BMC Medical Genomics最新文献

Background: Fabry disease is a rare and non-specific disease that is difficult and expensive to diagnose. This study aimed to investigate the clinical phenotypes and genetic characteristics of patients with Fabry disease characterised by the GLA IVS4 + 919G > A variant in China through a proposed pilot program integrating high-risk and family screening.

Methods: The 31-months-long pilot program assessed high-risk screening for Fabry disease in 388 patients by integrating previous screening methods that measure their dry blood spot (DBS) α-galactosidase A (α-GAL) activity, globotriaosylsphingosine (Lyso-GL-3), and GLA gene sequence at Ninghai First Hospital. Patients whose dried blood spot (DBS) α-GAL enzyme activity was low (< 2.40 µmol·L^- 1·h^- 1) or whose Lyso-GL-3 level was high (> 1.10 ng/mL) underwent GLA genetic testing for diagnostic confirmation. Gender-specific family screening and evaluation was carried out on the proband, and the clinical and genetic characteristics of Fabry disease characterised by the GLA IVS4 + 919G > A variant were summarised.

Results: A yield of Fabry disease diagnosis of 1.80% (7/388) was achieved, which is much larger than have been previously reported. These diagnoses include a 9.8-year-old girl, who was screened because of a high-risk profile of severe pain in the extremities, as well as 6 males, who were diagnosed with Fabry disease and who were screened because of unexplained left ventricular hypertrophy. All 7 diagnosed patients were carriers of the GLA IVS4 + 919G > A variant. Family screening of 7 probands revealed that 18 family members carried pathogenic variants, resulting in a diagnosis rate of 6.44% (25/388); 13 were clinically affected, 2 were asymptomatic carriers, and 3 declined further clinical assessment. The 25 patients had multiple affected organs and systems included the heart (60.00%), peripheral nerves (16.00%), kidney (36.00%), eye (20.00%), brain (12.00%), and gastrointestinal tract (24.00%).

Conclusions: Screening high-risk populations and family screening is critical for early diagnosis and timely intervention in patients with Fabry disease. The GLA IVS4 + 919G > A variant is associated with diverse phenotypes of Fabry disease and is highly prevalent in late-onset cases in Ninghai County, Zhejiang Province, Eastern China.

Background: DMBX1 is a transcription factor that plays important roles in various biological processes. However, systematic research on DMBX1 in colon cancer remains limited. This study aimed to investigate the expression characteristics of DMBX1 in colon cancer and its impact on prognosis and the immune microenvironment.

Methods: Gene expression and clinical data for colon cancer were downloaded from The Cancer Genome Atlas (TCGA) database. Analyses performed included differential gene expression analysis, mutation analysis, prognosis analysis, tumor microenvironment (TME) analysis (including immune cell infiltration, immune checkpoints, DNA repair genes, and methyltransferase correlation analysis), and functional enrichment analysis. Furthermore, the function of DMBX1 was validated through Western blot, Transwell, and cell scratch assays, including knockdown and overexpression of DMBX1.

Results: Differential expression analysis revealed that DMBX1 expression was significantly higher in colon cancer tissues compared to normal tissues. Its high expression was significantly associated with poorer patient survival (p < 0.05). Mutation analysis found that the DMBX1 gene has a relatively high mutation frequency in colon cancer, and different mutation types significantly affected its gene expression levels. Tumor microenvironment analysis indicated that DMBX1 gene expression was significantly correlated with the infiltration levels of various immune cells and the expression of immune checkpoint genes. Enrichment analysis results showed that DMBX1 is involved in multiple key biological processes and signaling pathways, particularly participating in the process of cell adhesion. After knocking down the DMBX1 gene, the expression of ZO-1 and E-cadherin increased, while the expression of Vimentin and Slug decreased, suggesting that DMBX1 may affect the invasion and metastasis of colon cancer by regulating the epithelial-mesenchymal transition (EMT) process. Conversely, overexpression of DMBX1 led to decreased expression of ZO-1 and E-cadherin and increased expression of Vimentin and Slug. Transwell and cell scratch assay results further validated that high expression of DMBX1 significantly increased the invasion and migration capabilities of colon cancer cells, while knocking down DMBX1 inhibited these capabilities.

Conclusion: Our findings suggest that DMBX1 may have potential as a prognostic biomarker for prognostic assessment in colon cancer and is associated with alterations in the tumor immune microenvironment.Mechanistically, DMBX1 likely primarily influences the occurrence and development of colon cancer by promoting the invasion and migration of colon cancer cells.

Background: Cardiovascular-kidney-metabolic (CKM) syndrome is increasingly recognized as a distinct disorder with important implications for health outcomes, but its heterogeneity of presentation and genetic underpinning remains poorly understood. We aimed to identify potential CKM subtypes and their genetic basis by analyzing biomarkers and health outcomes in a large biobank.

Methods: Blood and urine biomarkers from 121,918 participants in the Lifelines cohort were analyzed using topic modelling. Candidate CKM subtypes were operationally defined as blood-urine topics that were simultaneously and positively associated with self-reported kidney disease, type 2 diabetes, and cardiovascular disease. Genome-wide association studies were performed on 52,727 genotyped participants to identify common genetic variants linked to these candidate subtypes.

Results: Five candidate CKM subtypes were identified, each characterized by high levels of blood glucose, uric acid, urea and inflammation biomarkers, but differing in liver enzyme, cholesterol, and glycaemic profiles. Genetic analyses revealed 57 genome-wide significant variants, with the majority (35) not detected in single-biomarker analyses. Most variants were subtype-specific, suggesting that distinct biological pathways contribute to these candidate CKM subtypes.

Conclusions: Our analysis suggests distinct genetic architectures underlying different CKM manifestations and demonstrates that combining biomarkers in disease-relevant constellations improves detection of genetic variants.

Background: It is essential that studies of genomic sequencing (GS) in newborns and children include individuals from under-represented racial and ethnic groups (URG) to ensure future applications are equitably implemented. We conducted interviews with parents from URG to better understand their perspectives on GS research, develop strategies to reduce barriers to enrollment, and facilitate research participation.

Methods: Semi-structured interviews with 50 parents from URG.

Results: Nearly all parents said they would be interested in participating in an infant GS study. Parents were interested in participating in GS research for reasons including clinical utility, personal utility, and/or family health benefits. Deterrents to enrollment cited by parents were discomfort with enrollment procedures (e.g., not wanting a heel stick), limited emotional bandwidth, unfavorable perceptions of the study, and concerns about potential results. Most parents said they would want to receive all types of genetic results, including actionable and non-actionable, as well as childhood- and adult-onset.

Conclusion: Our findings demonstrate that parents from URG are interested in participating in GS research. Based upon these findings, we provide recommendations for designing GS studies that are responsive to their concerns.

Developmental dysplasia of the hip (DDH) is a multifactorial disorder that affects 0.56-3.8% of newborns worldwide. Recent research has identified several candidate genes potentially involved in DDH pathogenesis, with LRP1 investigated as a candidate gene due to its regulatory role in cartilage development. This study presents a genetic analysis of two female DDH patients (17 and 26 years old) diagnosed through radiographic examination. Genomic DNA was extracted from peripheral blood samples of the two female patients with DDH. We performed targeted genetic analysis of LRP1 exons 6, 32, 40, and 74, which have been previously implicated in DDH pathogenesis. DNA was extracted from peripheral blood samples, amplified via polymerase chain reaction (PCR), and analyzed using Sanger sequencing. Despite clear clinical DDH diagnoses, neither patient carried mutations in the examined LRP1 exons and displayed only wild-type sequences. These findings indicate that no pathogenic LRP1 variants were detected in these two DDH patients. This case report provides preliminary descriptive data on LRP1 exonic regions in DDH. The absence of detected variants in these specific loci suggests that future investigations should utilize high-throughput sequencing strategies in larger cohorts to more comprehensively explore the genetic basis of the disorder.