Human Genetics最新文献_第3页

Decade-long application of preimplantation genetic testing for DMD/BMD: analysis of five clinical strategies and embryo recombination patterns. DMD/BMD植入前基因检测的十年应用：五种临床策略和胚胎重组模式分析。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-02-19 DOI: 10.1007/s00439-025-02728-y

Weili Wang, Jing Dai, Xiao Hu, Wenbin He, Yifan Gu, Zhenxing Wan, Yi Zhang, Keli Luo, Wen Li, Qianjun Zhang, Fei Gong, Guangxiu Lu, Liang Hu, Yue-Qiu Tan, Ge Lin, Juan Du

{"title":"Decade-long application of preimplantation genetic testing for DMD/BMD: analysis of five clinical strategies and embryo recombination patterns.","authors":"Weili Wang, Jing Dai, Xiao Hu, Wenbin He, Yifan Gu, Zhenxing Wan, Yi Zhang, Keli Luo, Wen Li, Qianjun Zhang, Fei Gong, Guangxiu Lu, Liang Hu, Yue-Qiu Tan, Ge Lin, Juan Du","doi":"10.1007/s00439-025-02728-y","DOIUrl":"https://doi.org/10.1007/s00439-025-02728-y","url":null,"abstract":"This study aimed to find the most effective PGT-M strategy for Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD), and to reduce misdiagnosis caused by embryo recombination in DMD. A retrospective study was performed by analyzing 158 PGT-M cycles for DMD/BMD in Reproductive and Genetic Hospital of CITIC-Xiangya between 2009 and 2023. Patients' backgrounds were collected. The effectiveness and safety for five different PGT-M strategies (1-5), including mutation testing from cleavage or trophoblast ectoderm (TE) cells and additional linkage analysis post-TE cell amplification, were analyzed. The embryonic recombination events were assessed for these cycles. Mutation analysis showed that 62.4% of the 125 families had DMD deletions, 16.0% had duplications, and 21.6% had single nucleotide variants (SNVs). Among 125 families, 104 (83.2%) had previously affected fetus or offspring. The highest diagnosis rate (99.56%) was achieved with Strategy 5, which combined mutation testing with SNP-based linkage analysis in TE cells. This strategy 5 also demonstrated an advantage in cases with recombination near the mutation. An intragenic recombination rate of 5.5% was observed in embryos, predominantly in the hotspots (exons 45-55 and exons 3-9) of DMD deletion/duplication mutations. Prenatal diagnosis for 52 families and successful outcomes in all 85 healthy deliveries (live birth rate, 65.89%, 85/129) validated the accuracy and effectiveness of PGT-M. This study provides a highly effective PGT-M strategy (Strategy 5) for DMD/BMD by comparing five different strategies, with the diagnostic yield reaching 99.56%. The results underscore the significance of monitoring intragenic recombination in DMD, which is a frequent occurrence in DMD/BMD.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448848","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

Unilateral, bilateral symmetric or asymmetric isolated hearing loss in patients with heterozygous KITLG variants. 杂合子KITLG变异患者单侧、双侧对称或不对称孤立性听力损失。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-02-07 DOI: 10.1007/s00439-025-02730-4

Margaux Serey-Gaut, Ralyath Balogoun, Laurence Jonard, Geneviève Lina-Granade, Renaud Touraine, Marjolaine Willems, Nicola Hepp, Nanna Dahl Rendtorff, Mette Bertelsen, Natalie Loundon, Vincent Couloigner, Isabelle Lemiere, Judite de Oliveira, Serge Romana, Camille Porteret, Pierre Blanc, Luke Mansard, Sandrine Marlin, Anne-Françoise Roux, Véronique Pingault

{"title":"Unilateral, bilateral symmetric or asymmetric isolated hearing loss in patients with heterozygous KITLG variants.","authors":"Margaux Serey-Gaut, Ralyath Balogoun, Laurence Jonard, Geneviève Lina-Granade, Renaud Touraine, Marjolaine Willems, Nicola Hepp, Nanna Dahl Rendtorff, Mette Bertelsen, Natalie Loundon, Vincent Couloigner, Isabelle Lemiere, Judite de Oliveira, Serge Romana, Camille Porteret, Pierre Blanc, Luke Mansard, Sandrine Marlin, Anne-Françoise Roux, Véronique Pingault","doi":"10.1007/s00439-025-02730-4","DOIUrl":"https://doi.org/10.1007/s00439-025-02730-4","url":null,"abstract":"KITLG pathogenic variants have been associated to three distinct clinical presentations with different combinations of hearing loss and/or pigmentation abnormalities. However, its involvement in isolated hearing loss has not been confirmed since its initial description in two families. Besides, KITLG is so far the only gene prevailingly involved in unilateral isolated hearing loss. We therefore conducted a retrospective study of patients with KITLG alterations in the French national Reference Network for Genetic Hearing Loss and one case was added through the Genematcher exchange platform. We describe a series of monoallelic KITLG deletions and variations in a cohort of 14 symptomatic patients from eight unrelated families. All patients presented with unilateral, bilateral symmetric or asymmetric sensorineural hearing loss. When not profound, hearing loss was predominant on low frequencies. Most KITLG alterations are likely to result in loss-of-function and aggregate in the extracellular region, disrupting the KIT-binding domain or its structure. Penetrance is not complete, and unspecific pigmentation alterations were observed in only three patients. The present study confirms KITLG involvement in isolated unilateral, bilateral symmetric or asymmetric hearing loss. This confirmation indicates that genetic testing can be relevant in early-onset, non-sudden, isolated unilateral hearing loss.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364408","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

Global dysregulation of circular RNAs in frontal cortex and whole blood from DM1 and DM2. 额叶皮质和全血中DM1和DM2环状rna的全局失调。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-02-04 DOI: 10.1007/s00439-025-02729-x

Arvind Srinivasan, Dorota Magner, Piotr Kozłowski, Anna Philips, Arkadiusz Kajdasz, Paweł Wojciechowski, Marzena Wojciechowska

{"title":"Global dysregulation of circular RNAs in frontal cortex and whole blood from DM1 and DM2.","authors":"Arvind Srinivasan, Dorota Magner, Piotr Kozłowski, Anna Philips, Arkadiusz Kajdasz, Paweł Wojciechowski, Marzena Wojciechowska","doi":"10.1007/s00439-025-02729-x","DOIUrl":"https://doi.org/10.1007/s00439-025-02729-x","url":null,"abstract":"Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular disorders associated with expansions of microsatellites, respectively, in DMPK and CNBP. Their pathogenesis is linked to the global aberrant alternative splicing (AAS) of many genes and marks mostly muscular and neuronal tissues, while blood is the least affected. Recent data in DM1 skeletal muscles indicated that abnormalities in RNA metabolism also include global upregulation of circular RNAs (circRNAs). CircRNAs are a heterogeneous group considered splicing errors and by-products of canonical splicing. To elucidate whether circRNA dysregulation is an inherent feature of the myotonic environment, we perform their analysis in the frontal cortex and whole blood of DM1 and DM2 patients. We find a global elevation of circRNAs in both tissues, and its magnitude is neither correlated with the differences in their parental gene expression nor is associated with AAS published earlier. Aberrantly spliced cassette exons of linear transcripts affected in DM1 and DM2 are not among the circularized exons, which unique genomic features prerequisite back-splicing. However, the blueprint of the AAS of linear RNAs is found in a variety of circRNA isoforms. The heterogeneity of circRNAs also originates from the utilization of exonic and intronic cryptic donors/acceptors in back splice junctions, and intron-containing circRNAs are more characteristic of the blood. Overall, this study reveals circRNA dysregulation in various tissues from DM1 and DM2; however, their levels do not correlate with the AAS in linear RNAs, suggesting a potential independent regulatory mechanism underlying circRNA upregulation in myotonic dystrophy.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189244","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

Conventional and genetic association between migraine and stroke with druggable genome-wide Mendelian randomization. 偏头痛和中风与可用药全基因组孟德尔随机化之间的传统和遗传关联。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-01-22 DOI: 10.1007/s00439-024-02725-7

Xiaoyu Wang, Wendu Pang, Xin Hu, Tao Shu, Yaxin Luo, Junhong Li, Lan Feng, Ke Qiu, Yufang Rao, Yao Song, Minzi Mao, Yuyang Zhang, Jianjun Ren, Yu Zhao

{"title":"Conventional and genetic association between migraine and stroke with druggable genome-wide Mendelian randomization.","authors":"Xiaoyu Wang, Wendu Pang, Xin Hu, Tao Shu, Yaxin Luo, Junhong Li, Lan Feng, Ke Qiu, Yufang Rao, Yao Song, Minzi Mao, Yuyang Zhang, Jianjun Ren, Yu Zhao","doi":"10.1007/s00439-024-02725-7","DOIUrl":"https://doi.org/10.1007/s00439-024-02725-7","url":null,"abstract":"The genetic relationship between migraine and stroke remains underexplored, particularly in the context of druggable targets. Previous studies have been limited by small sample sizes and a lack of focus on genetic-targeted therapies for these conditions. We analyzed the association and causality between migraine and stroke using multivariable logistic regression in the UK Biobank cohort and Mendelian randomization (MR) analyses based on genome-wide association study (GWAS) data. Integrating expression quantitative trait loci (eQTLs) data from blood and brain regions, we explored the phenotypic and genetic links between migraine medications, drug target, and stroke. Additionally, we explored novel druggable genes for migraine and evaluated their effects on migraine signaling molecules and stroke risk. Migraine was significantly associated with stroke, particularly ischemic stroke (IS) and intracerebral hemorrhage (ICH), with MR analysis confirming a causal link to ICH. HTR1A emerged as a potential link between antidepressants (preventive medications for migraine) and stroke. We identified 17 migraine-related druggable genes, with 5 genes (HMGCR, TGFB1, TGFB3, KCNK5, IMPDH2) associated with nine existing drugs. Further MR analysis identified correlation of CELSR3 and IMPDH2 with cGMP pathway marker PRKG1, and identified KCNK5, PLXNB1, and MDK as novel migraine-associated druggable genes significantly linked to the stroke risks. These findings established the phenotypic and genetic link between migraine, its medication and stroke, identifying potential targets for single and dual-purpose therapies for migraine and stoke, and emphasized the need for further research to validate these associations.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004687","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

Human organoids for rapid validation of gene variants linked to cochlear malformations. 用于快速验证与耳蜗畸形相关的基因变异的人类类器官。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-01-09 DOI: 10.1007/s00439-024-02723-9

Mohammad Faraz Zafeer, Memoona Ramzan, Duygu Duman, Ahmet Mutlu, Serhat Seyhan, M Tayyar Kalcioglu, Suat Fitoz, Brooke A DeRosa, Shengru Guo, Derek M Dykxhoorn, Mustafa Tekin

{"title":"Human organoids for rapid validation of gene variants linked to cochlear malformations.","authors":"Mohammad Faraz Zafeer, Memoona Ramzan, Duygu Duman, Ahmet Mutlu, Serhat Seyhan, M Tayyar Kalcioglu, Suat Fitoz, Brooke A DeRosa, Shengru Guo, Derek M Dykxhoorn, Mustafa Tekin","doi":"10.1007/s00439-024-02723-9","DOIUrl":"10.1007/s00439-024-02723-9","url":null,"abstract":"Developmental anomalies of the hearing organ, the cochlea, are diagnosed in approximately one-fourth of individuals with congenital. The majority of patients with cochlear malformations remain etiologically undiagnosed due to insufficient knowledge about underlying genes or the inability to make conclusive interpretations of identified genetic variants. We used exome sequencing for the genetic evaluation of hearing loss associated with cochlear malformations in three probands from unrelated families deafness. We subsequently generated monoclonal induced pluripotent stem cell (iPSC) lines, bearing patient-specific knockins and knockouts using CRISPR/Cas9 to assess pathogenicity of candidate variants. We detected FGF3 (p.Arg165Gly) and GREB1L (p.Cys186Arg), variants of uncertain significance in two recognized genes for deafness, and PBXIP1(p.Trp574*) in a candidate gene. Upon differentiation of iPSCs towards inner ear organoids, we observed developmental aberrations in knockout lines compared to their isogenic controls. Patient-specific single nucleotide variants (SNVs) showed similar abnormalities as the knockout lines, functionally supporting their causality in the observed phenotype. Therefore, we present human inner ear organoids as a potential tool to validate the pathogenicity of DNA variants associated with cochlear malformations.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142948000","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

Integrative analysis of transcriptome and proteome wide association studies prioritized functional genes for obesity. 对转录组和蛋白质组广泛关联研究的综合分析确定了肥胖症功能基因的优先次序。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-01-01 Epub Date: 2024-11-04 DOI: 10.1007/s00439-024-02714-w

Qi-Gang Zhao, Xin-Ling Ma, Qian Xu, Zi-Tong Song, Fan Bu, Kuan Li, Bai-Xue Han, Shan-Shan Yan, Lei Zhang, Yuan Luo, Yu-Fang Pei

{"title":"Integrative analysis of transcriptome and proteome wide association studies prioritized functional genes for obesity.","authors":"Qi-Gang Zhao, Xin-Ling Ma, Qian Xu, Zi-Tong Song, Fan Bu, Kuan Li, Bai-Xue Han, Shan-Shan Yan, Lei Zhang, Yuan Luo, Yu-Fang Pei","doi":"10.1007/s00439-024-02714-w","DOIUrl":"10.1007/s00439-024-02714-w","url":null,"abstract":"Background: Genome-wide association studies have identified dozens of genomic loci for obesity. However, functional genes and their detailed genetic mechanisms underlying these loci are mainly unknown. In this study, we conducted an integrative study to prioritize plausibly functional genes by combining information from genome-, transcriptome- and proteome-wide association analyses.Methods: We first conducted proteome-wide association analyses and transcriptome-wide association analyses for the six obesity-related traits. We then performed colocalization analysis on the identified loci shared between the proteome- and transcriptome-association analyses. Finally, we validated the identified genes with other plasma/blood reference panels. The highlighted genes were assessed for expression of other tissues, single-cell and tissue specificity, and druggability.Results: We prioritized 4 high-confidence genes (FASN, ICAM1, PDCD6IP, and YWHAB) by proteome-wide association studies, transcriptome-wide association studies, and colocalization analyses, which consistently influenced the variation of obesity traits at both mRNA and protein levels. These 4 genes were successfully validated using other plasma/blood reference panels. These 4 genes shared regulatory structures in obesity-related tissues. Single-cell and tissue-specific analyses showed that FASN and ICAM1 were explicitly expressed in metabolism- and immunity-related tissues and cells. Furthermore, FASN and ICAM1 had been developed as drug targets.Conclusion: Our study provided novel promising protein targets for further mechanistic and therapeutic studies of obesity.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"31-41"},"PeriodicalIF":3.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142568057","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

Integrating transcriptomic and polygenic risk scores to enhance predictive accuracy for ischemic stroke subtypes. 整合转录组学和多基因风险评分，提高缺血性中风亚型的预测准确性。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-01-01 Epub Date: 2024-11-18 DOI: 10.1007/s00439-024-02717-7

Xuehong Cai, Haochang Li, Xiaoxiao Cao, Xinyan Ma, Wenhao Zhu, Lei Xu, Sheng Yang, Rongbin Yu, Peng Huang

{"title":"Integrating transcriptomic and polygenic risk scores to enhance predictive accuracy for ischemic stroke subtypes.","authors":"Xuehong Cai, Haochang Li, Xiaoxiao Cao, Xinyan Ma, Wenhao Zhu, Lei Xu, Sheng Yang, Rongbin Yu, Peng Huang","doi":"10.1007/s00439-024-02717-7","DOIUrl":"10.1007/s00439-024-02717-7","url":null,"abstract":"Ischemic stroke (IS), characterized by complex etiological diversity, is a significant global health challenge. Recent advancements in genome-wide association studies (GWAS) and transcriptomic profiling offer promising avenues for enhanced risk prediction and understanding of disease mechanisms. GWAS summary statistics from the GIGASTROKE Consortium and genetic and phenotypic data from the UK Biobank (UKB) were used. Transcriptome-Wide Association Studies (TWAS) were conducted using FUSION to identify genes associated with IS and its subtypes across eight tissues. Colocalization analysis identified shared genetic variants influencing both gene expression and disease risk. Sum Transcriptome-Polygenic Risk Scores (STPRS) models were constructed by combining polygenic risk scores (PRS) and polygenic transcriptome risk scores (PTRS) using logistic regression. The predictive performance of STPRS was evaluated using the area under the curve (AUC). A Phenome-wide association study (PheWAS) explored associations between STPRS and various phenotypes. TWAS identified 34 susceptibility genes associated with IS and its subtypes. Colocalization analysis revealed 18 genes with a posterior probability (PP) H4 > 75% for joint expression quantitative trait loci (eQTL) and GWAS associations, highlighting their genetic relevance. The STPRS models demonstrated superior predictive accuracy compared to conventional PRS, showing significant associations with numerous UKB phenotypes, including atrial fibrillation and blood pressure. Integrating transcriptomic data with polygenic risk scores through STPRS enhances predictive accuracy for IS and its subtypes. This approach refines our understanding of the genetic and molecular landscape of stroke and paves the way for tailored preventive and therapeutic strategies.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"43-54"},"PeriodicalIF":3.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647531","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

Genetic landscape in undiagnosed patients with syndromic hearing loss revealed by whole exome sequencing and phenotype similarity search. 全外显子组测序和表型相似性搜索揭示了未确诊综合征性听力损失患者的遗传景观。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-01-01 Epub Date: 2025-01-04 DOI: 10.1007/s00439-024-02719-5

Hideki Mutai, Fuyuki Miya, Kiyomitsu Nara, Nobuko Yamamoto, Satomi Inoue, Haruka Murakami, Kazunori Namba, Hiroshi Shitara, Shujiro Minami, Atsuko Nakano, Yukiko Arimoto, Noriko Morimoto, Taiji Kawasaki, Koichiro Wasano, Masato Fujioka, Yasue Uchida, Kimitaka Kaga, Kazuki Yamazawa, Yoshiaki Kikkawa, Kenjiro Kosaki, Tatsuhiko Tsunoda, Tatsuo Matsunaga

{"title":"Genetic landscape in undiagnosed patients with syndromic hearing loss revealed by whole exome sequencing and phenotype similarity search.","authors":"Hideki Mutai, Fuyuki Miya, Kiyomitsu Nara, Nobuko Yamamoto, Satomi Inoue, Haruka Murakami, Kazunori Namba, Hiroshi Shitara, Shujiro Minami, Atsuko Nakano, Yukiko Arimoto, Noriko Morimoto, Taiji Kawasaki, Koichiro Wasano, Masato Fujioka, Yasue Uchida, Kimitaka Kaga, Kazuki Yamazawa, Yoshiaki Kikkawa, Kenjiro Kosaki, Tatsuhiko Tsunoda, Tatsuo Matsunaga","doi":"10.1007/s00439-024-02719-5","DOIUrl":"10.1007/s00439-024-02719-5","url":null,"abstract":"There are hundreds of rare syndromic diseases involving hearing loss, many of which are not targeted for clinical genetic testing. We systematically explored the genetic causes of undiagnosed syndromic hearing loss using a combination of whole exome sequencing (WES) and a phenotype similarity search system called PubCaseFinder. Fifty-five families with syndromic hearing loss of unknown cause were analyzed using WES after prescreening of several deafness genes depending on patient clinical features. Causative genes were identified in 22 families, including both established genes associated with syndromic hearing loss (PTPN11, CHD7, KARS1, OPA1, DLX5, MITF, SOX10, MYO7A, and USH2A) and those associated with nonsyndromic hearing loss (STRC, EYA4, and KCNQ4). Association of a DLX5 variant with incomplete partition type I (IP-I) anomaly of the inner ear was identified in a patient with cleft lip and palate and acetabular dysplasia. The study identified COL1A1, CFAP52, and NSD1 as causative genes through phenotype similarity search or by analogy. ZBTB10 was proposed as a novel candidate gene for syndromic hearing loss with IP-I. A mouse model with homozygous Zbtb10 frameshift variant resulted in embryonic lethality, suggesting the importance of this gene for early embryonic development. Our data highlight a wide spectrum of rare causative genes in patients with syndromic hearing loss, and demonstrate that WES analysis combined with phenotype similarity search is a valuable approach for clinical genetic testing of undiagnosed disease.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"93-112"},"PeriodicalIF":3.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142927239","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

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-01-01 Epub Date: 2024-07-10 DOI: 10.1007/s00439-024-02686-x

Yen-Yu Chen, Chi-Sheng Chen, Jee-Fu Huang, Wen-Hsiu Su, Chia-Yang Li, Wei-Shiun Chen, En-Sheng Lin, Wan-Long Chuang, Ming-Lung Yu, Shu-Chi Wang

{"title":"The obesity-related mutation gene on nonalcoholic fatty liver disease.","authors":"Yen-Yu Chen, Chi-Sheng Chen, Jee-Fu Huang, Wen-Hsiu Su, Chia-Yang Li, Wei-Shiun Chen, En-Sheng Lin, Wan-Long Chuang, Ming-Lung Yu, Shu-Chi Wang","doi":"10.1007/s00439-024-02686-x","DOIUrl":"10.1007/s00439-024-02686-x","url":null,"abstract":"The prevalence of overweight and obesity is increasing, leading to metabolic-associated fatty liver disease (MAFLD) characterized by excessive accumulation of liver fat and a risk of developing hepatocellular carcinoma (HCC). The driver gene mutations may play the roles of passengers that occur in single 'hotspots' and can promote tumorigenesis from benign to malignant lesions. We investigated the impact of high body weight and BMI on HCC survival using The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) dataset. To explore the effects of obesity-related gene mutations on HCC, we collected driver mutation genes in 34 TCGA patients with BMI ≥ 27 and 23 TCGA patients with BMI < 27. The digital PCR performing the PBMC samples for the variant rate by clinical cohort of 96 NAFLD patients. Our analysis showed that obesity leads to significantly worse survival outcomes in HCC. Using cbioportal, we identified 414 driver mutation genes in patients with obesity and 127 driver mutation genes in non-obese patients. Functional analysis showed that obese-related genes significantly enriched the regulated lipid and insulin pathways in HCC. The insulin secretion pathway in patients with obesity HCC-specific survival identified ABCC8 and PRKCB as significant genes (p < 0.001). It revealed significant differences in gene mutation and gene expression profiles compared to non-obese patients. The digital PCR test ABCC8 variants were detected in PBMC samples and caused a 14.5% variant rate, significantly higher than that of non-obese NAFLD patients. The study findings showed that the gene ABCC8 was a patient with the obesity-related gene in NAFLD, which provides the probability that ABCC8 mutation contributes to the pre-cancer lesion biomarker for HCC.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"1-14"},"PeriodicalIF":3.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563310","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

T1R2/T1R3 polymorphism affects sweet and fat perception: Correlation between SNP and BMI in the context of obesity development. T1R2/T1R3多态性影响甜味和脂肪感知：肥胖发展过程中 SNP 与 BMI 之间的相关性。

IF 3.8 2区生物学

Human Genetics Pub Date : 2025-01-01 Epub Date: 2024-08-06 DOI: 10.1007/s00439-024-02690-1

Vinithra Ponnusamy, Gowtham Subramanian, Keerthana Vasanthakumar, Karthi Muthuswamy, Prabha Panneerselvan, Vasanth Krishnan, Selvakumar Subramaniam

{"title":"T1R2/T1R3 polymorphism affects sweet and fat perception: Correlation between SNP and BMI in the context of obesity development.","authors":"Vinithra Ponnusamy, Gowtham Subramanian, Keerthana Vasanthakumar, Karthi Muthuswamy, Prabha Panneerselvan, Vasanth Krishnan, Selvakumar Subramaniam","doi":"10.1007/s00439-024-02690-1","DOIUrl":"10.1007/s00439-024-02690-1","url":null,"abstract":"Genetic variations in taste receptors are associated with gustatory perception and obesity, which in turn affects dietary preferences. Given the increasing tendency of people with obesity choosing sweet, high-fat meals, the current study assessed the cross-regulation of two polymorphisms of the sweet taste receptor (T1R2/T1R3), rs35874116 and rs307355, on fat sensitivity in Indian adults. We investigated the association between taste sensitivity and BMI in the T1R2, T1R3, and CD36 polymorphic and non-polymorphic groups. The general labelled magnitude scale (gLMS) was used to assess the taste sensitivity of 249 participants in addition to anthropometric data. TaqMan Probe-based RT-PCR was employed to determine the polymorphisms. Additionally, the colorimetric method utilizing 3, 5-dinitro salicylic acid was used to evaluate the participants' salivary amylase activity. The mean detection thresholds for linoleic acid (LA) and sucrose were greater in individuals with obesity (i.e., 0.97 ± 0.08 mM and 0.22 ± 0.02 M, respectively) than in healthy adults (p < 0.0001), indicating lower sensitivity. Moreover, it was found that a greater proportion of persons with obesity fall into the polymorphic groups (i.e., 52% with genotype CD36 AA, 44% with genotype T1R2 CC, and 40% with genotype T1R3 TT). All three single nucleotide polymorphisms support the Hardy-Weinberg equilibrium (p = 0.78). The Pearson correlation analysis between LA and the sucrose detection threshold revealed a significant (p < 0.0001) positive relationship with an r value of 0.5299. Moreover, salivary amylase activity was significantly (p < 0.05) higher in the polymorphic sub-groups. The results of our study imply that genetic variations in T1R2/T1R3 receptors affect perception of both sweetness and fat, which may have an effect on obesity.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":" ","pages":"15-30"},"PeriodicalIF":3.8,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897334","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}

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