC, affecting tumor development, an invasion, and metastatic growth. Comprehending the complicated interactions and mechanisms that regulate PAI1 in OC may lead to more efficient evaluation and treatment strategies and ultimately enhance patient outcomes.

Duchenne's muscular dystrophy (DMD) is a severe X-linked disorder characterized by progressive muscle degeneration, leading to loss of ambulation, respiratory failure, and premature death. It affects approximately 1 in 3,500 live male births and is caused by mutations in the dystrophin gene, which impairs muscle fiber stability. Current treatments are limited to managing symptoms and slowing disease progression, with no curative therapies available. The advent of CRISPR/Cas9 gene-editing technology has introduced a promising approach for directly correcting the genetic mutations responsible for DMD. This review explores the potential of CRISPR/Cas9 as a transformative therapy for DMD, highlighting its successes in preclinical models, the challenges associated with its delivery, and the obstacles to its clinical application. While preclinical studies demonstrate the efficacy of CRISPR/Cas9 in restoring dystrophin expression and improving muscle function, significant hurdles remain, including optimizing delivery methods and ensuring long-term safety.

We report a 7-year-old girl born with pyloric atresia but without congenital epidermolysis bullosa or skin fragility. Nail dysplasia developed at age 8 months and throughout childhood she suffered from onycholysis and mild nail hypertrophy. Whole-exome sequencing demonstrated biallelic mutations in alpha6 integrin (ITGA6): p. Q139* and R153W. ITGA6 normally forms a protein heterodimer with beta4 integrin (ITGB4), and this dimer participates in anchoring the basal skin cells to the extracellular matrix. Biallelic mutations in each gene are well known to cause epidermolysis bullosa and pyloric atresia. However, this child had ostensibly normal skin without any evidence of skin fragility. In a literature search, we identified 11 cases involving ITGA6 mutations, and all had epidermolysis skin changes. Thus, this case adds to the reported phenotype of ITGA6 disease since it is the first to show absence of an epidermolysis bullosa phenotype in the setting of pyloric atresia and nail dysplasia.

Background  The widespread implementation of computed tomography has significantly increased the detection of small pulmonary nodules, including atypical adenomatous hyperplasia, minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC). Few studies have focused on the genomic differences between MIA and IAC. Methods  We retrospectively analyzed patients with lung adenocarcinoma (LUAD) who underwent surgery from January 2020 to December 2023. Patients were categorized into MIA and IAC groups. The mutation status of common driver genes was assessed using next-generation sequencing. Results  A total of 422 LUAD patients were included in the study, comprising 119 MIA cases and 303 IAC cases. MIA patients were younger and predominantly female compared with IAC patients. EGFR mutations were detected in 251 patients (59.5%), with the frequency of EGFR mutations increasing from 37.0% in MIA to 68.3% in IAC ( p  < 0.001). TP53 mutations were found in 108 patients (25.6%), with 7 patients (5.9%) in MIA and 101 patients (33.3%) in IAC ( p  < 0.001). ERBB2 mutations were identified in 23 MIA patients (19.3%) and 20 IAC patients (6.6%) ( p  < 0.001). Additionally, CDKN2A mutations were detected in 23 IAC patients (7.6%), while no mutations in this gene were found in the MIA group. Moreover, ALK and RET gene fusions were identified in 11 patients, respectively. Conclusion  ERBB2 mutations and RET fusions are early genomic events in LUAD, while TP53 and CDKN2A mutations and ALK fusions occur later. Genomic intratumor heterogeneity likely arises early, before invasive characteristics develop.