Annals of Human Genetics最新文献

{"title":"Identification and Functional Verification of Variants Associated With Clubfoot and Arthrogrypotic Hand Deformation in a Multigeneration Polish Family.","authors":"Ewa Hordyjewska-Kowalczyk, Akshaya Ramanujam, Adrian Odrzywolski, Annemieke Verkerk, Joyce van Meurs, Grzegorz Kandzierski, Przemko Tylzanowski","doi":"10.1111/ahg.70024","DOIUrl":"https://doi.org/10.1111/ahg.70024","url":null,"abstract":"<p><strong>Background: </strong>Clubfoot, or talipes equinovarus (TEV), is an autosomal dominant foot malformation characterized by a variable clinical picture, ranging from mild to severe deformity. While its genetic basis has been partly elucidated, the underlying molecular mechanisms remain incompletely understood.</p><p><strong>Methods: </strong>We investigated a five-generation Polish family presenting autosomal dominant clubfoot associated with arthrogrypotic hand deformation. Genotyping was performed to identify variants co-segregating with the phenotype. Aberrant splicing effects were assessed in the proband's sample, and functional validation was carried out in zebrafish.</p><p><strong>Results: </strong>Two variants were identified that segregated with the phenotype. The first, TMEM256 c.118-4dup, is an intronic duplication resulting in aberrant splicing. The pathogenicity of the misspliced TMEM256 products was confirmed in zebrafish. The second variant, MYH3 c.1123G>A;p.(Glu375Lys), is a previously reported missense change potentially explaining the arthrogryposis-like hand deformations in the affected family members.</p><p><strong>Conclusions: </strong>Our findings reveal TMEM256 as a potential novel candidate gene for clubfoot and highlight the contribution of MYH3 variants to the broader clinical spectrum observed. These findings contribute to understanding the genetic complexity underlying clubfoot, providing unique insights into potential novel candidate gene and pathways involved in this condition.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association Between Different Types of Lipids and Alzheimer's Disease, Parkinson's Disease, and Epilepsy: A Mendelian Randomization and Bioinformatics Analysis.","authors":"Jiayu Zhang, Anqi Song, Yi Xiang, Jiaqi Liu, Baixiang Li, Xueting Li","doi":"10.1111/ahg.70025","DOIUrl":"https://doi.org/10.1111/ahg.70025","url":null,"abstract":"<p><strong>Background: </strong>With the increasing prevalence of neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy (EP) worldwide, there is a growing burden on medical and healthcare resources. Therefore, it is crucial to identify the etiology of these diseases and implement targeted preventive, diagnostic, and treatment measures to address the existing shortage of medical resources. Lipids are integral components of biological membranes. They not only function in energy storage and maintaining cell structure but also play a pivotal role in intercellular communication and signal transmission. Hence, lipids may hold significant implications in the pathogenesis and progression of the aforementioned disorders.</p><p><strong>Methods: </strong>Utilizing two-sample Mendelian randomization (MR) in this investigation, the IEU OpenGWAS database was analyzed to explore the potential causal association between 159 lipids and the mentioned conditions, with sensitivity analysis being performed. Differentially expressed genes (DEGs) were obtained through data analysis of these three diseases in the GEO database, followed by enrichment analysis and protein-protein interaction (PPI) network analysis.</p><p><strong>Results: </strong>The findings indicated a potential causal association between the onset and progression of these disorders and 20 lipids categorized into six groups, which include sterol esters (SEs), ceramides (Cer), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and triacylglycerol (TAG). Furthermore, these lipids were found to regulate biological processes and pathways associated with endocytosis, synaptic vesicular circulation, signal release, MAPK signaling pathway, PI3 kinase (PI3K)-AKT signaling pathway, dopaminergic synapses, and malaria infection. It is worth noting that based on the comprehensive scores of protein interactions in the STRING database, as well as their connectivity and association strength with other proteins in the network, heat shock factor binding protein 1 (HSPB1), which is closely related to lipids and has a relatively close relationship with diseases, was identified as a key protein for AD. Similarly, RAB3A was identified as a key protein for PD. CD160 serves as the key protein of EP.</p><p><strong>Conclusion: </strong>This study, by combining MR with bioinformatics analysis, discovered the potential lipid-based biological processes, pathways, and biomarkers of AD, PD, and EP, respectively, suggesting new therapeutic targets for us, deepening our understanding of the mechanisms of neurological diseases, and providing support for future clinical interventions.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Variant of STAG1 Gene and Literature Review.","authors":"Meihua Xie, Liyun Xie, Jianlong Zhuang, Hening Li, Hongxia Zhou, Xiaojuan Yue","doi":"10.1111/ahg.70023","DOIUrl":"https://doi.org/10.1111/ahg.70023","url":null,"abstract":"<p><strong>Objective: </strong>To explore the clinical presentation and genetic etiology of a child with intellectual disability, speech developmental delay, learning difficulties, behavioral stereotype, and obsessive-compulsive disorder, and to identify new variants.</p><p><strong>Methods and results: </strong>In this study, Karyotype and copy number variant sequencing (CNV-seq) were performed to detect chromosome abnormalities in this family. The whole exome sequencing (WES) was performed to investigate additional genetic variants in this family. Minigene array was used to verify whether the novel variant c.1027-2A>G really affected the splicing of STAG1 gene. Chromosomal karyotyping and CNV-seq analysis did not reveal any chromosomal abnormalities. The WES result demonstrated a de novo NM_005862.3:c.1027-2A>G variant in STAG1 gene in the patient. This splicing variant was classified as likely pathogenic based on ACMG/AMP guidelines. Minigene array results showed that the variant could result in the appearance of premature termination codon.</p><p><strong>Conclusion: </strong>Our study identified a novel pathogenic locus, c.1027-2A>G, associated with Intellectual developmental disorder, autosomal dominant 47 (MRD47).</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144939986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prevalence of the Main Human Genetic Variants Related to Resistance to Malaria in a Population of the Colombian Pacific Coast.","authors":"Diana Carolina Ortega, María Paula Arango, Sergio Cañón, Heiber Cárdenas, Ranulfo González, Guillermo Barreto","doi":"10.1111/ahg.70022","DOIUrl":"https://doi.org/10.1111/ahg.70022","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to determine the prevalence of Duffy, HbS, HbC, G6PD, and β-thalassemia variants through molecular characterisation in a representative sample of the population from the urban area of Buenaventura, Colombia.</p><p><strong>Material and methods: </strong>A total of 819 individuals were randomly selected from 12 communities within the city. Molecular analysis was performed using PCR-RFLP and allele-specific PCR. Data were analysed using descriptive statistics, tests of independence, and regression analysis.</p><p><strong>Results: </strong>Frequencies of 3.1%, 2.2%, 72.2%, 2.1%, 2.8%, and 11% were found for the resistance alleles HbS, HbC, Duffy, β-thalassemia-29, β-thalassemia-88 and G6PD, respectively. In addition, adolescents and young adults (13 to 26 years) presented the highest proportion of resistance genotypes. Likewise, the communities of the insular zone of Buenaventura had the highest proportion of resistance genotypes.</p><p><strong>Conclusions: </strong>These findings should be considered by public health and disease prevention authorities, as they highlight specific age groups and communities that may be more susceptible to malaria infection. They also identify groups that may contribute to the persistence and potential increase in the prevalence of haemoglobinopathies in the population over time.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144940026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Centenary Special Issue of the Annals of Human Genetics","authors":"John Armour,&nbsp;Rosemary Ekong","doi":"10.1111/ahg.70018","DOIUrl":"10.1111/ahg.70018","url":null,"abstract":"","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 5","pages":"239-240"},"PeriodicalIF":1.2,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144788108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Determinants of Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer Identified by Whole Exome Sequencing.","authors":"Jelena Peric, Sandra Dragicevic, Marko Miladinov, Aleksandra Djikic Rom, Jasna Bjelanovic, Jelena Kovac, Jovana Despotovic, Tamara Babic, Jelena Ljubicic, Dunja Pavlovic, Jovana Rosic Stojkovic, Ivan Dimitrijevic, Goran Barisic, Velimir Markovic, Aleksandra Nikolic","doi":"10.1111/ahg.70019","DOIUrl":"https://doi.org/10.1111/ahg.70019","url":null,"abstract":"<p><strong>Background: </strong>Neoadjuvant chemoradiotherapy (nCRT) is essential for treating locally advanced rectal cancer (LARC), however response to nCRT varies, and reliable predictors are lacking.</p><p><strong>Methods: </strong>This study used whole exome sequencing analysis to investigate genetic differences between tumors highly responsive and non-responsive to nCRT. Five patients with good response and two patients without response to nCRT were used as a discovery set.</p><p><strong>Results: </strong>The analysis identified 15 InDels and 202 non-synonymous SNVs exclusively present in tumors of non-responders, mainly in genes regulating the cell cycle, adhesion, and migration. In contrast, 9 InDels and 122 non-synonymous SNVs were exclusively present in tumors of good responders, primarily in extracellular matrix remodeling and immunity-related genes. Six variants in transmembrane transporter genes were selected as candidate biomarkers and validated in 33 LARC patients.</p><p><strong>Conclusion: </strong>The results suggest that SLC16A6 rs7222013 and SLC25A2 rs3749780 may serve as potential predictors of poor nCRT response in LARC patients.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygenic Risk Score for Cancer in African Population: A Systematic Review.","authors":"Wafaa M Rashed, Olagunju Abdulrahmon A","doi":"10.1111/ahg.70016","DOIUrl":"https://doi.org/10.1111/ahg.70016","url":null,"abstract":"<p><strong>Purpose: </strong>The aim of this systematic review is to identify all genome-wide association study (GWAS)-based polygenic risk score (PRS) studies (with different PRS approaches) reported in African ancestry populations diagnosed with any type of cancer. Additionally, this review assessed the role of PRS in advancing precision medicine through its clinical utility across different cancer types in African populations.</p><p><strong>Methods: </strong>We searched PubMed from January 2009 to April 2023 and included GWAS-based PRS studies for cancer patients of African genetic ancestry.</p><p><strong>Results: </strong>Among the 33 eligible studies, prostate cancer and breast cancer were the most common types in adults, whereas only one publication reported the risk association of neuroblastoma (a pediatric cancer). The most common PRS approach used was ancestry-specific PRS. Clinical utility of the calculated PRS varies across cancer types, with inconsistent results. Our systematic review found a limited number of PRS studies on cancer patients (adult and pediatric) of African ancestry, and these studies showed less clinical utility compared to those conducted in European ancestry populations.</p><p><strong>Conclusion: </strong>To make PRS clinically actionable for African ancestry populations, it is crucial to increase the number of large-scale, population-specific GWAS, improve the representation of African-ancestry cohorts, and refine PRS models to better reflect the genetic diversity within African populations.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144758973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The History of the Panmictic Population Concept and Its Legacy in Contemporary Population Genetics","authors":"Andy Walton,&nbsp;Alex Aylward,&nbsp;Mark G. Thomas,&nbsp;Adam Rutherford","doi":"10.1111/ahg.70015","DOIUrl":"10.1111/ahg.70015","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> ABSTRACT</h3>\u0000 \u0000 <p>The panmictic population concept is at the heart of population, evolutionary and conservation genetics. However, in nature, true panmictic populations are vanishingly rare. As an idea conceived for modelling evolutionary dynamics, it has been thought that the assumption of panmixia was formalised during the development of the Modern Synthesis. Here, we show that while the idea's longevity is almost certainly due to its mathematical convenience, it became embedded in evolutionary thought much earlier, initially as a way to reconcile long-standing essentialist ideas with the advent of Darwin's theories. Though the principles of essentialism and reversion have been largely rejected, these ideas persist in shaping assumptions made about populations in contemporary genetics research, including how they are conceptualised and sampled. This legacy has important implications for the interpretation of genomic findings in human evolution, conservation and medicine. From an evaluation of this history and its legacy, we contend that while the panmictic population concept has been, and continues to be useful, with the generation of terabytes of genomic data in the 21st century, its utility is likely to diminish as the need for continuous space models grows.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 5","pages":"274-284"},"PeriodicalIF":1.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.70015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expanding the LOXHD1 Mutational Spectrum: A North Indian Case of ARNSHL.","authors":"Pratiksha Chheda, Tavisha Dama, Tanmay Deshpande","doi":"10.1111/ahg.70017","DOIUrl":"https://doi.org/10.1111/ahg.70017","url":null,"abstract":"","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":""},"PeriodicalIF":1.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726876","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Causal Relationships Between Gastroesophageal Reflux Disease and Myocardial Infarction: Insights From Univariable and Multivariable Mendelian Randomization Analyses.","authors":"Xiaoya Zheng, Teng Hu, Tianxiang Fang, Pengpeng Su, Yingsong Wang, Ning Huangfu","doi":"10.1111/ahg.70012","DOIUrl":"https://doi.org/10.1111/ahg.70012","url":null,"abstract":"<p><strong>Background: </strong>Observational studies have indicated that gastroesophageal reflux disease (GERD) is connected to myocardial infarction (MI). Nonetheless, the question of causality in these relationships remains unresolved, given the potential influence of confounding variables. The aim is to study the causal link of GERD with MI and determine whether MI factors have any mediation effects in the causative chain.</p><p><strong>Methods: </strong>GERD (129,080 cases and 473,524 controls) and MI (831,000 individuals) were obtained from the latest genome-wide association study summary-level data. Two-sample Mendelian randomization (MR) analyses were performed to assess the associations of genetically predicted GERD with MI risk. After adjusting for several confounders, multivariable MR was employed to determine the independent impacts of GERD on MI risk. Two-step MR analyses were carried out to investigate the mediating impacts of these modifiable factors in the relationships between GERD and MI.</p><p><strong>Results: </strong>The current univariable MR analysis indicated that GERD was connected to MI (odds ratio [OR] = 1.61; 95% confidence interval [CI]: 1.48-1.76; p = 1.01 × 10^-26), whereas this correlation remained after controlling for body mass index, cigarettes per day, and alcohol consumption. Two-step MR found that several MI-associated risk factors mediated the associations between GERD and MI, with hypertension (mediation proportion: 14.4%) and type-2 diabetes mellitus (12.0%) exhibiting higher mediation proportions among the mediating networks.</p><p><strong>Conclusion: </strong>This study identifies modifiable cardiovascular risk factors that may mediate the GERD-MI association, with hypertension (14.4%) and T2DM (12.0%) identified as the predominant modifiable mediators. These findings highlight the clinical importance of integrated cardiometabolic monitoring in GERD patients, suggesting that targeted management of blood pressure and glycemic control may mitigate MI risk in GERD populations.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e70012"},"PeriodicalIF":1.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}