Human Genomics最新文献

Background: Pharmacogenomic (PGx) testing improves treatment outcomes by tailoring therapy to a patient's genetic profile. However, PGx implementation faces global challenges, including costs, reimbursement, and regulations. Initial PGx guidelines exist in the United Arab Emirates (UAE), but insurers' perspectives remain understudied. This study explores insurers' views on policies and strategies to expand PGx adoption and overcome implementation barriers.

Methods: This qualitative study used a semi-structured interview design to explore the perspectives of twelve executive and middle management insurance representatives selected through purposive convenience and snowball sampling. Thematic analysis was conducted inductively, supported by comparative analysis, the Institutional Theory, the TAM, and SWOT analysis to interpret the findings.

Results: Analysis revealed variable awareness of PGx, highlighting both perceived benefits and significant barriers. Key findings included economic constraints, limited physician and public awareness, and policy challenges related to cost-effectiveness and infrastructure. Ethical and privacy concerns were minimal but were noted, with potential implications for insurance premiums. Participants stressed the need for collaborative efforts to align PGx with UAE healthcare goals and highlighted the role of advanced health information systems in facilitating integration. Differences emerged between executive and middle-level management: the former emphasised strategic policies and long-term returns on investment, while the latter focused on practical operational barriers.

Conclusions: Advancing PGx in the UAE requires local cost-effectiveness studies, clear government-led coverage guidelines, and collaborative action among insurers, providers, regulators, and academia. These findings may inform health systems with similar public-private insurance arrangements, where phased adoption strategies and education initiatives are key to sustainable implementation.

Flagellogenesis in mammalian sperm is essential for sperm motility and successful egg fertilization. Multiple morphological abnormalities of the sperm flagella (MMAF) represent a condition characterized by various structural defects in the flagellum. While CFAP57 has been identified as a factor in the pathogenic mechanisms of MMAF, the precise molecular regulation underlying this process remains unclear. Here, we report novel biallelic mutations in the CFAP57 gene identified in two infertile males from two unrelated families. The first patient carried a homozygous nonsense mutation in CFAP57 [NM_001195831.2: c.3250 C > T (p.R1084X)], while the second was compound heterozygous for two missense mutations c.1340T > C (p.V447A) and c.1856G > A (p.R619H). CRISPR-Cas9-generated CFAP57 mutant mice recapitulated human MMAF phenotypes, exhibiting structural flagellar defects and complete infertility. Using immunoprecipitation-mass spectrometry (IP-MS), we identified MYH10, a non-muscle myosin II isoform, as an interaction partner of CFAP57. Immunofluorescence analysis confirmed that both MYH10 and CFAP57 localize to the sperm flagella. We further examined the precise localization of MYH10 at the ultrastructural level using immunoelectron microscopy. Gold particles conjugated to the MYH10 antibody were predominantly detected in the sperm flagella. In sperm with CFAP57 mutations, MYH10 was mislocalized to the mid-piece region while being notably absent from the principal and end pieces. This mislocalization affected the expression of IFT88, a key component of the intraflagellar transport (IFT) system that plays a critical role in mammalian flagellar assembly. Fortunately, ICSI can overcome CFAP57-associated male infertility. Together, our findings establish CFAP57 as an important mediator of sperm flagellogenesis that orchestrates MYH10 and IFT88 positioning and intraflagellar transport dynamics to maintain flagellar integrity, providing molecular insights into MMAF-associated male infertility.

Background: Hepatocellular carcinoma (HCC) is often diagnosed in the late stage, with limited effectiveness of traditional treatments and a low overall survival rate. The underlying molecular mechanisms of HCC require further study.

Methods: Differential and survival analyses evaluated IGF2BP3 expression and prognosis. CCK8 and colony formation assays assessed the impact of IGF2BP3 on tumor malignancy. GEO data screened potential substrates modified by IGF2BP3. RIP-qPCR validated N6-methyladenosine (m6A) modification, while animal models confirmed the tumor-promoting effects of IGF2BP3.

Results: Abnormally high expression of IGF2BP3 is associated with poor prognosis in HCC. IGF2BP3 activates the JAK2-STAT3 pathway through m6a modification of IL4R mRNA in HCC. Then, STAT3 regulates the nuclear localization of METTL3 through WTAP.

Conclusion: In this study, we show that IGF2BP3 binds to and stabilizes IL4R mRNA, activating the JAK2/STAT3 pathway. STAT3 enhances METTL3's nuclear retention via WTAP, coordinating the m6A modification of IGF2BP3 in HCC.

Background: The accurate identification of complex kinship relationships remains a significant challenge in forensic practice. Traditional kinship identification methods, which primarily rely on length polymorphisms of short tandem repeats (STRs), often face difficulty in achieving sufficient discriminatory power for complex relationships due to the limited genetic information they provide. While next-generation sequencing (NGS) enables the detection of allelic sequence polymorphisms within STRs, its practical value for different kinship analyses in specific populations requires comprehensive evaluation. To this end, the present study investigated the genetic polymorphisms of 52 STRs, with a focus on both length and sequence variations, aiming to evaluate the system efficacy and forensic application value of the amplification system in the forensic identification of complex kinship analyses.

Results: The 52 STRs were highly polymorphic in the studied Baoan group. The acquisition of sequence polymorphism information significantly enhanced the genetic polymorphisms of STRs, and the number of alleles increased by 61.00% compared to length-based polymorphisms alone. Kinship performance was evaluated by simulating 1,000 kinship pairs and 1,000 unrelated individual pairs on the basis of the allele frequencies of 52 STRs, and the influence of different combinations of STR loci on the identification efficacies of different kinship was assessed by using the likelihood ratio (LR) method and identical by state (IBS) method, respectively. When the LR was greater than 10,000 or less than 0.0001 as the judgment threshold, the system efficacy of the 52 STR loci based on sequence polymorphisms for forensic identifications of full siblings and unrelated individuals was 99.85%, and those of half-siblings, grandparents-grandchildren, uncle-nephews and unrelated individuals were 61.50%, 60.95%, and 61.00%, respectively.

Conclusions: The availability of sequence polymorphism data and the increased number of STR loci could enhance the efficacy of the detection systems for kinship identifications to a certain extent. These results highlight the potential of combining length and sequence polymorphisms of STRs in forensic practice, offering a valuable tool for addressing the challenge of complex kinship identification. Future research should validate these thresholds in casework samples and expand the number of STR loci to enhance the detection efficacy for distant relationships.

Background: Syndactyly demonstrates high genetic heterogeneity, with many cases lacking molecular diagnosis despite known HOXD13 involvement, suggesting conventional methods may miss a sub-class of variants.

Results: Integrated whole-exome sequencing (WES) and whole-genome sequencing (WGS) analyses identified three novel HOXD13 variants: one 2-bp heterozygous deletion c.314_315del, p.(Lys105ArgfsTer131), and two heterozygous polyalanine expansions (PAE): c.186_212dup, p.(Ala63_Ala71dup) and c.203_204insAGCAGCGGCGGCTGCGGCGGCGGC, p.(Ala64_Ala71dup). WGS successfully identified cryptic variants undetectable by WES technology.

Conclusions: Our findings demonstrate the utility of WGS in identifying HOXD13 variants and support the genotype-phenotype correlation of polyalanine expansions in limb malformations, providing new insights for molecular diagnosis.

Purpose: Diethyl phthalate (DEP), a widely distributed environmental contaminant, is epidemiologically linked to prostate cancer (PCa). However, its molecular mechanisms beyond endocrine disruption remain poorly defined. We aimed to investigate the core mechanisms potentially underlying DEP-associated prostate carcinogenesis within a genome-exposome interaction framework.

Methods: We employed an integrated, multi-level framework combining: (1) Integrated chemical structure-based target prediction; (2) Cross-dataset meta-analysis of PCa transcriptomics (7 GEO datasets) for Differentially Expressed Gene (DEG) identification and Weighted Gene Co-expression Network Analysis (WGCNA); (3) Ensemble machine learning (113 models incorporating RF, XGBoost) for core target screening, augmented by SHAP interpretable to predict potential DEP targets.e AI; and (4) Molecular docking validation (AutoDock Vina, binding free energy assessment).

Results: Integration pinpointed 9 key DEP-PCa targets. Functional enrichment implicated calcium signaling dysregulation, neuroendocrine pathway disruption, and smooth muscle dysfunction as central mechanisms. Machine learning distilled five core regulators: TRPM8, CTSB, CA14, GSTM2, and MYLK. SHAP analysis quantified TRPM8 and CA14 as dominant predictors and revealed critical non-linear interactions: synergistic TRPM8-MYLK co-expression and a CTSB expression threshold effect. Computational validation predicted high-affinity binding of DEP to all five core targets, suggesting potential direct interactions.

Conclusion: Our integrated analysis suggests that DEP may promote prostate carcinogenesis via a multidimensional network centered on calcium signaling perturbation, neuroendocrine dysregulation, and tumor microenvironment acidification, potentially illustrating a genome-exposome interaction mechanism beyond endocrine disruption. We propose that our analytical framework could serve as a reproducible approach for translational exposomics.

Background: Carrier screening for severe recessive genetic diseases in couples undergoing premarital examinations is a crucial strategy for reducing the incidence of birth defects and promoting reproductive health. However, many high-prevalence but genetically complex diseases cannot be reliably detected using conventional PCR-based methods or short-read next-generation sequencing (NGS).

Results: In this study, 1,203 couples who received free premarital medical examinations at seven units in Shanghai were recruited. PacBio long-read sequencing (LRS) was applied for simultaneous carrier screening of five genetically complex monogenic diseases, including spinal muscular atrophy (SMA), α-/β-thalassemia, congenital adrenal hyperplasia (CAH) (refers to 21-hydroxylase deficiency, 21-OHD), and fragile X syndrome (FXS). A total of 161 individuals were identified as carriers of a single disease, while four individuals carried pathogenic variants associated with two distinct diseases. Four couples were determined to be at high reproductive risk, including one classic CAH family, one SMA family, one hemoglobin H (Hb H) disease family, and one family in which the female was an FXS premutation carrier. In addition, one couple at risk of having a child with non-classic CAH (NCCAH), as well as one male individual with a confirmed diagnosis of NCCAH, were identified.

Conclusions: LRS provides substantial clinical value for comprehensive carrier screening in the premarital population. It enables accurate detection of structural variants and repeat expansions that are often missed by conventional methods. These findings support the integration of LRS into routine premarital genetic screening protocols to enhance early identification of at-risk couples and improve reproductive decision-making.