Human Genomics最新文献

{"title":"Analysis of public perceptions on the use of artificial intelligence in genomic medicine.","authors":"Jack E Harrison, Fiona Lynch, Zornitza Stark, Danya F Vears","doi":"10.1186/s40246-024-00686-6","DOIUrl":"10.1186/s40246-024-00686-6","url":null,"abstract":"<p><strong>Purpose: </strong>Next generation sequencing has led to the creation of large pools of genomic data with analysis rather than data generation now the limiting factor. Artificial intelligence (AI) may be required to optimize the benefits of these data, but little is known about how the public feels about the use of AI in genomics.</p><p><strong>Methods: </strong>We conducted focus groups with members of the Australian public. Participants were recruited via social media advertisements. We explored potential uses of AI in genomic medicine, the benefits, risks, and the possible social implications of its use.</p><p><strong>Results: </strong>Participants (n = 34) largely felt comfortable with AI analysing their own genomic data and generally agreed about its benefits. Concerns were raised over data security, the potential for misdiagnosis, and bias AI may perpetuate. Many participants wanted checking mechanisms for when results were generated using AI.</p><p><strong>Conclusions: </strong>The insights gained from these discussions help to understand public concerns around the use of AI in genomic medicine. Our findings can help to inform both policies around genomic AI and how to educate the public on its use.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"128"},"PeriodicalIF":3.8,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11575060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ralationship between polymorphisms and diplotypes of HLA-G 3'UTR and fetuses with abnormal chromosomes or unexplained pregnancy loss (UPL).","authors":"Danping Xu, Yiyang Zhu, Jun Wang, Heqin Guan, Xiuzhen Shen","doi":"10.1186/s40246-024-00695-5","DOIUrl":"10.1186/s40246-024-00695-5","url":null,"abstract":"<p><strong>Objectives: </strong>Human leukocyte antigen G (HLA-G) plays a crucial role in pregnancy. Pregnancy loss (PL) is caused by a variety of causes, such as fetal chromosomal abnormalities, maternal hypertension and diabetes, immune causes, spontaneous immune diseases, infections, unknown causes, etc. This study reports on the association of fetal HLA-G 3'UTR polymorphisms and diplotypes with chromosomally abnormal fetuses (CAF) or unexplained pregnancy loss (UPL).</p><p><strong>Methods: </strong>A total of 552 specimens were collected and grouped by next-generation sequencing technology (NGS) and fetal survival: UPL (112 cases), CAF (170 cases) and control (258 cases). The polymorphisms of HLA-G 3'UTR in all samples were detected by Sanger sequencing. The genotypes, haplotypes and diplotypes of HLA-G 3'UTR were analyzed. The classification and regression tree (CART) analysis was used to evaluate the role of HLA-G diplotypes in predicting fetal outcomes. The correlations between CAF or UPL and maternal age, paternal age, times of miscarrage, times of delivery were analyzed by logistic regression.</p><p><strong>Results: </strong>The frequencies of HLA-G + 2960del/del and + 3035CC genotypes were remarkablly increased in CAF than those in control group. The frequencies of HLA-G + 2960ins/del, + 3010CC, + 3035TC, + 3142GG, + 3187AA in CAF were significantly lower than those in normal fetuses. Through genetic models and logistic regression analysis, the dominant model of HLA-G 3'UTR genotypes [such as + 2960 (OR = 1.27, 95% CI = 1.05-1.54, p = 0.016), + 3010 (OR = 0.78, 95% CI = 0.63-0.97, p = 0.026), + 3035 (OR = 1.22, 95% CI = 1.00-1.49, p = 0.047), + 3142 (OR = 0.76, 95% CI = 0.62-0.95, p = 0.014) and + 3187 (OR = 0.80, 95% CI = 0.65-0.99, p = 0.041)] were dramatically associated with CAF. However, the frequencies of HLA-G + 3010GC, + 3142GC and + 3187AG in fetuses with UPL were memorably decreased than those in normal fetuses. No significant difference was found in the frequencies of HLA-G haplotypes in all groups. However, the frequency of UTR-1 positive specimens in CAF was significantly higher than that in UPL and control group. At the same time, the frequency of UTR-1/UTR-3 diplotypes in CAF was observably higher than that in UPL and control group, while the UTR-1/UTR-7 frequency in UPL was signally lower than that in control group. Multivariate logistic regression analysis indicated that positive HLA-G UTR-1 (OR = 1.8, 95% CI = 1.16-2.81, p = 0.009), times of abortion (OR = 1.23, 95% CI = 1.02-1.50, p = 0.035), and times of delivery (OR = 0.31, 95% CI = 0.20-0.48, p < 0.001) were correlated with CAF.</p><p><strong>Conclusions: </strong>This study suggests that HLA-G 3'UTR polymorphisms and diplotypes play an important role in the process of successful pregnancy of the embryos with abnormal chromosomes after fertilization. At the same time, Different alleles or diplotypes also affect the development of embryos with UPL.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"126"},"PeriodicalIF":3.8,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11572094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methyltransferase-like 3 represents a prospective target for the diagnosis and treatment of kidney diseases.","authors":"Bin Song, Xiaolong Wu, Yan Zeng","doi":"10.1186/s40246-024-00692-8","DOIUrl":"10.1186/s40246-024-00692-8","url":null,"abstract":"<p><p>Kidney disease is marked by complex pathological mechanisms and significant therapeutic hurdles, resulting in high morbidity and mortality rates globally. A deeper understanding of the fundamental processes involved can aid in identifying novel therapeutic targets and improving treatment efficacy. Current comprehensive data analyses indicate the involvement of methyltransferase-like 3 (METTL3) and its role in RNA N⁶-methyladenosine methylation in various renal pathologies, including acute kidney injury, renal fibrosis, and chronic kidney disease. However, there is a paucity of thorough reviews that clarify the functional mechanisms of METTL3 and evaluate its importance in enhancing therapeutic outcomes. This review seeks to systematically examine the roles, mechanisms, and potential clinical applications of METTL3 in renal diseases. The findings presented suggest that METTL3 is implicated in the etiology and exacerbation of kidney disorders, affecting their onset, progression, malignancy, and responsiveness to chemotherapeutic agents through the regulation of specific genetic pathways. In conclusion, this review underscores a detrimental correlation between METTL3 and kidney diseases, highlighting the therapeutic promise of targeting METTL3. Additionally, it offers critical insights for researchers concerning the diagnosis, prognosis, and treatment strategies for renal conditions.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"125"},"PeriodicalIF":3.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shared genetics between breast cancer and predisposing diseases identifies novel breast cancer treatment candidates.","authors":"Panagiotis N Lalagkas, Rachel D Melamed","doi":"10.1186/s40246-024-00688-4","DOIUrl":"10.1186/s40246-024-00688-4","url":null,"abstract":"<p><strong>Background: </strong>Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing opportunities. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drugs, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drugs for repurposing, but also to highlight shared etiology explaining repurposing.</p><p><strong>Methods: </strong>We compile breast cancer's predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics data to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways. Similarly, for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer.</p><p><strong>Results: </strong>We identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 74 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher's exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing.</p><p><strong>Conclusions: </strong>Our novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known predisposing diseases. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"124"},"PeriodicalIF":3.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and characterization of novel ferroptosis-related genes in acute myocardial infarction.","authors":"Qiaoyu Zhou, Ruizheng Shi, Jia Liu, Zhaoya Liu","doi":"10.1186/s40246-024-00693-7","DOIUrl":"10.1186/s40246-024-00693-7","url":null,"abstract":"<p><strong>Background: </strong>Acute myocardial infarction (AMI) is a leading cause of death and morbidity worldwide. Ferroptosis, a form of regulated cell death, plays a critical role in modulating immune functions during AMI. This study aimed to identify ferroptosis-related hub genes that could serve as potential therapeutic targets in the progression of AMI.</p><p><strong>Methods: </strong>Bioinformatics was used to identify overlapping genes associated with ferroptosis and the infiltration of 22 immune cells by Cell-type Identification by Estimating Relative Subsets of RNA Transcript (CIBERSORT) analysis. The expression of ferroptosis-related genes in AMI was validated across independent datasets, clinical samples, and in vitro cellular experiments. The predictive value for heart failure was evaluated in the first dimension of principal component analysis (PCA) using receiver operating characteristic (ROC) analysis.</p><p><strong>Results: </strong>The study identified 11 key ferroptosis-related genes significantly correlated with immune cell abundance. CIBERSORT analysis highlighted immune dysregulation in AMI. JDP2, DUSP1, TLR4, NFS1, and SLC1A5 were identified as potential biomarkers for AMI progression. Additionally, JDP2, DUSP1, and DDIT4 demonstrated strong predictive value for long-term heart failure.</p><p><strong>Conclusion: </strong>This study highlights the potential association of ferroptosis-related genes with the pathogenesis of AMI, suggesting a role in the molecular mechanisms that may underlie acute coronary events.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"123"},"PeriodicalIF":3.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Minigene-based splice assays provide new insights on intronic variants of the PKHD1 gene.","authors":"Yiyin Zhang, Ran Zhang, Xiaomeng Shi, Xuyan Liu, Changying Li, Yan Zhang, Zhi Wang, Dan Qiao, Fengjiao Pan, Bingying Zhang, Ning Xu, Bingzi Dong, Leping Shao","doi":"10.1186/s40246-024-00675-9","DOIUrl":"10.1186/s40246-024-00675-9","url":null,"abstract":"<p><strong>Background: </strong>Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare hereditary disorder caused by variants in PKHD1. Currently, aberrant splicing has been reported to play important roles in genetic disease. Our goal is to analyze intronic variants in PKHD1 at the mRNA level.</p><p><strong>Results: </strong>The 12 candidate variants were introduced into the corresponding minigene and functionally assayed in HEK 293T and Hela cells. We identified 11 variants that induce splicing alterations, resulting in various consequences such as skipping of exons, intron retention and protein truncation.</p><p><strong>Conclusions: </strong>This underlined the importance of mRNA-level assessment for genetic diagnostics in related genetic disorders.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"122"},"PeriodicalIF":3.8,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of oxidative stress- and ferroptosis-related prognostic signature in gastric cancer and identification of CDH19 as a novel biomarker.","authors":"Shibo Wang, Siyi Zhang, Xiaoxuan Li, Chuanyu Leng, Xiangxue Li, Jing Lv, Shufen Zhao, Wensheng Qiu, Jing Guo","doi":"10.1186/s40246-024-00682-w","DOIUrl":"10.1186/s40246-024-00682-w","url":null,"abstract":"<p><strong>Background: </strong>Ferroptosis is a unique mode of cell death that is iron-dependent and associated with oxidative stress and lipid peroxidation. Oxidative stress and ferroptosis are essential mechanisms leading to metabolic abnormalities in cells and have been popular areas in cancer research.</p><p><strong>Methods: </strong>Initially, 76 oxidative stress and ferroptosis-related genes (OFRGs) were acquired by intersecting the gene sets from oxidative stress and ferroptosis. Afterwards, optimal OFRGs were screened using PPI networks, and individuals were separated into two OFRG subtypes (K = 2). Subsequently, we successfully constructed and verified a prognostic signature comprising SLC7A2, Cadherin 19 (CDH19), and CCN1. To further uncover potential biomarkers of gastric cancer (GC), we examined the expression level of CDH19, investigated the effects of knocking down CDH19 on the biological behavior of GC cells, and explored whether CDH19 is involved in ferroptosis and oxidative stress processes.</p><p><strong>Results: </strong>According to the findings, individuals in the low-risk scoring group have less infiltration of immune suppressive cells, fewer occurrences of immune escape and dysfunction, greater efficacy in chemotherapy and immunotherapy, and better survival outcomes. The qRT-PCR assay indicated that CDH19 expression was significantly higher in GC cells. Through experiments, we demonstrated that knocking down CDH19 can affect the transcription levels of ACSL4 and GPX4, increase intracellular iron ion concentration and accumulation of reactive oxygen species (ROS), and inhibit the proliferation and migration of GC cells.</p><p><strong>Conclusion: </strong>We developed an OFRG-related signature to predict the prognosis and treatment responsiveness of individuals with GC and identified CDH19 as a possible therapeutic target for GC.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"121"},"PeriodicalIF":3.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Best practices for germline variant and DNA methylation analysis of second- and third-generation sequencing data.","authors":"Ferdinando Bonfiglio, Andrea Legati, Vito Alessandro Lasorsa, Flavia Palombo, Giulia De Riso, Federica Isidori, Silvia Russo, Simone Furini, Giuseppe Merla, Fabio Coppedè, Marco Tartaglia, Alessandro Bruselles, Tommaso Pippucci, Andrea Ciolfi, Michele Pinelli, Mario Capasso","doi":"10.1186/s40246-024-00684-8","DOIUrl":"10.1186/s40246-024-00684-8","url":null,"abstract":"<p><p>This comprehensive review provides insights and suggested strategies for the analysis of germline variants using second- and third-generation sequencing technologies (SGS and TGS). It addresses the critical stages of data processing, starting from alignment and preprocessing to quality control, variant calling, and the removal of artifacts. The document emphasized the importance of meticulous data handling, highlighting advanced methodologies for annotating variants and identifying structural variations and methylated DNA sites. Special attention is given to the inspection of problematic variants, a step that is crucial for ensuring the accuracy of the analysis, particularly in clinical settings where genetic diagnostics can inform patient care. Additionally, the document covers the use of various bioinformatics tools and software that enhance the precision and reliability of these analyses. It outlines best practices for the annotation of variants, including considerations for problematic genetic alterations such as those in the human leukocyte antigen region, runs of homozygosity, and mitochondrial DNA alterations. The document also explores the complexities associated with identifying structural variants and copy number variations, underscoring the challenges posed by these large-scale genomic alterations. The objective is to offer a comprehensive framework for researchers and clinicians, ensuring that genetic analyses conducted with SGS and TGS are both accurate and reproducible. By following these best practices, the document aims to increase the diagnostic accuracy for hereditary diseases, facilitating early diagnosis, prevention, and personalized treatment strategies. This review serves as a valuable resource for both novices and experts in the field, providing insights into the latest advancements and methodologies in genetic analysis. It also aims to encourage the adoption of these practices in diverse research and clinical contexts, promoting consistency and reliability across studies.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"120"},"PeriodicalIF":3.8,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drosophila Toxicogenomics: genetic variation and sexual dimorphism in susceptibility to 4-Methylimidazole.","authors":"Katelynne M Collins, Elisabeth Howansky, Sarah C Macon-Foley, Maria E Adonay, Vijay Shankar, Richard F Lyman, Nestor Octavio Nazario-Yepiz, Jordyn K Brooks, Rachel A Lyman, Trudy F C Mackay, Robert R H Anholt","doi":"10.1186/s40246-024-00689-3","DOIUrl":"10.1186/s40246-024-00689-3","url":null,"abstract":"<p><strong>Background: </strong>4-methylimidazole is a ubiquitous and potentially carcinogenic environmental toxicant. Genetic factors that contribute to variation in susceptibility to its toxic effects are challenging to assess in human populations. We used the Drosophila melanogaster Genetic Reference Panel (DGRP), a living library of natural genetic variation, to identify genes with human orthologs associated with variation in susceptibility to 4-methylimidazole.</p><p><strong>Results: </strong>We screened 204 DGRP lines for survival following 24-hour exposure to 4-methylimidazole. We found extensive genetic variation for survival, with a broad sense heritability of 0.82; as well as genetic variation in sexual dimorphism, with a cross-sex genetic correlation of 0.59. Genome-wide association analyses identified a total of 241 candidate molecular polymorphisms in or near 273 unique genes associated with survival. These polymorphisms had either sex-specific or sex-antagonistic effects, and most had putative regulatory effects. We generated interaction networks using these candidate genes as inputs and computationally recruited genes with known physical or genetic interactions. The network genes were significantly over-represented for gene ontology terms involving all aspects of development (including nervous system development) and cellular and organismal functions as well as canonical signaling pathways, and most had human orthologs.</p><p><strong>Conclusions: </strong>The genetic basis of variation in sensitivity to acute exposure to 4-methylimidazole in Drosophila is attributable to variation in genes and networks of genes known for their effects on multiple developmental and cellular processes, including possible neurotoxicity. Given evolutionary conservation of the underlying genes and pathways, these insights may be applicable to humans.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"119"},"PeriodicalIF":3.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel FLNC variants in pediatric cardiomyopathy: an insight into disease mechanisms.","authors":"Rui Dong, Xin Zhou, Haiyan Zhang, Bingyi Shi, Guohua Liu, Yi Liu","doi":"10.1186/s40246-024-00683-9","DOIUrl":"10.1186/s40246-024-00683-9","url":null,"abstract":"<p><strong>Background: </strong>FLNC gene variants have predominantly been reported in adult populations with cardiomyopathies, and early-onset cases are less common. The genotype-phenotype relationship indicates that dilated cardiomyopathy (DCM) is often associated with FLNC truncating variants.</p><p><strong>Methods: </strong>We conducted a comprehensive genetic analysis using next generation sequencing (NGS) to identify FLNC variants in patients with cardiovascular conditions. Detailed phenotypic and variant analyses were performed to characterize the clinical features and genetic alterations. Minigene assays and structural modeling were used to investigate the pathogenicity caused by the identified variants.</p><p><strong>Results: </strong>In a cohort of 58 patients, novel heterozygous FLNC variants, c.3962A > T (p.Glu1321Val) and c.7543C > T (p.Leu2515Phe), were identified in patients presenting with dilated and mixed restrictive/hypertrophic cardiomyopathies, respectively. The c.3962A > T variant disrupted normal splicing, as demonstrated through the splicing prediction tool and minigene studies, further emphasizing its pathogenic potential.</p><p><strong>Conclusion: </strong>For missense variants of FLNC in patients with DCM, the splicing effect of the variant should be carefully checked. Early detection and intervention are crucial given the high risk of sudden cardiac death and severe cardiac complications.</p>","PeriodicalId":13183,"journal":{"name":"Human Genomics","volume":"18 1","pages":"118"},"PeriodicalIF":3.8,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11520881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}