Global Medical Genetics最新文献

Background  Anaplastic lymphoma kinase ( ALK ) fusion events account for 3 to 7% of genetic alterations in patients with nonsmall cell lung cancer (NSCLC). This study aimed to explore the landscape of ALK fusion-positive and ALK fusion-negative in a large cohort of NSCLC patients. Methods  The formalin-fixed paraffin-embedded specimens of NSCLC patients who underwent next-generation sequencing from 2020 to 2023 in Yinfeng Gene Technology Co., Ltd. Clinical laboratory were included in this study. Results  In the current study, a total of 180 (3.20%) patients tested positive for ALK fusions in 5,622 NSCLC samples. Within the ALK -positive cohort, a total of 228 ALK fusions were identified. Furthermore, five novel ALK fusion partners, including DAB1-ALK , KCMF1-ALK , KIF13A-ALK , LOC643770-ALK , and XDH-ALK were identified. In cases with ALK fusion-positive, TP53 alterations were the most prevalent (26.3%), followed by CDKN2A (8.4%), epidermal growth factor receptor ( EGFR , 5.6%), and ALK (5.6%). By contrast, EGFR alterations were most prevalent (51%) in patients with ALK fusion-negative NSCLC, followed by TP53 (42.7%), KRAS (11.6%), and CDKN2A (11.3%). A total of 10 cases where ALK fusion co-occurred with EGFR mutations were also identified. Notably, the ALK fusion positivity rate was higher in younger patients ( p  < 0.0001) and in female patients ( p  = 0.0429). Additionally, positive ALK test results were more prevalent in patients with high programmed death-ligand 1 expression, especially when applying a 50% cutoff. Conclusions  Collectively, these findings offer valuable genomic insights that could inform the personalized clinical care of patients with NSCLC harboring ALK fusions within the context of precision medicine.

Objective  Myelodysplastic syndrome (MDS) is a malignant clonal disorder of hematopoietic stem cells which is characterized by morphologic dysplasia. However, the pathological characteristics of megakaryocytes (MKs) in MDS patients with gene mutation are not well established. Methods  Bone marrow MK specimens from 104 patients with primary MDS were evaluated, and all patients were distributed into two groups according to gene mutation associated with functional MKs. The morphologic and cellular characteristics of MKs and platelets were recorded and compared. Results  The more frequently mutated genes in MDS patients were TUBB1 (11.54%), VWF (8.65%), NBEAL2 (5.77%), and the most common point mutation was TUBB1 p.(R307H) and p.(Q43P). Patients with MK mutation showed a decrease in adenosine diphosphate-induced platelet aggregation, high proportion of CD34 ⁺ CD61 ⁺ MKs (10.00 vs. 4.00%, p  = 0.012), and short overall survival (33.15 vs. 40.50 months, p  = 0.013). Further, patients with a higher percent of CD34 ⁺ CD61 ⁺ MKs (≧20.00%) had lower platelet counts (36.00 × 10 ⁹ /L vs. 88.50 × 10 ⁹ /L, p  = 0.015) and more profound emperipolesis ( p  = 0.001). By analyzing RNA-sequencing of MKs, differentially expressed mRNA was involved in physiological processes including platelet function and platelet activation, especially for MDS patients with high percent of CD34 ⁺ CD61 ⁺ MKs. The high levels of expression of CD62P, CXCL10, and S100A9 mRNA, shown by RNA sequencing, were validated by PCR assay. Conclusion  High proportion of CD34 ⁺ CD61 ⁺ MKs was a poor prognostic factor in MDS patients with MK mutation. CD62P, CXCL10, and S100A9 may be the potential targets to evaluate the molecular link between gene defects and platelet function.

Introduction  CRISPR-Cas9 gene editing, leveraging bacterial defense mechanisms, offers precise DNA modifications, holding promise in curing genetic diseases. This review critically assesses its potential, analyzing evidence on therapeutic applications, challenges, and future prospects. Examining diverse genetic disorders, it evaluates efficacy, safety, and limitations, emphasizing the need for a thorough understanding among medical professionals and researchers. Acknowledging its transformative impact, a systematic review is crucial for informed decision-making, responsible utilization, and guiding future research to unlock CRISPR-Cas9's full potential in realizing the cure for genetic diseases. Methods  A comprehensive literature search across PubMed, Scopus, and the Web of Science identified studies applying CRISPR-Cas9 gene editing for genetic diseases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria covered in vitro and in vivo models targeting various genetic diseases with reported outcomes on disease modification or potential cure. Quality assessment revealed a generally moderate to high risk of bias. Heterogeneity prevented quantitative meta-analysis, prompting a narrative synthesis of findings. Discussion  CRISPR-Cas9 enables precise gene editing, correcting disease-causing mutations and offering hope for previously incurable genetic conditions. Leveraging inherited epigenetic modifications, it not only fixes mutations but also restores normal gene function and controls gene expression. The transformative potential of CRISPR-Cas9 holds promise for personalized treatments, improving therapeutic outcomes, but ethical considerations and safety concerns must be rigorously addressed to ensure responsible and safe application, especially in germline editing with potential long-term implications.

Background  A retrospective study was performed to evaluate the patterns of cytogenomic findings detected from a case series of products of conception (POC) in recurrent pregnancy loss (RPL) over a 16-year period from 2007 to 2023. Results  This case series of RPL was divided into a single analysis (SA) group of 266 women and a consecutive analysis (CA) group of 225 women with two to three miscarriages analyzed. Of the 269 POC from the SA group and the 469 POC from the CA group, a spectrum of cytogenomic abnormalities of simple aneuploidies, compound aneuploidies, polyploidies, and structural rearrangements/pathogenic copy number variants (pCNVs) were detected in 109 (41%) and 160 cases (34%), five (2%) and 11 cases (2%), 35 (13%) and 36 cases (8%), and 10 (4%) and 19 cases (4%), respectively. Patterns with recurrent normal karyotypes, alternating normal and abnormal karyotypes, and recurrent abnormal karyotypes were detected in 74 (33%), 71 (32%), and 80 (35%) of consecutive miscarriages, respectively. Repeat aneuploidies of monosomy X and trisomy 16, triploidy, and tetraploidy were detected in nine women. Conclusions  A comparable spectrum of cytogenomic abnormalities was noted in the SA and CA groups of RPL. A skewed likelihood of 2/3 for recurrent normal and abnormal karyotypes and 1/3 for alternating normal and abnormal karyotypes in consecutive miscarriages was observed. Routine cytogenetic analysis should be performed for consecutive miscarriages. Further genomic sequencing to search for detrimental and embryonic lethal variants causing miscarriages and pathogenic variants inducing aneuploidies and polyploidies should be considered for RPL with recurrent normal and abnormal karyotypes.

We report a 4-year-old girl with neurodevelopmental abnormalities who has maternal uniparental isodisomy of chromosome 2 leading to homozygosity for a likely pathogenic variant in SPR , and a variant of uncertain significance in ZNF142 . Biallelic pathogenic variants in SPR lead to sepiapterin reductase deficiency (SRD), a dopa-responsive dystonia. Pathogenic variants in ZNF142 are associated with an autosomal recessive neurodevelopmental disorder characterized by impaired speech and hyperkinetic movements, which has significant clinical overlap with SRD. Our patient showed dramatic improvement in motor skills after treatment with levodopa. We also reviewed 67 published reports of uniparental disomy of chromosome 2 (UPD2) associated with various clinical outcomes. These include autosomal recessive disorders associated with loci on chromosome 2, infants with UPD2 whose gestations were associated with confined placental mosaicism for trisomy 2 leading to intrauterine growth restriction with good postnatal catchup growth, and normal phenotypes in children and adults with an incidental finding of either maternal or paternal UPD2. These latter reports provide support for the conclusion that genes located on chromosome 2 are not subject to imprinting. We also explore the mechanisms giving rise to UPD2.

Background  In addition to its multifaceted physiological functions, vitamin D is recognized for its protective role against cancer. To manifest its effects, vitamin D engages with the vitamin D receptor ( VDR ) gene responsible for its encoding. Investigations have unveiled that polymorphisms within the VDR gene exert influence over the expression and/or functionality of the VDR protein. Notably, certain VDR gene polymorphisms have emerged as particularly pertinent in the context of tumorigenesis, including Fok1 (rs2228570), Bsm1 (rs1544410), Taq1 (rs771236), and Apa1 (rs7975232). This study aims to scrutinize the correlation between the Bsm1 and Apa1 polymorphisms and the susceptibility to breast cancer development. Materials and Methods  In this study, 50 patients suffering from breast cancer with less than 6 months breast cancer diagnosis and 50 healthy control individuals have been chosen. Restriction fragment length polymorphism polymerase chain reaction was used to determine the genotype of polymorphisms. Results  The results of the statistical analysis showed that among the studied polymorphisms, there was no correlation with the development of breast cancer. Conclusion  Studies on various cancers have produced inconsistent results regarding vitamin D's role in the development and progression of cancer. Therefore, further research is necessary to determine vitamin D's role in cancer development and progression.

The fusion genes NRG1 and NRG2 , members of the epidermal growth factor (EGF) receptor family, have emerged as key drivers in cancer. Upon fusion, NRG1 retains its EGF-like active domain, binds to the ERBB ligand family, and triggers intracellular signaling cascades, promoting uncontrolled cell proliferation. The incidence of NRG1 gene fusion varies across cancer types, with lung cancer being the most prevalent at 0.19 to 0.27%. CD74 and SLC3A2 are the most frequently observed fusion partners. RNA-based next-generation sequencing is the primary method for detecting NRG1 and NRG2 gene fusions, whereas pERBB3 immunohistochemistry can serve as a rapid prescreening tool for identifying NRG1 -positive patients. Currently, there are no approved targeted drugs for NRG1 and NRG2 . Common treatment approaches involve pan-ERBB inhibitors, small molecule inhibitors targeting ERBB2 or ERBB3, and monoclonal antibodies. Given the current landscape of NRG1 and NRG2 in solid tumors, a consensus among diagnostic and treatment experts is proposed, and clinical trials hold promise for benefiting more patients with NRG1 and NRG2 gene fusion solid tumors.

Dyslexia is a genetic and heritable disorder that has yet to discover the treatment of it, especially at the molecular and drug intervention levels. This review provides an overview of the current findings on the environmental and genetic factors involved in developmental dyslexia. The latest techniques used in diagnosing the disease and macromolecular factors findings may contribute to a higher degree of development in detangling the proper management and treatment for dyslexic individuals. Furthermore, this review tried to put together all the models used in the current dyslexia research for references in future studies that include animal models as well as in vitro models and how the previous research has provided consistent data across many years and regions. Thus, we suggest furthering the studies using an organoid model based on the existing gene polymorphism, pathways, and neuronal function input.

Epidemiological and experimental evidence has linked chronic inflammation to the etiology of myeloproliferative neoplasm (MPN). However, it remains unclear whether genetic associations with specific inflammatory biomarkers are causal or due to bias. This study aimed to assess the effect of C-reactive protein (CRP) and systemic inflammatory regulators on MPN within a bidirectional Mendelian randomization design. Genetic associations with MPN were derived from a publicly available genome-wide association study (GWAS) comprising 1,086 cases and 407,155 controls of European ancestry. Additionally, data on inflammation were extracted from two GWASs focusing on CRP and cytokines. The causal relationships between exposure and outcome were explored using the inverse variance weighted (IVW) method. To confirm the final results, multiple sensitivity analyses, including MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier (MR-PRESSO), were simultaneously employed. Our results suggest that lower levels of macrophage-migration inhibitory factor (IVW estimate odds ratio [OR IVW] per SD genetic cytokines change: 0.641; 95% confidence interval [CI]: 0.427-0.964; p  = 0.032) and higher levels of interleukin-2 receptor α (lL2Rα, 1.377, 95% CI: 1.006-1.883; p  = 0.046) are associated with an increased risk of MPN. Genetically predicted MPN is related to increased levels of RANTES (IVW estimate β: 0.043, 95% CI: 0.002-0.084; p  = 0.039) and interleukin-10 (IVW estimate β: 0.030, 95% CI: 0.001-0.060; p  = 0.041). This study provides evidence for a causal relationship between CRP, systemic inflammatory regulators, and MPN, and new insights into the etiology, prevention, and prognosis of MPN.

Immunoglobulin heavy chain variable ( IGHV ) region mutations, TP53 mutation, fluorescence in situ hybridization (FISH), and cytogenetic analysis are the most important prognostic biomarkers used in chronic lymphocytic leukemia (CLL) patients in our daily practice. In real-life environment, there are scarce studies that analyze the correlation of these factors with outcome, mainly referred to time to first treatment (TTFT) and overall survival (OS). This study aimed to typify IGHV mutation status, family usage, FISH aberrations, and complex karyotype (CK) and to analyze the prognostic impact in TTFT and OS in retrospective study of 375 CLL patients from a Spanish cohort. We found unmutated CLL (U-CLL) was associated with more aggressive disease, shorter TTFT (48 vs. 133 months, p  < 0.0001), and shorter OS (112 vs. 246 months, p  < 0.0001) than the mutated CLL. IGHV3 was the most frequently used IGHV family (46%), followed by IGHV1 (30%) and IGHV4 (16%). IGHV5-51 and IGHV1-69 subfamilies were associated with poor prognosis, while IGHV4 and IGHV2 showed the best outcomes. The prevalence of CK was 15% and was significantly associated with U-CLL. In the multivariable analysis, IGHV2 gene usage and del13q were associated with longer TTFT, while VH1-02, +12, del11q, del17p, and U-CLL with shorter TTFT. Moreover, VH1-69 usage, del11q, del17p, and U-CLL were significantly associated with shorter OS. A comprehensive analysis of genetic prognostic factors provides a more precise information on the outcome of CLL patients. In addition to FISH cytogenetic aberrations, IGHV and TP53 mutations, IGHV gene families, and CK information could help clinicians in the decision-making process.