Annals of Human Genetics最新文献

{"title":"Recent Statistical Innovations in Human Genetics.","authors":"David J Balding, Doug Speed","doi":"10.1111/ahg.12606","DOIUrl":"https://doi.org/10.1111/ahg.12606","url":null,"abstract":"<p><p>We review three areas of human genetics that have been developed in the past few decades, in which statistical innovation has made a crucial contribution with recent important advances and the potential for further rapid progress. The first topic is the development of mathematical models for the genealogy underlying samples of genome-wide genetic data. Coalescent theory emerged in the 1980s, leaped ahead in the past decade and is now burgeoning into new application areas in population, evolutionary and medical genetics. The second is the development of statistical methods for genome-wide association studies which has made great strides over two decades, including exciting recent developments for association testing based on coalescent theory and improved methods for trait prediction. Finally, we review the statistical ideas that helped resolve the controversies surrounding the introduction of forensic DNA profiling in the early 1990s. Big advances in interpretation of the predominant autosomal DNA profiles have set a benchmark for other areas of forensic science, but the statistical assessment of uniparentally inherited profiles (derived from the mitochondrial DNA or the Y chromosome) remains unsatisfactory.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12606"},"PeriodicalIF":1.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511471","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 SPTB Variations Cause Hereditary Spherocytosis With Cholangiolithiasis and Severe Intrahepatic Cholestasis.","authors":"Lin-Lin Li, Sadik Ali, Qiong Bin","doi":"10.1111/ahg.70006","DOIUrl":"https://doi.org/10.1111/ahg.70006","url":null,"abstract":"<p><strong>Background: </strong>Hereditary spherocytosis (HS) is a chronic non-immune hemolytic anemia caused by congenital defects in the erythrocyte membrane. Gene variations can lead to HS, and the SPTB gene variation is one of them. However, HS with cholangiolithiasis and extremely intrahepatic cholestasis had been rarely discussed as a phenotype caused by SPTB gene variation, and the pathogenic mechanism of this gene variation is still unclear.</p><p><strong>Methods: </strong>Clinical data were collected, genetic analysis was carried out by high throughput sequencing and Sanger sequencing, and then pathogenic mechanism of gene variation was revealed by Western blot analysis.</p><p><strong>Results: </strong>Two children were admitted because of severe jaundice and finally confirmed as HS complicated with cholangiolithiasis and severe intrahepatic cholestasis. After conservative treatments, symptoms of cholangiolithiasis and intrahepatic cholestasis relieved. Respectively, two novel heterozygous variations of SPTB gene, (NM_001024858.4: c.493_494insTG, p. Q165fs) and (NM_001024858.4: c.1715delT, p. L572X), were identified in these two families. Western blot analysis revealed that these two pathogenic variations all cause decreased protein expression of β-spectrin.</p><p><strong>Conclusions: </strong>We have identified two novel SPTB variations in HS with cholangiolithiasis and intrahepatic cholestasis. Moreover, our study enhances current understanding of the phenotype and molecular mechanisms associated with SPTB variation.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e70006"},"PeriodicalIF":1.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473891","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 Polymorphisms of 16 X-STR Loci in the Yi Ethnic Minority of Chuxiong Yi Autonomous Prefecture in Yunnan Province in China.","authors":"Linlin Liu, Hecheng Zheng, Tiantian Zou, Xiangping Li, Renwu Huang, Lili Qing, Shengjie Nie, Liping Hu","doi":"10.1111/ahg.12602","DOIUrl":"https://doi.org/10.1111/ahg.12602","url":null,"abstract":"<p><strong>Background: </strong>To study the genetic characteristics of X-chromosome short tandem repeats (X-STRs) in the Yunnan Yi ethnic minority.</p><p><strong>Methods: </strong>We analyzed the allele frequencies and forensic parameters for 16 X-STR loci in 432 unrelated Yi individuals (206 males and 226 females) in Chuxiong Yi Autonomous Prefecture, Yunnan Province.</p><p><strong>Results: </strong>A total of 130 alleles were detected. Except for DXS6800, the other loci are highly polymorphic in the Yunnan Yi ethnicity. The combined values of discrimination for males (PDM) and females (PDF) were 0.999999999968561 and 0.999999999999993, respectively, which can be used for forensic medical identification and genetic studies. On the basis of the results of population comparison, there seems to be a relatively close evolutionary relationship between adjacent populations and different ethnic groups in the same region.</p><p><strong>Conclusions: </strong>This study contributes to X-chromosome genetic polymorphism data for the Yunnan Yi ethnicity and further enriches reference materials on the Chinese Yi ethnic minority.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e12602"},"PeriodicalIF":1.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309470","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 Effects of Inflammatory Cytokines on Urethral Stricture Disease: A Bidirectional Mendelian Randomization Study.","authors":"Yue Chong, Li Xue, Zihe Peng, Zhenlong Wang, Delai Fu, Zhixin Huang, Tie Chong","doi":"10.1111/ahg.70002","DOIUrl":"https://doi.org/10.1111/ahg.70002","url":null,"abstract":"<p><strong>Background: </strong>Inflammation has been reported to be associated with urethral stricture, whereas rarely any studies have reported the causal relationship between inflammatory cytokines and urethral stricture. We investigated the causal effects between inflammatory cytokines and urethral stricture with Mendelian randomization (MR).</p><p><strong>Methods: </strong>Genome-wide association study (GWAS) summary statistics on 41 inflammatory cytokines from 8293 Finns and 787 patients with urethral stricture were included for bidirectional MR analysis. The causality between inflammatory cytokines and urethral stricture was estimated using inverse variance weighting (IVW), weighted median, and model selection. Multiple sensitivity analyses (including pleiotropy, heterogeneity, and leave-one-out tests) were performed to evaluate the robustness and dependability of the MR results, followed by Bayesian colocalization, phenotype scanning, and protein-protein interaction (PPI) analysis.</p><p><strong>Results: </strong>We identified a significant causal relationship between three inflammatory cytokines (granulocyte colony-stimulating factor [GCSF], stem cell growth factor beta [SCGFb], and interleukin-5 [IL5]) and urethral stricture. GCSF (odds ratio [OR] = 4.722, 95% confidence interval [CI] = 1.367-16.303, p = 0.014) and SCGFb (OR = 1.209, 95% CI = 1.06-1.379, p = 0.004) increased the risk of urethral stricture, whereas IL5 decreased the risk of urethral stricture (OR = 0.782, 95% CI = 0.626-0.976, p = 0.029). Reverse MR showed no reverse causality between inflammatory cytokines, with significant causality and urethral stricture. PPI analysis showed that the three inflammatory cytokines interacted with multiple fibrosis-related genes: transforming growth factor beta 1, nitric oxide synthase 2, and C-X-C motif chemokine receptor 3.</p><p><strong>Conclusion: </strong>Our study demonstrated that the inflammatory cytokines GCSF, SCGFb, and IL5 are significantly associated with urethral stricture, providing valuable insights for the prevention and diagnosis of urethral stricture.</p>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":" ","pages":"e70002"},"PeriodicalIF":1.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257247","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":"Genetics and Genomics in Health and Disease: A Focus on African Populations","authors":"Tinashe Chikowore,&nbsp;Opeyemi Soremekun,&nbsp;Felix P. Chilunga","doi":"10.1111/ahg.12603","DOIUrl":"10.1111/ahg.12603","url":null,"abstract":"","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 4","pages":"133-134"},"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,&nbsp;Patrick Fuanani,&nbsp;Gerrye Mubungu,&nbsp;Prince Makay,&nbsp;Mamy Ngole,&nbsp;Georgette Ngweme,&nbsp;François-Pantaléon Kajingulu,&nbsp;Denise Perry,&nbsp;Akanchha Kesari,&nbsp;Giacomo Calzetti,&nbsp;Carlo Rivolta,&nbsp;Koenraad Devriendt,&nbsp;Prosper Lukusa Tshilobo,&nbsp;Erin Thorpe,&nbsp;Ryan J. Taft,&nbsp;Aimé Lumaka","doi":"10.1111/ahg.12604","DOIUrl":"10.1111/ahg.12604","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose/Introduction</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Materials and methods</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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: <i>ADAM9</i>, <i>RP1</i>, <i>MERTK</i>, <i>CYP4V2</i>, <i>USH2A</i>, and <i>IFT140</i>. One SNV and one intragenic CNV were novel. The SNV was assumed to be in <i>trans</i> with an intragenic SNV in three families, consistent with the well-known autosomal recessive inheritance for IRD in those genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 4","pages":"141-148"},"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,&nbsp;Gerrye Mubungu,&nbsp;Prosper Lukusa Tshilobo,&nbsp;Koenraad Devriendt,&nbsp;Aimé Lumaka","doi":"10.1111/ahg.12598","DOIUrl":"10.1111/ahg.12598","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methodology</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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, <i>p</i> = 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, <i>p</i> = 0.000. There was no statistically significant difference depending on age and sex.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 4","pages":"228-234"},"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}