Human Genetics最新文献_第3页

Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans. frizzled 类受体 5 的同基因低态突变会导致人类眼部黑瘤伴小角膜综合征。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-12-01 Epub Date: 2024-11-06 DOI: 10.1007/s00439-024-02712-y

Vianney Cortés-González, Miguel Rodriguez-Morales, Paris Ataliotis, Claudine Mayer, Julie Plaisancié, Nicolas Chassaing, Hane Lee, Jean-Michel Rozet, Florencia Cavodeassi, Lucas Fares Taie

{"title":"Homozygosity for a hypomorphic mutation in frizzled class receptor 5 causes syndromic ocular coloboma with microcornea in humans.","authors":"Vianney Cortés-González, Miguel Rodriguez-Morales, Paris Ataliotis, Claudine Mayer, Julie Plaisancié, Nicolas Chassaing, Hane Lee, Jean-Michel Rozet, Florencia Cavodeassi, Lucas Fares Taie","doi":"10.1007/s00439-024-02712-y","DOIUrl":"10.1007/s00439-024-02712-y","url":null,"abstract":"Ocular coloboma (OC) is a congenital disorder caused by the incomplete closure of the embryonic ocular fissure. OC can present as a simple anomaly or, in more complex forms, be associated with additional ocular abnormalities. It can occur in isolation or as part of a broader syndrome, exhibiting considerable genetic heterogeneity. Diagnostic yield for OC remains below 30%, indicating the need for further genetic exploration. Mutations in the Wnt receptor FZD5, which is expressed throughout eye development, have been linked to both isolated and complex forms of coloboma. These mutations often result in a dominant-negative effect, where the mutated FZD5 protein disrupts WNT signaling by sequestering WNT ligands. Here, we describe a case of syndromic bilateral OC with additional features such as microcornea, bone developmental anomalies, and mild intellectual disability. Whole exome sequencing revealed a homozygous rare missense variant in FZD5. Consistent with a loss-of-function effect, overexpressing of fzd5 mRNA harboring the missense variant in zebrafish embryos does not influence embryonic development, whereas overexpression of wild-type fzd5 mRNA results in body axis duplications. However, in vitro TOPFlash assays revealed that the missense variant only caused partial loss-of-function, behaving as a hypomorphic mutation. We further showed that the mutant protein still localized to the cell membrane and maintained proper conformation when modeled in silico, suggesting that the impairment lies in signal transduction. This hypothesis is further supported by the fact that the variant affects a highly conserved amino acid known to be crucial for protein-protein interactions.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1509-1521"},"PeriodicalIF":3.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interpreting the actionable clinical role of rare variants associated with short QT syndrome. 解读与短 QT 综合征相关的罕见变异的可操作临床作用。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-12-01 Epub Date: 2024-11-06 DOI: 10.1007/s00439-024-02713-x

Estefanía Martínez-Barrios, Andrea Greco, José Cruzalegui, Sergi Cesar, Nuria Díez-Escuté, Patricia Cerralbo, Fredy Chipa, Irene Zschaeck, Leonel Slanovic, Alipio Mangas, Rocío Toro, Josep Brugada, Georgia Sarquella-Brugada, Oscar Campuzano

{"title":"Interpreting the actionable clinical role of rare variants associated with short QT syndrome.","authors":"Estefanía Martínez-Barrios, Andrea Greco, José Cruzalegui, Sergi Cesar, Nuria Díez-Escuté, Patricia Cerralbo, Fredy Chipa, Irene Zschaeck, Leonel Slanovic, Alipio Mangas, Rocío Toro, Josep Brugada, Georgia Sarquella-Brugada, Oscar Campuzano","doi":"10.1007/s00439-024-02713-x","DOIUrl":"10.1007/s00439-024-02713-x","url":null,"abstract":"Genetic testing is recommended in the diagnosis of short QT syndrome. This rare inherited lethal entity is characterized by structural normal hearts with short QT intervals in the electrocardiogram. Few families diagnosed with this arrhythmogenic disease have been reported worldwide so far, impeding a comprehensive understanding of this syndrome. Unraveling the origin of the disease helps to the early identification of genetic carriers at risk. However, only rare variants with a definite deleterious role should be actionable in clinical practice. Our aim was to perform a comprehensive update and reinterpretation, according to the American College of Medical Genetics and Genomics recommendations of all rare variants currently associated with short QT syndrome. We identified 34 rare variants. Reanalysis showed that only nine variants played a deleterious role associated with a definite short QT syndrome phenotype. These variants were located in the four main genes: KCNQ1, KCNH2, KCNJ2 or SLC4A3. Additional rare variants located in other genes were associated with other conditions with phenotypic shortened QT intervals, but not definite diagnosis of short QT syndrome. Periodically updating of rare variants, especially those previously classified as unknown, helps to clarify the role of rare variants and translate genetic data into clinical practice.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1499-1508"},"PeriodicalIF":3.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Germline copy number variants and endometrial cancer risk. 基因拷贝数变异与子宫内膜癌风险。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-12-01 Epub Date: 2024-11-04 DOI: 10.1007/s00439-024-02707-9

Cassie E Stylianou, George A R Wiggins, Vanessa L Lau, Joe Dennis, Andrew N Shelling, Michelle Wilson, Peter Sykes, Frederic Amant, Daniela Annibali, Wout De Wispelaere, Douglas F Easton, Peter A Fasching, Dylan M Glubb, Ellen L Goode, Diether Lambrechts, Paul D P Pharoah, Rodney J Scott, Emma Tham, Ian Tomlinson, Manjeet K Bolla, Fergus J Couch, Kamila Czene, Thilo Dörk, Alison M Dunning, Olivia Fletcher, Montserrat García-Closas, Reiner Hoppe, Helena Jernström, Rudolf Kaaks, Kyriaki Michailidou, Nadia Obi, Melissa C Southey, Jennifer Stone, Qin Wang, Amanda B Spurdle, Tracy A O'Mara, John Pearson, Logan C Walker

{"title":"Germline copy number variants and endometrial cancer risk.","authors":"Cassie E Stylianou, George A R Wiggins, Vanessa L Lau, Joe Dennis, Andrew N Shelling, Michelle Wilson, Peter Sykes, Frederic Amant, Daniela Annibali, Wout De Wispelaere, Douglas F Easton, Peter A Fasching, Dylan M Glubb, Ellen L Goode, Diether Lambrechts, Paul D P Pharoah, Rodney J Scott, Emma Tham, Ian Tomlinson, Manjeet K Bolla, Fergus J Couch, Kamila Czene, Thilo Dörk, Alison M Dunning, Olivia Fletcher, Montserrat García-Closas, Reiner Hoppe, Helena Jernström, Rudolf Kaaks, Kyriaki Michailidou, Nadia Obi, Melissa C Southey, Jennifer Stone, Qin Wang, Amanda B Spurdle, Tracy A O'Mara, John Pearson, Logan C Walker","doi":"10.1007/s00439-024-02707-9","DOIUrl":"10.1007/s00439-024-02707-9","url":null,"abstract":"Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10-63). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p < 0.01) with endometrial cancer risk. Pathway analysis of the candidate loci revealed an enrichment of genes involved in the 16p11.2 proximal deletion syndrome, driven by a large recurrent deletion (chr16:29,595,483-30,159,693) identified in 0.15% of endometrial cancer cases and 0.02% of control participants. Together, these data provide evidence that rare copy number variants have a role in endometrial cancer susceptibility and that the proximal 16p11.2 BP4-BP5 region contains 25 candidate risk gene(s) that warrant further analysis to better understand their role in human disease.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1481-1498"},"PeriodicalIF":3.8,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11576655/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

VCAT: an integrated variant function annotation tools. VCAT：综合变异功能注释工具。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-08-27 DOI: 10.1007/s00439-024-02699-6

Bi Huang, Cong Fan, Ken Chen, Jiahua Rao, Peihua Ou, Chong Tian, Yuedong Yang, David N Cooper, Huiying Zhao

{"title":"VCAT: an integrated variant function annotation tools.","authors":"Bi Huang, Cong Fan, Ken Chen, Jiahua Rao, Peihua Ou, Chong Tian, Yuedong Yang, David N Cooper, Huiying Zhao","doi":"10.1007/s00439-024-02699-6","DOIUrl":"10.1007/s00439-024-02699-6","url":null,"abstract":"The development of sequencing technology has promoted discovery of variants in the human genome. Identifying functions of these variants is important for us to link genotype to phenotype, and to diagnose diseases. However, it usually requires researchers to visit multiple databases. Here, we presented a one-stop webserver for variant function annotation tools (VCAT, https://biomed.nscc-gz.cn/zhaolab/VCAT/ ) that is the first one connecting variant to functions via the epigenome, protein, drug and RNA. VCAT is also the first one to make all annotations visualized in interactive charts or molecular structures. VCAT allows users to upload data in VCF format, and download results via a URL. Moreover, VCAT has annotated a huge number (1,262,041,068) of variants collected from dbSNP, 1000 Genomes projects, gnomAD, ICGC, TCGA, and HPRC Pangenome project. For these variants, users are able to searcher their functions, related diseases and drugs from VCAT. In summary, VCAT provides a one-stop webserver to explore the potential functions of human genomic variants including their relationship with diseases and drugs.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1311-1322"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal swab DNA of individuals with spinocerebellar ataxia type 3/Machado-Joseph disease. 脊髓小脑共济失调 3 型/马加多-约瑟夫病患者血液和口腔拭子 DNA 中 ATXN3 CAG 重复的体细胞扩增与年龄有关。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-10-08 DOI: 10.1007/s00439-024-02698-7

Ahmed M Sidky, Ana Rosa Vieira Melo, Teresa T Kay, Mafalda Raposo, Manuela Lima, Darren G Monckton

{"title":"Age-dependent somatic expansion of the ATXN3 CAG repeat in the blood and buccal swab DNA of individuals with spinocerebellar ataxia type 3/Machado-Joseph disease.","authors":"Ahmed M Sidky, Ana Rosa Vieira Melo, Teresa T Kay, Mafalda Raposo, Manuela Lima, Darren G Monckton","doi":"10.1007/s00439-024-02698-7","DOIUrl":"10.1007/s00439-024-02698-7","url":null,"abstract":"Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is caused by the expansion of a genetically unstable polyglutamine-encoding CAG repeat in ATXN3. Longer alleles are generally associated with earlier onset and frequent intergenerational expansions mediate the anticipation observed in this disorder. Somatic expansion of the repeat has also been implicated in disease onset and slowing the rate of somatic expansion has been proposed as a therapeutic strategy. Here, we utilised high-throughput ultra-deep MiSeq amplicon sequencing to precisely define the number and sequence of the ATXN3 repeat, the genotype of an adjacent single nucleotide variant and quantify somatic expansion in blood and buccal swab DNA of a cohort of individuals with SCA3 from the Azores islands (Portugal). We revealed systematic mis-sizing of the ATXN3 repeat and high levels of inaccuracy of the traditional fragment length analysis that have important implications for attempts to identify modifiers of clinical and molecular phenotypes. Quantification of somatic expansion in blood DNA and multivariate regression revealed the expected effects of age at sampling and CAG repeat length, although the effect of repeat length was surprisingly modest with much stronger associations with age. We also observed an association of the downstream rs12895357 single nucleotide variant with the rate of somatic expansion, and a higher level of somatic expansion in buccal swab DNA compared to blood. These data suggest that the ATXN3 locus in SCA3 patients in blood or buccal swab DNA might serve as a good biomarker for clinical trials testing suppressors of somatic expansion with peripheral exposure.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1363-1378"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GBF1 deficiency causes cataracts in human and mouse. GBF1 缺乏会导致人类和小鼠白内障。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-08-07 DOI: 10.1007/s00439-024-02697-8

Weimin Jia, Chenming Zhang, Yalin Luo, Jing Gao, Chao Yuan, Dazhi Zhang, Xiaopei Zhou, Yongyao Tan, Shuang Wang, Zhuo Chen, Guigang Li, Xianqin Zhang

{"title":"GBF1 deficiency causes cataracts in human and mouse.","authors":"Weimin Jia, Chenming Zhang, Yalin Luo, Jing Gao, Chao Yuan, Dazhi Zhang, Xiaopei Zhou, Yongyao Tan, Shuang Wang, Zhuo Chen, Guigang Li, Xianqin Zhang","doi":"10.1007/s00439-024-02697-8","DOIUrl":"10.1007/s00439-024-02697-8","url":null,"abstract":"Any opacification of the lens can be defined as cataracts, and lens epithelium cells play a crucial role in guaranteeing lens transparency by maintaining its homeostasis. Although several causative genes of congenital cataracts have been reported, the mechanisms underlying lens opacity remain unclear. In this study, a large family with congenital cataracts was collected and genetic analysis revealed a pathological mutation (c.3857 C > T, p.T1287I) in the GBF1 gene; all affected individuals in the family carried this heterozygous mutation, while unaffected family members did not. Functional studies in human lens epithelium cell line revealed that this mutation led to a reduction in GBF1 protein levels. Knockdown of endogenous GBF1 activated XBP1s in the unfolded protein response signal pathway, and enhances autophagy in an mTOR-independent manner. Heterozygous Gbf1 knockout mice also displayed typic cataract phenotype. Together, our study identified GBF1 as a novel causative gene for congenital cataracts. Additionally, we found that GBF1 deficiency activates the unfolded protein response and leads to enhanced autophagy, which may contribute to lens opacity.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1281-1291"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rare homozygous cilia gene variants identified in consanguineous congenital heart disease patients. 在近亲结婚的先天性心脏病患者中发现罕见的同源纤毛基因变异。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-09-30 DOI: 10.1007/s00439-024-02703-z

Daniel A Baird, Hira Mubeen, Canan Doganli, Jasmijn B Miltenburg, Oskar Kaaber Thomsen, Zafar Ali, Tahir Naveed, Asif Ur Rehman, Shahid Mahmood Baig, Søren Tvorup Christensen, Muhammad Farooq, Lars Allan Larsen

{"title":"Rare homozygous cilia gene variants identified in consanguineous congenital heart disease patients.","authors":"Daniel A Baird, Hira Mubeen, Canan Doganli, Jasmijn B Miltenburg, Oskar Kaaber Thomsen, Zafar Ali, Tahir Naveed, Asif Ur Rehman, Shahid Mahmood Baig, Søren Tvorup Christensen, Muhammad Farooq, Lars Allan Larsen","doi":"10.1007/s00439-024-02703-z","DOIUrl":"10.1007/s00439-024-02703-z","url":null,"abstract":"Congenital heart defects (CHD) appear in almost one percent of live births. Asian countries have the highest birth prevalence of CHD in the world. Recessive genotypes may represent a CHD risk factor in Asian populations with a high degree of consanguineous marriages. Genetic analysis of consanguineous families may represent a relatively unexplored source for investigating CHD etiology. To obtain insight into the contribution of recessive genotypes in CHD we analysed a cohort of forty-nine Pakistani CHD probands, originating from consanguineous unions. The majority (82%) of patient's malformations were septal defects. We identified protein altering, rare homozygous variants (RHVs) in the patient's coding genome by whole exome sequencing. The patients had a median of seven damaging RHVs each, and our analysis revealed a total of 758 RHVs in 693 different genes. By prioritizing these genes based on variant severity, loss-of-function intolerance and specific expression in the developing heart, we identified a set of 23 candidate disease genes. These candidate genes were significantly enriched for genes known to cause heart defects in recessive mouse models (P < 2.4e-06). In addition, we found a significant enrichment of cilia genes in both the initial set of 693 genes (P < 5.4e-04) and the 23 candidate disease genes (P < 5.2e-04). Functional investigation of ADCY6 in cell- and zebrafish-models verified its role in heart development. Our results confirm a significant role for cilia genes in recessive forms of CHD and suggest important functions of cilia genes in cardiac septation.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1323-1339"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142345798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Methodologies underpinning polygenic risk scores estimation: a comprehensive overview. 多基因风险分数估算的基础方法：全面概述。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-10-19 DOI: 10.1007/s00439-024-02710-0

Carene Anne Alene Ndong Sima, Kathryn Step, Yolandi Swart, Haiko Schurz, Caitlin Uren, Marlo Möller

{"title":"Methodologies underpinning polygenic risk scores estimation: a comprehensive overview.","authors":"Carene Anne Alene Ndong Sima, Kathryn Step, Yolandi Swart, Haiko Schurz, Caitlin Uren, Marlo Möller","doi":"10.1007/s00439-024-02710-0","DOIUrl":"10.1007/s00439-024-02710-0","url":null,"abstract":"Polygenic risk scores (PRS) have emerged as a promising tool for predicting disease risk and treatment outcomes using genomic data. Thousands of genome-wide association studies (GWAS), primarily involving populations of European ancestry, have supported the development of PRS models. However, these models have not been adequately evaluated in non-European populations, raising concerns about their clinical validity and predictive power across diverse groups. Addressing this issue requires developing novel risk prediction frameworks that leverage genetic characteristics across diverse populations, considering host-microbiome interactions and a broad range of health measures. One of the key aspects in evaluating PRS is understanding the strengths and limitations of various methods for constructing them. In this review, we analyze strengths and limitations of different methods for constructing PRS, including traditional weighted approaches and new methods such as Bayesian and Frequentist penalized regression approaches. Finally, we summarize recent advances in PRS calculation methods development, and highlight key areas for future research, including development of models robust across diverse populations by underlining the complex interplay between genetic variants across diverse ancestral backgrounds in disease risk as well as treatment response prediction. PRS hold great promise for improving disease risk prediction and personalized medicine; therefore, their implementation must be guided by careful consideration of their limitations, biases, and ethical implications to ensure that they are used in a fair, equitable, and responsible manner.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1265-1280"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142464152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genotypic and phenotypic correlations in tooth agenesis: insights from WNT10A and EDA mutations in syndromic and non-syndromic forms. 牙齿缺失的基因型和表型相关性：综合征和非综合征中 WNT10A 和 EDA 基因突变的启示。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-09-25 DOI: 10.1007/s00439-024-02705-x

Youmei Wu, Ling Lai, Junyang Chen, Xinzhu Li, Jin Hou

引用次数: 0

Integrative genomic analyses identify neuroblastoma risk genes involved in neuronal differentiation. 整合基因组分析确定了参与神经元分化的神经母细胞瘤风险基因。

IF 3.8 2区生物学

Human Genetics Pub Date : 2024-11-01 Epub Date: 2024-08-27 DOI: 10.1007/s00439-024-02700-2

Matilde Tirelli, Ferdinando Bonfiglio, Sueva Cantalupo, Annalaura Montella, Marianna Avitabile, Teresa Maiorino, Sharon J Diskin, Achille Iolascon, Mario Capasso

{"title":"Integrative genomic analyses identify neuroblastoma risk genes involved in neuronal differentiation.","authors":"Matilde Tirelli, Ferdinando Bonfiglio, Sueva Cantalupo, Annalaura Montella, Marianna Avitabile, Teresa Maiorino, Sharon J Diskin, Achille Iolascon, Mario Capasso","doi":"10.1007/s00439-024-02700-2","DOIUrl":"10.1007/s00439-024-02700-2","url":null,"abstract":"Genome-Wide Association Studies (GWAS) have been decisive in elucidating the genetic predisposition of neuroblastoma (NB). The majority of genetic variants identified in GWAS are found in non-coding regions, suggesting that they can be causative of pathogenic dysregulations of gene expression. Nonetheless, pinpointing the potential causal genes within implicated genetic loci remains a major challenge. In this study, we integrated NB GWAS and expression Quantitative Trait Loci (eQTL) data from adrenal gland to identify candidate genes impacting NB susceptibility. We found that ZMYM1, CBL, GSKIP and WDR81 expression was dysregulated by NB predisposing variants. We further investigated the functional role of the identified genes through computational analysis of RNA sequencing (RNA-seq) data from single-cell and whole-tissue samples of NB, neural crest, and adrenal gland tissues, as well as through in vitro differentiation assays in NB cell cultures. Our results indicate that dysregulation of ZMYM1, CBL, GSKIP, WDR81 may lead to malignant transformation by affecting early and late stages of normal program of neuronal differentiation. Our findings enhance the understanding of how specific genes contribute to NB pathogenesis by highlighting their influence on neuronal differentiation and emphasizing the impact of genetic risk variants on the regulation of genes involved in critical biological processes.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1293-1309"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11522082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142080182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0