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.
Methods
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.
Results
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.
Conclusions
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.
背景：遗传性球形红细胞增多症（HS）是一种由先天性红细胞膜缺陷引起的慢性非免疫性溶血性贫血。基因变异可导致HS， SPTB基因变异是其中之一。然而，HS合并胆管结石和极度肝内胆汁淤积作为SPTB基因变异引起的表型很少被讨论，该基因变异的致病机制尚不清楚。方法：收集临床资料，采用高通量测序和Sanger测序进行遗传分析，然后采用Western blot分析揭示基因变异的致病机制。结果：2例患儿因严重黄疸入院，最终确诊为HS合并胆管结石和严重肝内胆汁淤积。经保守治疗后，胆管结石及肝内胆汁淤积症状减轻。在这两个家族中分别鉴定出两个新的SPTB基因杂合变异（NM_001024858.4: c.493_494insTG, p. Q165fs）和（NM_001024858.4: c.1715delT, p. L572X）。Western blot分析显示，这两种致病变异均导致β-spectrin蛋白表达降低。结论：我们在HS合并胆管结石和肝内胆汁淤积的患者中发现了两种新的SPTB变异。此外，我们的研究增强了目前对SPTB变异相关的表型和分子机制的理解。
{"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":"10.1111/ahg.70006","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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 <i>SPTB</i> gene variation is one of them. However, HS with cholangiolithiasis and extremely intrahepatic cholestasis had been rarely discussed as a phenotype caused by <i>SPTB</i> gene variation, and the pathogenic mechanism of this gene variation is still unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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 <i>SPTB</i> 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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>We have identified two novel <i>SPTB</i> variations in HS with cholangiolithiasis and intrahepatic cholestasis. Moreover, our study enhances current understanding of the phenotype and molecular mechanisms associated with <i>SPTB</i> variation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 6","pages":"450-458"},"PeriodicalIF":1.2,"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}
Linlin Liu, Hecheng Zheng, Tiantian Zou, Xiangping Li, Renwu Huang, Lili Qing, Shengjie Nie, Liping Hu
Background
To study the genetic characteristics of X-chromosome short tandem repeats (X-STRs) in the Yunnan Yi ethnic minority.
Methods
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.
Results
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.
Conclusions
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.
{"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":"10.1111/ahg.12602","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>To study the genetic characteristics of X-chromosome short tandem repeats (X-STRs) in the Yunnan Yi ethnic minority.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 6","pages":"446-449"},"PeriodicalIF":1.2,"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}
Yue Chong, Li Xue, Zihe Peng, Zhenlong Wang, Delai Fu, Zhixin Huang, Tie Chong
Background
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).
Methods
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.
Results
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.
Conclusion
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.
背景：炎症已被报道与尿道狭窄相关，但很少有研究报道炎症细胞因子与尿道狭窄之间的因果关系。我们用孟德尔随机化（MR）研究了炎症细胞因子与尿道狭窄之间的因果关系。方法：采用全基因组关联研究（GWAS）对8293名芬兰人和787例尿道狭窄患者41种炎症因子进行双向MR分析。使用逆方差加权（IVW）、加权中位数和模型选择来估计炎症细胞因子与尿道狭窄之间的因果关系。进行多重敏感性分析（包括多效性、异质性和留一检验）来评估MR结果的稳健性和可靠性，随后进行贝叶斯共定位、表型扫描和蛋白质-蛋白质相互作用（PPI）分析。结果：我们发现三种炎症细胞因子（粒细胞集落刺激因子[GCSF]、干细胞生长因子β [SCGFb]和白细胞介素-5 [IL5]）与尿道狭窄之间存在显著的因果关系。GCSF（比值比[OR] = 4.722, 95%可信区间[CI] = 1.367 ~ 16.303, p = 0.014）和SCGFb （OR = 1.209, 95% CI = 1.06 ~ 1.379, p = 0.004）增加尿道狭窄的风险，而IL5降低尿道狭窄的风险（OR = 0.782, 95% CI = 0.626 ~ 0.976, p = 0.029）。反向MR显示炎症因子与尿道狭窄无反向因果关系，与尿道狭窄有显著的因果关系。PPI分析显示，这三种炎症因子与多种纤维化相关基因相互作用：转化生长因子β 1、一氧化氮合酶2和C-X-C基序趋化因子受体3。结论：我们的研究表明炎性细胞因子GCSF、SCGFb和IL5与尿道狭窄有显著相关性，为尿道狭窄的预防和诊断提供了有价值的见解。
{"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":"10.1111/ahg.70002","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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, <i>p</i> = 0.014) and SCGFb (OR = 1.209, 95% CI = 1.06–1.379, <i>p</i> = 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, <i>p</i> = 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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 6","pages":"434-445"},"PeriodicalIF":1.2,"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}
Tinashe Chikowore, Opeyemi Soremekun, Felix P. Chilunga
{"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":"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}
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
Purpose/Introduction
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).
Materials and methods
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.
Results
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.
Conclusion
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.
{"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":"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}
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.
Methodology
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.
Results
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.
Conclusion
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.
{"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":"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}
John Henry McDermott, Videha Sharma, Jessica Keen, William Gerard Newman
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.
{"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":"10.1111/ahg.12601","url":null,"abstract":"<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":"89 5","pages":"398-405"},"PeriodicalIF":1.2,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/ahg.12601","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
Objective
We aimed to elucidate the epigenetic alterations in ALK and EGFR genes in NSCLC patients.
Methods
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.
Results
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).
Conclusion
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.
{"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":"10.1111/ahg.12597","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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 (<i>ALK</i>) and epidermal growth factor receptor <i>(EGFR)</i> 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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>We aimed to elucidate the epigenetic alterations in <i>ALK</i> and <i>EGFR</i> genes in NSCLC patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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 <i>EGFR</i> and <i>ALK</i> genes promoter was examined by bioinformatics tools such as UCSC, GTEx portal, and iMETHYL servers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There was a significant difference in the methylation pattern of <i>EGFR</i> (Region II) (<i>p</i> = 0.02) between the case and control groups and also that patients who were methylated in this region of the <i>EGFR</i> promoter had a higher stage than non-methylated patients, which was statistically significant (<i>p</i> = 0.03).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We analyzed methylation changes of <i>EGFR</i> and <i>ALK</i> genes in patients suffering from NSCLC. Alteration of <i>EGFR</i> gene methylation pattern could play an important role in the pathogenesis of NSCLC. To delineate the potential role of <i>ALK</i> somatic alterations, further investigations are warranted.</p>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 6","pages":"425-433"},"PeriodicalIF":1.2,"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}
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.
Methods
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.
Results
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).
Conclusion
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.
观察性研究表明系统性红斑狼疮（SLE）与中风之间存在关联。然而，这种关联的遗传因果关系仍然不完全清楚。本研究利用孟德尔随机化（MR）研究SLE与卒中风险之间的潜在因果关系。方法：我们使用了来自最大的全基因组关联研究（GWASs）的SLE和卒中的汇总统计数据。主要MR分析采用逆方差加权（IVW）方法，补充分析采用MR- egger和加权中位数（WM）方法。另外进行敏感性和异质性分析以确保结果的稳健性。结果：IVW分析显示SLE与缺血性卒中风险增加之间存在潜在的因果关系（优势比[OR] = 1.039, 95%可信区间[CI]: 1.014-1.066, p = 0.002）。然而，SLE与大动脉卒中（OR: 1.024, 95% CI: 0.975-1.076, p = 0.326）、心栓塞性卒中（OR: 1.014, 95% CI: 0.948-1.085, p = 0.667）、小血管卒中（OR: 0.983, 95% CI: 0.942-1.026, p = 0.458）、脑出血（OR: 0.992, 95% CI: 0.934-1.054, p = 0.804）之间没有显著的遗传关联。结论：这项MR研究提供了支持SLE和缺血性卒中风险增加之间因果关系的遗传证据。这些发现强调了积极监测和预防缺血性卒中对减轻SLE患者脑血管合并症的重要性。考虑到种族特异性基因组异质性的存在，在解释这些结果时需要谨慎。
{"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":"10.1111/ahg.12599","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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, <i>p</i> = 0.002). However, no significant genetic association was observed between SLE and large artery stroke (OR: 1.024, 95% CI: 0.975–1.076, <i>p</i> = 0.326), cardioembolic stroke (OR: 1.014, 95% CI: 0.948–1.085, <i>p</i> = 0.667), small vessel stroke (OR: 0.983, 95% CI: 0.942–1.026, <i>p</i> = 0.458), or intracerebral hemorrhage (OR: 0.992, 95% CI: 0.934–1.054, <i>p</i> = 0.804).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 6","pages":"407-414"},"PeriodicalIF":1.2,"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}
Qi Zhao, Xiangfei Sun, Ying Jiang, Qi Liu, Di Zhang
Background
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.
Methods and materials
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.
Results
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.
Conclusion
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.
{"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":"10.1111/ahg.12600","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and materials</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>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>\u0000 </section>\u0000 </div>","PeriodicalId":8085,"journal":{"name":"Annals of Human Genetics","volume":"89 6","pages":"415-424"},"PeriodicalIF":1.2,"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}
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