Frontiers in Genetics最新文献

Loeys-Dietz syndrome (LDS) is a connective tissue disorder representing a wide spectrum of phenotypes, ranging from isolated thoracic aortic aneurysm or dissection to a more severe syndromic presentation with multisystemic involvement. Significant clinical variability has been noted for both related and unrelated individuals with the same pathogenic variant. We report a family of five affected individuals with notable phenotypic variability who appear to have two distinct molecular causes of LDS, one attributable to a missense variant in TGFBR2 and the other an intronic variant 6 bp upstream from a splice junction in TGFB2. We tested the functional impacts of the variant identified in the proband alongside other variants in the region reported in ClinVar using a splice reporter system, which resulted in non-canonical splicing products for several variants including the proband. Molecular validation of the splicing products suggests that the TGFB2 variants tested impact splicing by reducing efficiency of the canonical acceptor in favor of an alternate acceptor within the exon. These data combined with clinical phenotypes and segregation of the variant with disease support the conclusion that this intronic TGFB2 variant may cause LDS in this patient and her mother. These analyses demonstrate that underappreciated intronic variants that alter splicing can be relevant for clinical phenotypes of connective tissue disease. This case highlights the importance of prompt familial cascade testing, clinical evaluation with detailed dysmorphology exam, comprehensive genetic testing, and collaboration between clinicians and scientists to characterize variants of uncertain significance to properly assess risk in LDS patients.

Introduction: We investigated the relationship between systematic regulators of inflammation and the risk of age-related macular degeneration (AMD), both wet and dry forms, by using bidirectional, two-sample Mendelian randomization (MR).

Methods: We performed bidirectional two-sample Mendelian randomization analysis using genome-wide study (GWAS) data for 91 plasma proteins from 14,824 individuals of European descent across 11 study groups. Next, we utilized data from the FinnGen consortium to study AMD using the inverse- variance-weighted approach for Mendelian randomization. Additional analyses involved MR-Egger, Weighted median, Weighted mode, MR-PRESSO, and MR- Steiger filtering techniques.

Results: We identified 16 cytokines associated AMD outcomes and post FDR correction, higher levels of fibroblast growth factor 19 and leukemia inhibitory factor receptor were associated with decreased risk for AMD, while higher levels of tumour necrosis factor ligand superfamily member 14 were associated with increased risk for AMD. Additionally, higher levels of interleukin-10 receptor subunit alpha were associated with decreased risk for wet AMD, higher levels of leukemia inhibitory factor receptor were associated with decreased risk for dry AMD, and higher levels of signaling lymphocytic activation molecule were associated with increased risk for dry AMD. Genetic susceptibility to AMD was associated with elevated levels of TNF-related activation-induced cytokines (TNFSF11), and genetic susceptibility to wet AMD was associated with elevated levels of TNFSF11, interleukin-18 receptor 1 (IL18R1), and CUB domain-containing protein 1 (CDCP1).

Discussion: This research enhances our understanding of systemic inflammation in AMD, providing insights into etiology, diagnosis, and treatment of AMD and its forms.

Background: Observational studies have reported changes in gut microbiota abundance caused by long-term statin medication therapy. However, the causal relation between statin medication and gut microbiota subsets based on genetic variants remains unclear.

Methods: We used genome-wide association study (GWAS) data on statin medication from the FinnGen database and gut microbiota abundance GWAS data from the IEU OpenGWAS project. A Mendelian randomization (MR) analysis was conducted to evaluate the causal effect of statin medication on gut microbiota abundance using the inverse variance weighting (IVW) method, MR-Egger regression, and weighted median approach. Meanwhile, heterogeneity and pleiotropy analyses were also undertaken in this study.

Results: Statin medication was negatively correlated with five species of gut microbiota abundance: Parabacteroides (Beta_IVW = -0.2745, 95% CI = (-0.4422, -0.1068), and P _IVW = 0.0013), Ruminococcaceae UCG-009 (Beta_IVW = -0.1904, 95% CI = (-0.3255, -0.0553), and P _IVW = 0.0057), Coprococcus 1 (Beta_IVW = -0.1212, 95% CI = (-0.2194, -0.0231), and P _IVW = 0.0154), Ruminococcaceae UCG-010 (Beta_IVW = -0.1149, 95% CI = (-0.2238, -0.0060), and P _IVW = 0.0385), and Veillonellaceae (Beta_IVW = -0.0970, 95% CI = (-0.2238, 0.0060), and P _IVW = 0.0400) and positively correlated with one species of gut microbiota: Desulfovibrio (Beta_IVW = 0.2452, 95% CI = (0.0299, 0.4606), and P _IVW = 0.0255). In addition, no significant heterogeneity or pleiotropy was detected in the abovementioned gut microbiota.

Conclusion: This Mendelian randomization analysis indicates a causal relationship between statin medication and six gut microbiota species. These findings may provide new strategies for health monitoring in populations taking long-term statin medications.

Introduction: Silver-Russell syndrome (SRS) is an imprinting disorder characterized by intrauterine and postnatal growth retardation. The pathogenic alterations and phenotypes are heterogeneous.

Methods: Here, we present a rare pedigree of duplications with different methylation patterns in 11p15.5, which caused SRS or a normal phenotype across three generations.

Results: Duplications of maternal IC2 (copy number of 3) with enhanced methylation (methylation index of 0.62) resulted in typical SRS.

Conclusion: The result added to the complexity of the molecular genetics of SRS.

[This corrects the article DOI: 10.3389/fgene.2024.1427205.].

Although lab-coat genomics scientists are highly skilled and involved in pioneering work, few studies have examined their perceptions on what they do, and how they relate with others in interdisciplinary work. Recognizing that gap, we were curious to talk with scientists about their current work and positionalities related to the use of genomics for bioremediation. Using unstructured open-ended interviews and thematic analysis, we interviewed researchers with diverse genomics-related expertise. Emerging topics were grouped into two broad categories akin to Bronfenbrenner's nested developmental model: microsystem matters, comprising technical advances, barriers, and localized concerns; and macrosystem matters, exploring wider reflections and the philosophies of genomics and society. At the microsystem level, findings revealed differences of opinion about methodological steps, but there was agreement about the incompleteness of databases and the absence of established reference values. These two problems may not only impact a project's progress but also the ability to gauge success, affecting budgeting, human resource needs, and overall stress. At the macrosystem level, scientists voiced concerns about how different social groups perceive and accept genomics applications, as those tend to be viewed by lay persons as genetic interventions. Another focus was on how academic publication slows progress because it is orientated toward positive results while gaps in knowledge could be filled by publishing negative results or methodological barriers. This study underscores scientists' self-awareness within the genomics discipline, acknowledging how their beliefs and biases shape research outcomes. It illuminates critical reflections essential for navigating societal and scientific landscapes in genomics research.

Background: Noonan syndrome (NS) is a rare group of autosomal genetic disorders. In recent years, with the exploration and development of molecular diagnostic techniques, more and more researchers have begun to pay attention to NS. However, there is still a lack of reports on the bibliometric analysis of NS worldwide. This study aims to assess the current research status and development trend of NS, to explore the research hotspots and emerging topics, and to point out the direction for future scientific research.

Methods: Web of Science Core Collection was selected as the search database for bibliometric analysis of NS-related publications from 1998 to 2023. Statistical and visual analysis of the number of publications, countries, institutions, authors, journals, keywords, and references were analyzed using Citespace, VOSviewer, Scimago Graphica, and BibliometrixR.

Results: A total of 2041 articles were included in this study. The United States had the highest number of publications, and Istituto Superiore di Sanità, Italy, was the institution with the highest number of publications. TARTAGLIA M was the scientist with the highest number of publications and citations. Among the journals, AMERICAN JOURNAL OF MEDICAL GENETICS PART A has the highest output, and Nature Genetics is the most frequently cited. The reference with the highest outburst intensity is Roberts AE, LANCET, 2013. the cluster diagram divides all the keywords into seven categories, with the most vigorous outburst being "of function mutations."

Conclusion: Research hotspots in the field of NS focus on the correspondence between NS genotype and phenotype and the precise diagnosis of NS. Future research efforts will explore more deeply from the perspective of long-term intervention strategies for NS. There is an urgent need to rely on significant research countries, institutions, journals, and authors to lead the construction of a more robust global collaborative network that will enhance research efficacy.

Olmsted syndrome is characterized by symmetrically distributed, destructive, inflammatory palmoplantar keratoderma with periorificial keratotic plaques, most commonly due to gain-of-function mutations in the transient receptor potential vanilloid 3 (TRPV3) gene, which involves multiple pathological functions of the skin, such as hyperkeratosis, dermatitis, hair loss, itching, and pain. Recent studies suggest that mutations of TRPV3 located in different structural domains lead to cases of varying severity, suggesting a potential genotype-phenotype correlation resulting from TRPV3 gene mutations. This paper reviews the genetics and pathogenesis of Olmsted syndrome, as well as the potential management and treatment. This review will lay a foundation for further developing the individualized treatment for TRPV3-related Olmsted syndrome.

Background: Research links arthropathies with adverse pregnancy outcomes. This study aims to explore its connection to postpartum hemorrhage (PPH) through Mendelian randomization (MR) analysis.

Methods: The study used GWAS data from the IEU OpenGWAS database for PPH and arthropathies. After selecting instrumental variables, bidirectional MR analysis was conducted using MR-Egger, Weighted median, Simple mode, Weighted mode, and IVW methods. Sensitivity analysis was then performed to assess MR results reliability. Finally, enrichment analysis of genes corresponding to arthropathies SNPs in forward MR was conducted to explore their biological function and signaling pathways.

Results: The forward MR results revealed that arthropathies was causally related to PPH, and arthropathies was a risk factor for PPH. Whereas, there was not a causal relationship between PPH and arthropathies by reverse MR analysis. It illustrated the reliability of the MR analysis results by the sensitivity analysis without heterogeneity, horizontal pleiotropy, and SNPs of severe bias by LOO analysis. Furthermore, a total of 33 genes corresponding to SNPs of arthropathies were obtained, which were mainly enriched in regulation of response to biotic stimulus, spliceosomal snRNP complex and ligase activity in GO terms, and natural killer cell-mediated cytotoxicity in KEGG pathways.

Conclusion: This study supported that arthropathies was a risk factor for PPH, and the pathways involved the genes corresponding to SNPs were analyzed, which could provide important reference and evidence for further exploring the molecular mechanism between arthropathies and PPH.