Search Results (1,550)

Pancreatic neuroendocrine neoplasms (PNENs) are a diverse group of rare tumor subtypes, representing less than 2% of all pancreatic tumors. Often detected late in the clinical course, they are associated with high rates of morbidity and mortality. Hereditary syndromes such as multiple endocrine neoplasia type-1 and von Hippel–Lindau are associated with the development of PNENs, although only a small portion of total tumors have a genetic basis. This review aims to explore the recent advances in laboratory diagnostics, imaging modalities, medical management, and surgical approaches to hormone-producing PNENs (including some common, less common, and some rare subtypes), with the goal of assisting physicians in the integration of evidence-based information into their practice. Full article

High-grade serous ovarian cancer (HGSOC) is the most common and aggressive subtype of ovarian cancer, accounting for approximately 70% of cases. This study investigates genetic mutations and their associations with overall survival (OS), complete cytoreduction (R0), and platinum response in patients undergoing either primary debulking surgery followed by adjuvant chemotherapy (PDS) or neoadjuvant chemotherapy followed by interval debulking surgery (NACT). Genetic analysis was performed on 43 primary HGSOC tumor samples using targeted massive parallel sequencing via next-generation sequencing (NGS). Clinical and molecular data were evaluated collectively and through subgroup comparisons between PDS and NACT cohorts. All analyzed samples harbored genetic alterations. Univariate survival analysis revealed that the total number of mutations (p = 0.0035), as well as mutations in HRAS (p = 0.044), FLT3 (p = 0.023), TP53 (p = 0.03), and ERBB4 (p = 0.007), were significantly associated with poorer OS. Multivariate Cox regression integrating clinical and molecular data confirmed that ERBB4 mutations are independently associated with adverse outcomes. These findings reveal a distinctive mutational landscape between the PDS and NACT groups and suggest that ERBB4 alterations may define a particularly aggressive tumor phenotype. This study contributes to a deeper understanding of HGSOC biology and may support the development of novel therapeutic targets and personalized treatment strategies in the context of precision oncology. Full article

Diagnosing hypermobility disorders and Ehlers-Danlos syndrome (EDS) in children is challenging due to overlapping features with generalized joint hypermobility (GJH) and the lack of biomarkers. Background/Objectives: This study aims to describe the clinical and genetic features of pediatric EDS patients and identify key comorbidities and correlations. Methods: This is a single-center observational study of patients under 18 diagnosed with suspicion of EDS (2018–2024) at a tertiary pediatric hospital. Diagnoses were made using 2017 criteria. Results: Forty-one patients (46% female; mean age 11.1 ± 2.8 years) were included. Based on 2017 criteria, 61% had hypermobile EDS (hEDS)/hypermobility spectrum disorder (HSD), 22% classical EDS, 7.3% vascular, and 9.7% other subtypes. Musculoskeletal (90.2%), cutaneous (68.3%), and psychiatric (56.1%) symptoms were most frequent. Significant associations included older age with psychiatric symptoms (p = 0.029), Beighton score with dislocations (p = 0.026), and less atrophic scarring in hEDS (p < 0.008). Genetic testing (73% performed) confirmed pathogenic variants (11 novel) in EDS with a known molecular cause. Conclusions: This study proposes a clinically guided approach and diagnostic algorithm for youth hypermobility, emphasizing precision medicine principles, while highlighting the urgent need for further research to identify hEDS biomarkers. Full article

Background: Charcot–Marie–Tooth disease (CMT) is a genetically and phenotypically heterogeneous hereditary neuropathy. Axonal CMT type 2 (CMT2) subtypes often exhibit overlapping clinical features, which makes molecular genetic analysis essential for accurate diagnosis and subtype differentiation. Methods: This retrospective study included five pediatric patients who presented with gait disturbance, muscle weakness, and foot deformities and were subsequently diagnosed with axonal forms of CMT. Clinical data, electrophysiological studies, neuroimaging, and genetic analyses were evaluated. Whole exome sequencing (WES) was performed in three sporadic cases, while targeted CMT gene panel testing was used for two siblings. Variants were interpreted using ACMG guidelines, supported by public databases (ClinVar, HGMD, and VarSome), and confirmed by Sanger sequencing when available. Results: All had absent deep tendon reflexes and distal muscle weakness; three had intellectual disability. One patient was found to carry a novel homozygous frameshift variant (c.2568_2569del) in the IGHMBP2 gene, consistent with CMT2S. Other variants were identified in the NEFH (CMT2CC), DYNC1H1 (CMT2O), and MPV17 (CMT2EE) genes. Notably, a previously unreported co-occurrence of MPV17 mutation and congenital heart disease was observed in one case. Conclusions: This study expands the clinical and genetic spectrum of pediatric axonal CMT and highlights the role of early physical examination and molecular diagnostics in detecting rare variants. Identification of a novel IGHMBP2 variant and unique phenotypic associations provides new insights for future genotype–phenotype correlation studies. Full article

Limb–girdle muscular dystrophy (LGMD) encompasses a heterogeneous group disease, genetic and phenotypically. There are more than 30 subtypes divided into two groups: autosomal dominant and recessive. LGMDs are characterised by muscle weakness; however, psychosocial factors seem to be affected too, such as HRQoL. Given the lack of literature in this respect, the present cross-sectional study aimed to create a patient profile comparing both dominant and recessive forms by analysing HRQoL through the INQoL, and sociodemographic data. The LGMD-recessive group had a worse HRQoL compared to the dominant group, specifically in the dimensions of muscle weakness (p = 0.007), emotion (p = 0.046), independence (p = 0.029), and body image (p = 0.022). In addition, in the LGMD-dominant group, 77.9% of the relational indicator was explained by age (B = 0.907, p = 0.012), which can be understood as a limitation in their social role due to the disease progression. In contrast, no sociodemographic variables were found to be predictive of the HRQoL of patients with recessive forms of LGMD. These results are relevant for clinical practice, as they reflect the most affected areas of HRQoL in LGMD patients, differentiating between recessive and dominant forms. Full article

Background: Hemiplegic migraine (HM) is a rare and severe subtype of migraine with a complex genetic basis. Although pathogenic variants in CACNA1A, ATP1A2, and SCN1A explain some familial cases, a significant proportion of patients remain genetically undiagnosed. Increasing evidence points to an overlap between migraine and cerebral small vessel disease (SVD), implicating vascular dysfunction in HM pathophysiology. Objective: This study aimed to identify rare or novel variants in genes associated with SVD in a cohort of patients clinically diagnosed with HM who tested negative for known familial hemiplegic migraine (FHM) pathogenic variants. Methods: We conducted a case-control association analysis of whole exome sequencing (WES) data from 184 unrelated HM patients. A targeted panel of 34 SVD-related genes was assessed. Variants were prioritised based on rarity (MAF ≤ 0.05), location (exonic/splice site), and predicted pathogenicity using in silico tools. Statistical comparisons to gnomAD’s Non-Finnish European population were made using chi-square tests. Results: Significant variants were identified in several SVD-related genes, including LRP1 (p.Thr4077Arg), COL4A1 (p.Pro54Leu), COL4A2 (p.Glu1123Gly), and TGFBR2 (p.Met148Leu and p.Ala51Pro). The LRP1 variant showed the strongest association (p < 0.001). All key variants demonstrated pathogenicity predictions in multiple computational models, implicating them in vascular dysfunction relevant to migraine mechanisms. Conclusions: This study provides new insights into the genetic architecture of hemiplegic migraine, identifying rare and potentially deleterious variants in SVD-related genes. These findings support the hypothesis that vascular and cellular maintenance pathways contribute to migraine susceptibility and may offer new targets for diagnosis and therapy. Full article

Congenital hypothyroidism (CH) is a leading preventable cause of neurocognitive impairment. Its incidence appears to be rising in several countries. We analysed 27 years of newborn-screening data (1997–2023) from the largest Chilean screening centre, covering 3,225,216 newborns (51.1% of national births), to characterise temporal trends and potential drivers of CH incidence. Annual CH incidence was modelled with Prais–Winsten regression to correct for first-order autocorrelation; additional models assessed trends in gestational age, sex, biochemical markers, and aetiological subtypes. We identified 1550 CH cases, giving a mean incidence of 4.9 per 10,000 live births and a significant yearly increase of 0.067 per 10,000 (95 % CI 0.037–0.098; p < 0.001). Mild cases (confirmation TSH < 20 mU/L) rose (+0.89 percentage points per year; p = 0.002). The program’s recall was low (0.05%). Over time, screening and diagnostic TSH values declined, total and free T4 concentrations rose, gestational age at diagnosis fell, and a shift from thyroid ectopy toward hypoplasia emerged; no regional differences were detected. The sustained increase in CH incidence, alongside falling TSH thresholds and growing detection of in situ glands, suggests enhanced recognition of milder disease. Ongoing surveillance should integrate environmental, iodine-nutrition, and genetic factors to clarify the causes of this trend. Full article

The HIV-1 aspartic protease is an effective target for the treatment of HIV/AIDS. Current therapy utilizes a selection of nine protease inhibitors (PIs) in combination with other classes of antiretroviral drugs. Although PIs were originally developed based on the knowledge of the HIV-1 subtype B protease, the existence of other HIV-1 subtypes and the effects of drug resistance on currently available PIs have become a major challenge in the treatment of HIV/AIDS. Specifically, the HIV-1 subtype C accounts for more than half of the global HIV infections. Considering the importance and relevance of the subtype C virus, in this timely review we discuss the effect of polymorphisms in the HIV-1 subtype C protease on drug resistance, flap flexibility, and hinge region dynamics. We discuss novel paradigms of protease inhibition that attempt to overcome the limitations of currently available inhibitors which fall short considering genetic diversity and resistance mutations. Full article

Background/Objectives: Melanoma is an aggressive skin cancer influenced by genetic and immunological factors. The PDCD1 gene encodes PD-1, a receptor involved in immune evasion and therapeutic response. This study aimed to evaluate the association of PDCD1 variants (rs2227982, rs36084323, rs7421861) and its relative gene expression with melanoma in a Mexican population. Methods: An analytical cross-sectional study was conducted with 262 samples: 131 from melanoma patients (newly diagnosed and treatment-naïve) and 131 from cancer-free controls. Genotyping was performed using real-time PCR. PDCD1 expression was assessed by qPCR, normalized with GAPDH, using the 2^−ΔΔCt method and the Pfaffl model. Statistical comparisons included allele/genotype frequencies, expression levels, and clinicopathological associations. Results: No significant association was found between the studied PDCD1 variants and melanoma susceptibility. However, PDCD1 was significantly overexpressed in melanoma samples (2.42-fold increase; p < 0.01), consistent across both quantification methods. Significant associations were also observed between histopathological subtype and Breslow thickness, and between subtype and anatomical site (p < 0.01). Conclusions: Although PDCD1 variants showed no association with melanoma risk, the gene’s overexpression highlights its potential relevance in melanoma immunobiology. These findings contribute to the molecular characterization of melanoma in the Mexican population and support future research on PDCD1 as an immunological biomarker. Full article

Background: Acute necrotising encephalopathy (ANE) is a rare and severe type of encephalopathy with bilateral symmetrical brain lesions, often following a viral prodrome. ANE type 1 (ANE1) is a disease subtype with a predisposing mutation in the gene encoding RAN binding protein 2 (RANBP2). Methods: We report a case of a 3-year-old girl with clinical symptoms of ANE and brain MRI findings suggesting ANE1, which was subsequently confirmed by genetic analysis. Results: MRI of the brain demonstrated symmetrical high T2/FLAIR signal changes in the lateral geniculate bodies, claustrum, ventromedial thalami, subthalamic nuclei, mamillary bodies, and brainstem, with partly corresponding diffusion restriction, as well as additional haemorrhagic changes in the lateral geniculate bodies on susceptibility weighted imaging. Genetic analysis revealed a heterozygous pathogenic variant of the RANBP2 gene. With immunosuppressive and supportive treatment, the patient fully recovered and was discharged after 10 days in the hospital with no residual symptoms. Conclusions: Recognition of the characteristic MRI findings in ANE1 can facilitate a timely diagnosis and enhance the clinical management of the patient and their relatives, especially given the high risk of disease recurrence. Full article

Background/Objectives: Non-syndromic cleft lip with or without palate (NSCL/P) is a common, multifactorial congenital anomaly. As genetic associations can be population-specific, this study aimed to investigate single-nucleotide polymorphisms (SNPs) in the VAX1, MAFB, and WNT3 genes for association with NSCL/P in a Japanese cohort. Methods: A case–control study was conducted with 310 Japanese patients with NSCL/P and 308 ethnically matched healthy controls from Aichi Gakuin Dental Hospital. We genotyped SNPs rs7078160 (VAX1), rs13041247 (MAFB), and rs3809857 (WNT3) using TaqMan assays. Associations were assessed using chi-squared tests, with results stratified by sex and corrected for multiple comparisons using the Bonferroni method. Results: The VAX1 rs7078160 A allele was significantly associated with an increased risk for NSCL/P (OR = 1.67, p < 0.00001). The association was particularly strong in females (OR = 1.93, p < 0.00001) but not significant in males after correction. The MAFB rs13041247 variant showed a nominal protective association with the NSCLO subtype that was not significant after Bonferroni correction. No significant association was found for WNT3. A notable gene–gene interaction was observed, where carrying risk alleles for both VAX1 and MAFB significantly increased overall NSCL/P risk (OR = 2.65, p = 0.00008). Conclusions: VAX1 rs7078160 is a significant risk factor for NSCL/P in the Japanese population, with a pronounced female-specific effect. A synergistic interaction between VAX1 and MAFB elevates disease risk, whereas WNT3 was not implicated in this cohort. These findings underscore the population-specific genetic architecture of NSCL/P. Full article

Ischemic stroke is a complex, multifactorial disorder with a significant heritable component. Recent developments in genome-wide association studies (GWASs) have identified several common variants associated with clinical outcomes, stroke subtypes, and overall risk. Key loci implicated in biological pathways related to vascular integrity, lipid metabolism, inflammation, and atherogenesis include 9p21 (ANRIL), HDAC9, SORT1, and PITX2. Although polygenic risk scores (PRSs) hold promise for early risk prediction and stratification, their clinical utility remains limited by Eurocentric bias and missing heritability. Integrating multiomics approaches, such as functional genomics, transcriptomics, and epigenomics, enhances our understanding of stroke pathophysiology and paves the way for precision medicine. This review summarizes the current genetic landscape of ischemic stroke, emphasizing how evolving methodologies are shaping its prevention, diagnosis, and treatment. Full article

Background: Thyroid neoplasms exhibit a diverse molecular landscape, and the 2022 WHO classification emphasizes the critical role of molecular profiling in thyroid cancer management; however, comprehensive mutational data from fine-needle aspiration cytology (FNAC) samples using targeted next-generation sequencing (NGS) are still limited, necessitating further investigation to guide clinical practice. Purpose: To characterize the mutational landscape of thyroid neoplasms using targeted NGS of FNAC samples and to assess the clinical implications of molecular profiling. Materials and Methods: This retrospective study included 952 patients with thyroid carcinomaneoplasms who underwent surgery at Sun Yat-sen Memorial Hospital from 2021 to 2023. Preoperative ultrasound, FNAC, and targeted NGS were performed. NGS panels covering 18, 88, and pan-cancer genes were used to analyze FNAC samples. Molecular alterations were correlated with clinical and pathological features. Results: The most frequent mutation was BRAF^V600E (84.45%), followed by RET (6.41%), BRCA1/2 (4.41%) and RAS (4.41%). Patients were categorized into BRAF-like (830 cases), RAS-like (36 cases), high-risk mutations (25 cases), and other mutations (28 cases). High-risk mutations were associated with older age and larger tumor size. BRAF-like tumors had a higher lymph node metastasis rate (58.77%) compared to RAS-like tumors (33.33%). Tumor mutation burden varied significantly among different thyroid neoplasm subtypes. Conclusions: Molecular profiling using targeted NGS of FNAC samples provides valuable insights into the genetic landscape of thyroid neoplasms and has significant clinical implications for diagnosis and personalized treatment strategies. Further validation with paired tumor and plasma samples is warranted. Full article

Background: Non-syndromic orofacial clefts (NSOFCs) are one of the common congenital malformations in Vietnam, with 1.4 per 1000 live births, with notable sex differences in occurrence. This case–control study aims to investigate potential sex-specific interactions of WNT3 and NOG polymorphisms across NSOFC subtypes in a Vietnamese population. Methods: A total of 720 participants were separated into 4 groups with a male/female ratio of 1:1 (160 individuals with cleft lip and palate (NSCLP), 160 with cleft lip only (NSCLO), 160 with cleft palate only (NSCPO), 240 healthy controls). Two single-nucleotide polymorphisms (SNPs), rs3809857 and rs227731, were genotyped by using the StepOnePlus Real-Time PCR System. Results: The most significant findings were found in the male NSCLO group under a recessive model of WNT3 rs3809857 after applying Bonferroni correction, as a five-fold protective factor with OR = 0.18 (95% confidence interval: 0.05–0.64, p = 0.0033). Additionally, the weak or moderate protective association between rs3809857 and male NSCLP was found with p < 0.05 under the dominant model. However, there were no significant findings in the female NSOFC subtypes associated with WNT3. Conversely, NOG rs227731 results showed a weak increased risk in female NSCLO and NSCPO with p < 0.05. Conclusion: this study identified the critical role of WNT3 rs3809857 in reducing NSCLO risk in males. These findings support the potential influence of sex as a modifying factor in the genetic susceptibility to non-syndromic orofacial clefts. Full article

Background: Genetic alterations in CSF3R, typically associated with chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML), rarely occur in other myeloid neoplasms. Methods: This study characterized the clinical, morphologic, cytogenetic, and molecular features of 13 patients with non-CNL non-aCML myeloid neoplasms with CSF3R alterations. Patients (median age, 77 years) were categorized into groups with a myelodysplastic/myeloproliferative neoplasm (MDS/MPN) (n = 5), acute leukemia (n = 4), and other myeloid neoplasms (n = 4) based on the WHO 2022 and ICC criteria. Results: The CSF3R p.Thr618Ile mutation was most frequent (11/13), with additional pathogenic variants including p.Gln743Ter and frameshift mutations affecting the cytoplasmic tail. Variant allele frequencies (VAFs) ranged from 2% to 49%, with the highest median VAF in the MDS/MPN group. Co-mutations varied by subtype; MDS/MPN, NOS, and CMML cases frequently harbored mutations in epigenetic regulators (ASXL1, TET2) and splicing factors (SF3B1, SRSF2, ZRSR2), while acute leukemia cases showed alterations in JAK3, STAT3, and NRAS. Survival analysis revealed distinct patterns across the three diagnostic groups, with MDS/MPN having the poorest prognosis. Conclusion: This study expands the recognized spectrum of CSF3R-related myeloid neoplasms and highlights the clinical and molecular heterogeneity associated with these mutations, emphasizing the need for comprehensive molecular profiling and the potential for targeted therapies. Full article