Annals of Human Genetics最新文献

{"title":"Genetics and Genomics in Health and Disease: A Focus on African Populations.","authors":"Tinashe Chikowore, Opeyemi Soremekun, Felix P Chilunga","doi":"10.1111/ahg.12603","DOIUrl":"https://doi.org/10.1111/ahg.12603","url":null,"abstract":"","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12603"},"PeriodicalIF":1.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075526","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":"First Insights Into the Phenotype and Genotype of Inherited Retinal Disorders in the Democratic Republic of Congo (DRC).","authors":"Nadine Nsiangani Lusambo, Patrick Fuanani, Gerrye Mubungu, Prince Makay, Mamy Ngole, Georgette Ngweme, François-Pantaléon Kajingulu, Denise Perry, Akanchha Kesari, Giacomo Calzetti, Carlo Rivolta, Koenraad Devriendt, Prosper Lukusa Tshilobo, Erin Thorpe, Ryan J Taft, Aimé Lumaka","doi":"10.1111/ahg.12604","DOIUrl":"https://doi.org/10.1111/ahg.12604","url":null,"abstract":"<p><strong>Purpose/introduction: </strong>Inherited retinal disorders (IRD) are a highly heterogeneous group of retinal diseases often characterized by progressive bilateral degeneration of rod and cone photoreceptors. Very little information is available on the genotype and phenotype of IRD in Central Africa. We investigated genetic causes of IRD in a well-characterized group of patients from the Democratic Republic of Congo (DRC).</p><p><strong>Materials and methods: </strong>Ten patients, from eight families, with a clinical diagnosis of IRD in Kinshasa (DRC) were investigated. Each patient underwent general, dysmorphological and ophthalmic examination. DNA was extracted in the Centre for Human Genetics of the University of Kinshasa and clinical Whole Genome Sequencing (cWGS) was performed at Illumina Clinical Service Laboratory through the Illumina iHope program.</p><p><strong>Results: </strong>The eight probands comprised 4 males and 4 females aged between 17.5 and 76 years. Nyctalopia and reduced visual acuity were the main complaints. All patients had normal hearing and were nondysmorphic. Fundus examination revealed bone-spicule pigment in all patients. Twelve plausible causal variants were identified in six genes: ADAM9, RP1, MERTK, CYP4V2, USH2A, and IFT140. One SNV and one intragenic CNV were novel. The SNV was assumed to be in trans with an intragenic SNV in three families, consistent with the well-known autosomal recessive inheritance for IRD in those genes.</p><p><strong>Conclusion: </strong>We report on the first cohort of African IRD patients investigated by cWGS. Our results indicate that also in Congolese patients, the spectrum of causal genes is broad and we expand the spectrum of causal variants in known IRD genes. This report demonstrates the power of cWGS, especially for genetically heterogeneous diseases.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12604"},"PeriodicalIF":1.0,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075524","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":"Automated Evaluation of D-Score for Facial Dysmorphism Analysis in Central African Children With Developmental Disorders.","authors":"Prince Makay, Gerrye Mubungu, Prosper Lukusa Tshilobo, Koenraad Devriendt, Aimé Lumaka","doi":"10.1111/ahg.12598","DOIUrl":"https://doi.org/10.1111/ahg.12598","url":null,"abstract":"<p><strong>Introduction: </strong>Dysmorphism is an important characteristic, but its evaluation is largely subjective. A good clinical assessment (dysmorphism) can facilitate a more accurate and efficient diagnosis. We therefore evaluated an automated artificial intelligence tool for facial dysmorphism, D-score, available in Face2Gene.</p><p><strong>Methodology: </strong>We evaluated 2D frontal facial photographs of pediatric individuals with a developmental delay/intellectual disability from the Democratic Republic of Congo (144) and Belgium (137) as being dysmorphic or not, first clinically, and second by D-score analysis. We determined the performance of D-score by calculating sensitivity, specificity, positive predictive value, negative predictive value, F1-score and Cohen's Kappa (κ). We also evaluated the effects of sex, age, and ethnicity on D-Score.</p><p><strong>Results: </strong>Of the 144 Congolese children, 69 (47.9%) were dysmorphic, compared to 40.9% in the Belgian cohort. D-score in the Congolese cohort showed a sensitivity of 85.5%, a specificity of 68%, a PPV of 71.1%, and an NPV of 83.6%. The F1-score was 0.78. The k was 0.531 (0.395-0.666) with a standard error of 0.069, p = 0.000. In the Belgian cohort, sensitivity was 71.4%, specificity 71.6%, PPV 63.5%, and NPV 78.4%. The F1-score was 0.672. The k was 0.422 (0.270-0.574) with a standard error of 0.078, p = 0.000. There was no statistically significant difference depending on age and sex.</p><p><strong>Conclusion: </strong>D-score is not replacing the gestalt facial evaluation, but it is promising to be used in clinical practice as a supplementary tool for precision in the dysmorphism evaluation, especially when dealing with rare or less common genetic conditions.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12598"},"PeriodicalIF":1.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144075520","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":"Embedding Pharmacogenetics Into Clinical Practice to Improve Patient Outcomes.","authors":"John Henry McDermott, Videha Sharma, Jessica Keen, William Gerard Newman","doi":"10.1111/ahg.12601","DOIUrl":"https://doi.org/10.1111/ahg.12601","url":null,"abstract":"<p><p>Pharmacogenomics, the use of germline genomic data to guide prescription to improve effective and safer medication, holds promise as a clinical intervention. To date in most health systems, there has been limited uptake of pharmacogenomic testing confined to a few single drug-gene associations. Here, we describe the current reactive model of single gene testing and the potential for this to change to a pre-emptive panel or genome-based approach. For this change to occur, three major challenges need to be addressed-the pharmacogenomic testing approach, the digital and data integration, and service delivery models. We explore some of the potential solutions and how pharmacogenomics can be integrated into routine care at scale for patient benefit.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12601"},"PeriodicalIF":1.0,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143952490","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":"Significant Association Among the Epigenetic Alterations in EGFR and ALK Genes and Non-Small Cell Lung Cancer: A Prospective Emerging Molecular Biomarker.","authors":"Fatemeh Sadri, Mohsen Alipour, Azim Nejatizadeh","doi":"10.1111/ahg.12597","DOIUrl":"https://doi.org/10.1111/ahg.12597","url":null,"abstract":"<p><strong>Background: </strong>Non-small cell lung cancer (NSCLC) is increasingly recognized as a heterogeneous set of diseases at the molecular level, and these differences likely could drive therapeutic decision-making. The anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) genes are two key oncogenes of tyrosine kinase that their expression is increased in lung cancer and activates their downstream signaling cascade. These two genes have been identified as therapeutic targets, and targeted therapies for these genes by tyrosine kinase inhibitors have been approved by the FDA.</p><p><strong>Objective: </strong>We aimed to elucidate the epigenetic alterations in ALK and EGFR genes in NSCLC patients.</p><p><strong>Methods: </strong>Fifty tissue samples of the paired NSCLC samples and adjacent normal tissues were evaluated by methylation-specific polymerase chain reaction (MS-PCR). Subsequently, the methylation status of the EGFR and ALK genes promoter was examined by bioinformatics tools such as UCSC, GTEx portal, and iMETHYL servers.</p><p><strong>Results: </strong>There was a significant difference in the methylation pattern of EGFR (Region II) (p = 0.02) between the case and control groups and also that patients who were methylated in this region of the EGFR promoter had a higher stage than non-methylated patients, which was statistically significant (p = 0.03).</p><p><strong>Conclusion: </strong>We analyzed methylation changes of EGFR and ALK genes in patients suffering from NSCLC. Alteration of EGFR gene methylation pattern could play an important role in the pathogenesis of NSCLC. To delineate the potential role of ALK somatic alterations, further investigations are warranted.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12597"},"PeriodicalIF":1.0,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958418","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":"Exploring the Causal Link Between Systemic Lupus Erythematosus and Stroke Risk Through Mendelian Randomization Study.","authors":"Lingwen Zhang, Yaxin Li, Wenhui Fan, Hua Xue","doi":"10.1111/ahg.12599","DOIUrl":"https://doi.org/10.1111/ahg.12599","url":null,"abstract":"<p><strong>Introduction: </strong>Observational studies have indicated an association between systemic lupus erythematosus (SLE) and stroke. However, the genetic causality of this association remains incompletely understood. This study utilizes Mendelian randomization (MR) to investigate the potential causal relationship between SLE and the risk of stroke.</p><p><strong>Methods: </strong>We utilized summary-level statistics data from the largest genome-wide association studies (GWASs) on SLE and stroke. The primary MR analysis was conducted using the inverse variance weighted (IVW) method, with supplementary analyses performed using the MR-Egger and weighted median (WM) methods. Sensitivity and heterogeneity analyses were additionally performed to ensure the robustness of the results.</p><p><strong>Results: </strong>The IVW analysis indicated a potential causal relationship between SLE and an increased risk of any ischemic stroke (odds ratio [OR] = 1.039, 95% confidence interval [CI]: 1.014-1.066, p = 0.002). However, no significant genetic association was observed between SLE and large artery stroke (OR: 1.024, 95% CI: 0.975-1.076, p = 0.326), cardioembolic stroke (OR: 1.014, 95% CI: 0.948-1.085, p = 0.667), small vessel stroke (OR: 0.983, 95% CI: 0.942-1.026, p = 0.458), or intracerebral hemorrhage (OR: 0.992, 95% CI: 0.934-1.054, p = 0.804).</p><p><strong>Conclusion: </strong>This MR study provides genetic evidence supporting a causal association between SLE and an increased risk of ischemic stroke. These findings underscore the significance of active monitoring and prevention of ischemic stroke to mitigate cerebrovascular comorbidities in SLE patients. Given the existence of ethnic-specific genomic heterogeneity, caution is warranted in interpreting these results.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12599"},"PeriodicalIF":1.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061928","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":"Mendelian Randomization Identifies Putative Aging-Related Causal Genes With Diagnostic Potential in Ulcerative Colitis.","authors":"Qi Zhao, Xiangfei Sun, Ying Jiang, Qi Liu, Di Zhang","doi":"10.1111/ahg.12600","DOIUrl":"https://doi.org/10.1111/ahg.12600","url":null,"abstract":"<p><strong>Background: </strong>Aging-related immunosenescence increases the risk of ulcerative colitis (UC), and investigating aging-related causal genes in UC patients may aid in deciphering the molecular pathophysiology of UC. This study aims to identify aging-related causal genes and explore their diagnostic value and underlying mechanisms in UC.</p><p><strong>Methods and materials: </strong>Colonic transcriptome data, aging-related genes, genome-wide association studies (GWAS) data, and cis-expression quantitative trait loci (cis-eQTL) data were collected from databases. Aging-related differentially expressed genes (ARDEGs) were identified, and functional enrichment analysis was performed. Summary-data-based Mendelian randomization (SMR) analysis and validation were performed to identify putative aging-related causal genes (PARCGs). The expression levels and diagnostic efficacies of the PARCGs were evaluated and validated. Their correlations with immune infiltration were explored.</p><p><strong>Results: </strong>371 ARDEGs were identified that were mainly involved in biological functions related to immunity, inflammation, and senescence. Through SMR, five genes (IRF1, CTSB, IL24, ME2, ERBB2) were first selected as latent aging-related causal genes (LARCGs), and their expression levels were causally correlated with the risk of UC (IRF1, OR: 3.23, 95% CI: 1.80-5.77; CTSB, OR: 1.30, 95% CI: 1.14-1.47; IL24, OR: 1.66, 95% CI: 1.24-2.22; ME2, OR: 0.75, 95% CI: 0.63-0.89; ERBB2, OR: 0.21, 95% CI: 0.10-0.45). By replicating SMR analysis using the two additional UC GWAS data, three PARCGs (IRF1, ME2, ERBB2) were further determined. IRF1 was upregulated, while ME2 and ERBB2 were downregulated in UC, and all three PARCGs showed diagnostic potential for UC. Furthermore, correlation analysis revealed multiple correlations between the PARCGs and immune cells.</p><p><strong>Conclusion: </strong>We identified three aging-related genes (IRF1, ME2, ERBB2) through SMR for the first time that are causally correlated to the risk of UC. Further analysis revealed their diagnostic potential and explored their correlation with immune infiltration in UC.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12600"},"PeriodicalIF":1.0,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143962600","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":"Opportunities and Challenges of Population Pharmacogenomics.","authors":"Yitian Zhou, Yoomi Park, Mahamadou D Camara, Volker M Lauschke","doi":"10.1111/ahg.12596","DOIUrl":"https://doi.org/10.1111/ahg.12596","url":null,"abstract":"<p><p>Pharmacological responses can vary significantly among patients from different ethnogeographic backgrounds. This variability can, at least in part, be attributed to population-specific genetic patterns in genes involved in drug absorption, distribution, metabolism, and excretion, as well as in genes associated with drug-induced toxicity. Identification of such ethnogeographic variability is thus crucial for the optimization of precise population-specific drug treatments. In this review, we summarize the current knowledge about the clinically actionable pharmacogenetic diversity of genes involved in drug metabolism (CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, TPMT, NUDT15, UGT1A1, and NAT2), drug-induced hypersensitivity reactions (HLA-A and HLA-B), and drug-induced acute hemolytic anemia (G6PD). We highlight risk populations with distinct allele frequencies and discuss implications for the customization of treatment. Subsequently, we discuss key challenges and opportunities in population pharmacogenomics, including the importance of considering distinct allele frequency patterns in indigenous or founder populations, interpreting pharmacogenomic response in admixed populations, addressing the investigation bias of the pharmacogenomic literature, and difficulties in including rare and population-specific variants into drug response predictions. The information provided here underscores the critical role of population pharmacogenomics in refining pharmacological treatment strategies and aspires to provide further guidance to maximize the benefits of precision medicine across populations.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12596"},"PeriodicalIF":1.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762615","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 the Familial Hypercholesterolaemia Phenotype.","authors":"Steve Eric Humphries, Marta Futema","doi":"10.1111/ahg.12594","DOIUrl":"https://doi.org/10.1111/ahg.12594","url":null,"abstract":"<p><p>Individuals with familial hypercholesterolaemia (FH) have severely elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C) from birth and as a consequence have an elevated morbidity and mortality due to the development of coronary heart disease (CHD). Monogenic FH can be caused by carrying a single copy of a pathogenic variant in any of four genes (LDLR/APOB/PCSK9/APOE), which are all involved in the clearance of LDL-C from the blood by the liver. FH is one of the most common inherited disorders, with an estimated prevalence of carriers of around 1/280 individuals in most populations and ancestry groups. However, such variants can be found usually only in 20%-30% of clinically FH subjects, and in the majority of the no-variant individuals, the phenotype is most likely explained by the inheritance of a greater-than-average number of common variants of small effect, with such individuals better given the diagnosis of 'polygenic hypercholesterolaemia'. Also, in a proportion of no-variant subjects who meet the clinical criteria, the most likely explanation is due to overproduction of Lp(a) which is an LDL-C particle with a bound copy of the 'little-a' protein. Here, we review the research that has elucidated the genetic architecture of the FH phenotype and discuss recent studies and future prospects of finding additional genes where variants can cause FH.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12594"},"PeriodicalIF":1.0,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762593","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":"Novel CTSA Variant Identified in a Thai Family With Late-Infantile Galactosialidosis","authors":"Lukana Ngiwsara,&nbsp;Dhachdanai Dhachpramuk,&nbsp;Phannee Sawangareetrakul,&nbsp;Sherry Vongphit,&nbsp;Punchama Pacharn,&nbsp;Jisnuson Svasti,&nbsp;Nithiwat Vatanavicharn","doi":"10.1111/ahg.12595","DOIUrl":"10.1111/ahg.12595","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> ABSTRACT</h3>\u0000 \u0000 <p>Galactosialidosis (GS) is a rare lysosomal storage disease (LSD) with variable onset caused by a defect in protective protein/cathepsin A (PPCA) encoded by the <i>CTSA</i> gene. The late-infantile onset is characterized by developmental delay, visceromegaly, coarse facies, and cherry-red macula. We report cases of late-infantile GS in a Thai-Lahu family, with affected members initially presenting with recurrent infections due to T-cell defects. The clinical features of LSD and cherry-red macula led us to perform lysosomal enzyme assays, which showed undetectable activity of PPCA. A novel homozygous missense <i>CTSA</i> variant (NM_000308.4): c.1307<i>A </i>&gt; <i>G</i> (p.Gln436Arg) was identified in affected individuals. In vitro functional analysis suggested that the variant may impair the dimerization process of PPCA, potentially disrupting proper protein maturation or function and leading to significantly reduced PPCA activity. Exome sequencing did not reveal any variants in other genes associated with primary immunodeficiencies. To date, our cases represent the first reported patients with GS and T-cell defects. Our study broadened the clinical and genotype spectrum of this rare disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 2-3","pages":"126-131"},"PeriodicalIF":1.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12595","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750836","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}