Human Genetics最新文献_第6页

Epigenetic silencing of DLEC1 correlates with tumor immune microenvironment and predicts immunotherapy prognosis in multiple cancers. DLEC1的表观遗传沉默与肿瘤免疫微环境相关并预测多种癌症的免疫治疗预后

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-04-20 DOI: 10.1007/s00439-026-02828-3

Ruijie Ming, Qi Xiong, Shuh-Ying Tan, Lili Li, Shujie Bao, Jianhua Wang, Lijuan Zhao, Xiaoqian He, Zeze Zheng, Yan Wang, Xiaoyu Liu, Jun Tang, Zhongjun Wu, Tingxiu Xiang, Qian Tao

{"title":"Epigenetic silencing of DLEC1 correlates with tumor immune microenvironment and predicts immunotherapy prognosis in multiple cancers.","authors":"Ruijie Ming, Qi Xiong, Shuh-Ying Tan, Lili Li, Shujie Bao, Jianhua Wang, Lijuan Zhao, Xiaoqian He, Zeze Zheng, Yan Wang, Xiaoyu Liu, Jun Tang, Zhongjun Wu, Tingxiu Xiang, Qian Tao","doi":"10.1007/s00439-026-02828-3","DOIUrl":"10.1007/s00439-026-02828-3","url":null,"abstract":"Cancer remains a major health issue globally, with increasing incidence and mortality rates. While immunotherapy has revolutionized cancer treatment, not all patients benefit, urging the identification of predictive biomarkers. This study utilized public datasets and tumor samples to examine the expression and promoter hypermethylation of DLEC1 in normal and tumor tissues, to evaluate its potential as prognostic and immunotherapy marker. In vitro and in vivo experiments on breast cancer (BrCa) cell lines were conducted to explore the functions and mechanisms of DLEC1. The prognostic significance of DLEC1 downregulation and its impact on immune cell infiltration and immunotherapy efficacy were analyzed using the GEO and TCGA databases. DLEC1 was frequently downregulated and methylated across multiple cancers. In BrCa, expression of DLEC1 inhibited tumor cell proliferation, induced apoptosis, and activated the interferon lambda1 signaling pathway, indicating its important role as a bona fide tumor suppressor and immunoregulator. High DLEC1 expression correlated with better prognosis in several cancer types and with increased immune cell infiltration. Cancer patients with high DLEC1 expression showed improved overall and progression-free survival under immune checkpoint inhibitor therapies, such as anti-CTLA4, anti-PD1 and anti-PDL1. DLEC1 promoter hypermethylation is a promising biomarker for cancer prognosis and potential immunotherapy response prediction. Its expression and promoter hypermethylation status could thus help to guide clinical treatment strategies for cancer patients, particularly of breast cancer.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722945","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

Improved functional JAG1 and NOTCH2 variant testing in patients with clinical or suspected Alagille syndrome using new low-Notch activity cells. 利用新型低notch活性细胞改进临床或疑似Alagille综合征患者JAG1和NOTCH2功能变异检测

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-04-18 DOI: 10.1007/s00439-026-02832-7

Nicole Buhl, Eva-Doreen Pfister, Daniel V Oliveira, Fabio Turetti, Eberhard Lurz, Ulrich Baumann, Nataliya Di Donato, Thomas Illig, Britta Skawran, Emma R Andersson, Jan Mašek, Amelie Stalke

{"title":"Improved functional JAG1 and NOTCH2 variant testing in patients with clinical or suspected Alagille syndrome using new low-Notch activity cells.","authors":"Nicole Buhl, Eva-Doreen Pfister, Daniel V Oliveira, Fabio Turetti, Eberhard Lurz, Ulrich Baumann, Nataliya Di Donato, Thomas Illig, Britta Skawran, Emma R Andersson, Jan Mašek, Amelie Stalke","doi":"10.1007/s00439-026-02832-7","DOIUrl":"10.1007/s00439-026-02832-7","url":null,"abstract":"The autosomal dominant multisystemic Alagille Syndrome (ALGS) is an important cause of pediatric cholestasis. ALGS is associated with pathogenic variants in JAGGED1 (JAG1) or NOTCH2, ligand and receptor components of the Notch-signaling pathway, respectively. The detected missense variants are commonly classified as variants of uncertain significance, hindering ALGS diagnosis. To overcome this issue, we have developed a CRISPR/Cas9-engineered Low-Notch activity (LNA) cells allowing for selective testing of JAG1-NOTCH2 signaling activity. We tested this approach on 9 patients with pediatric hepatopathies with phenotypes ranging from the full clinical ALGS spectrum to isolated neonatal cholestasis and atypical ALGS abnormalities who carried 5 JAG1 and 3 NOTCH2 missense variants of interest. Additionally, western blot analyses revealed an effect on protein expression for two JAG1 missense variants, one of which had altered glycosylation, potentially indicating pathogenic effects. For this JAG1 and one NOTCH2 de novo missense variant, luciferase-based Notch reporter activity was significantly reduced in LNA cells, while no change was observed in commonly used HEK293T, Huh7, or Hep2G cells. These findings allow independent confirmation of recently classified c.53T>G p.(Leu18Arg) in JAG1, and a re-classification of c.1235G>T p.(Cys412Phe) in NOTCH2 as likely pathogenic based on ACMG criteria. Collectively, we provide evidence that selective testing of JAG1-NOTCH2 interaction in the newly developed CRISPR-engineered cells, combined with a glycosylation assay, enables robust functional evaluation of ALGS-associated JAG1 and NOTCH2 variants.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13090200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716663","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

Correction: Variants in NR6A1 as a cause for congenital renal, vertebral and uterine anomalies. 更正：NR6A1变异是先天性肾脏、椎体和子宫异常的原因。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-04-13 DOI: 10.1007/s00439-026-02829-2

Adeline Jacquinet, Lydie Flasse, Manon Dohet, Romane Vanhaeren, Hélène Pendeville, Carol Saunders, Anna Lehman, Catherine Pienkowski, Karine Morcel, Daniel Guerrier, Vincent Bours, Bernard Peers

引用次数: 0

Integrating machine learning and spatial transcriptomics uncovers shared immunomodulatory deubiquitinases in MAFLD and HCC. 整合机器学习和空间转录组学揭示了MAFLD和HCC中共享的免疫调节去泛素酶。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-04-10 DOI: 10.1007/s00439-026-02833-6

Yu-Xi Han, Hongze Li, Wendi Xia, Junyi Ma, Jiaqi Zhang, Yiling Li

{"title":"Integrating machine learning and spatial transcriptomics uncovers shared immunomodulatory deubiquitinases in MAFLD and HCC.","authors":"Yu-Xi Han, Hongze Li, Wendi Xia, Junyi Ma, Jiaqi Zhang, Yiling Li","doi":"10.1007/s00439-026-02833-6","DOIUrl":"10.1007/s00439-026-02833-6","url":null,"abstract":"Hepatocellular carcinoma (HCC) represents a malignancy with high global mortality. Metabolic dysfunction-associated fatty liver disease (MAFLD) serves as a significant contributory pathogenic factor. Deubiquitinases (DUBs), which regulate protein homeostasis, are implicated in disease progression. This study focused on identifying shared mechanisms between MAFLD and HCC, screening for key DUB genes, and constructing a novel prognostic scoring system termed the Deubiquitination Score (DUBS). The DUBS significantly stratified patient survival, with a high-DUBS indicating poor prognosis and malignant tumor progression. Patients with a low-DUBS demonstrated enhanced responses to immunotherapy and prolonged survival. Their tumors exhibited characteristics of “hot tumors,” featuring abundant immune cell infiltration and an active tumor microenvironment, accompanied by higher microsatellite instability(MSI). The core gene identified, EIF3F, exhibited superior cross-disease diagnostic value between HCC and MAFLD. In vitro and in vivo experiments demonstrated that knockdown of EIF3F inhibited the proliferation and migration of HCC cell. Furthermore, the DUBS revealed associations with sensitivity to chemotherapeutic agents. In summary, this study provided an important molecular tool and mechanistic foundation for the early screening, prognostic assessment, differential diagnosis, and prediction of immunotherapy response in HCC. It also highlighted potential directions for targeted intervention and the development of combination therapeutic strategies.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13068746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645149","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

The genetic associations of DNAJC family members with Parkinson's disease: comprehensive evidence from burden analysis and Mendelian randomization. DNAJC家族成员与帕金森病的遗传关联：来自负担分析和孟德尔随机化的综合证据

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-04-09 DOI: 10.1007/s00439-026-02831-8

Dehao Yang, Jingxuan Xu, Yusheng Zhu, Yangguang Lu, Ruotong Yao, Zihan Ye, Bohuai Yu, Jiaxuan Chen, Tingxuan Zhang, Bowen Liu, Suwen Huang, Guangyong Chen

{"title":"The genetic associations of DNAJC family members with Parkinson's disease: comprehensive evidence from burden analysis and Mendelian randomization.","authors":"Dehao Yang, Jingxuan Xu, Yusheng Zhu, Yangguang Lu, Ruotong Yao, Zihan Ye, Bohuai Yu, Jiaxuan Chen, Tingxuan Zhang, Bowen Liu, Suwen Huang, Guangyong Chen","doi":"10.1007/s00439-026-02831-8","DOIUrl":"10.1007/s00439-026-02831-8","url":null,"abstract":"Background: Recent studies suggested that genetic mutations in the DNAJC family might elevate the risk of Parkinson's disease (PD). Nevertheless, the role of some DNAJC genes in PD remains controversial, and previous studies lacked downstream research. In this study, we aim to explore the relationship between DNAJC family genes and PD in a European cohort through a comprehensive method.Methods: Rare variants were identified by whole-exome sequencing from a cohort of 403 PD patients and 182 healthy controls. Fisher's exact test was conducted to assess the allelic associations. Gene-based burden analysis was conducted to detect the enrichment effect of mutations in DNAJC genes. Mendelian randomization was performed to explore the association of gene expression levels with PD risk. Finally, colocalization analysis was used to explore the shared genetic structure of DNAJC and PD.Results: In total, we identified 464 rare variants, 437 of which were significant at the allele level. At the gene level, rare variants in 7 genes (DNAJC1, DNAJC6, DNAJC10, DNAJC11, DNAJC13, DNAJC16 and DNAJC27) were enriched in PD patients. At the gene expression level, a positive causal association of DNAJC13 with PD was revealed. Colocalization analysis reinforced the genetic associations of DNAJC13 and DNAJC19 with PD risk by identifying shared variants.Conclusions: We provided convergent genetic evidence supporting DNAJC13 as a susceptibility gene for PD. We presented the first evidence that rare variants in DNAJC1, DNAJC11 and DNAJC16 were enriched in PD patients, and replicated the previously reported associations of DNAJC6, DNAJC10 and DNAJC27 with PD.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638703","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

DNA methylation signatures from peripheral blood revealed epigenetic alterations in Fanconi anemia. 外周血DNA甲基化特征揭示了范可尼贫血的表观遗传改变。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-03-27 DOI: 10.1007/s00439-026-02827-4

Merin George, Sumit Halder, Shafi Gowhar, Anjali Shah, Somprakash Dhangar, Jagadeeshwar Ghatanatti, Ramesh Aarthi, Pranoti Kini, Mamta Mangalani, Aruna Rajendran, Sandeep Nemani, Sangeeta Murlidar, Babu Rao Vundinti

{"title":"DNA methylation signatures from peripheral blood revealed epigenetic alterations in Fanconi anemia.","authors":"Merin George, Sumit Halder, Shafi Gowhar, Anjali Shah, Somprakash Dhangar, Jagadeeshwar Ghatanatti, Ramesh Aarthi, Pranoti Kini, Mamta Mangalani, Aruna Rajendran, Sandeep Nemani, Sangeeta Murlidar, Babu Rao Vundinti","doi":"10.1007/s00439-026-02827-4","DOIUrl":"10.1007/s00439-026-02827-4","url":null,"abstract":"Fanconi Anemia (FA) is a rare autosomal recessive disorder; characterized by bone marrow failure, congenital malformation, and a markedly increased risk of cancers. Despite well characterized genetic defects in the FA/BRCA pathway, the mechanisms underlining variable disease severity and cancer susceptibility remains unknown. We studied the role of global DNA methylation and its implication in the cancer predisposition in FA. Chromosomal breakage analysis from peripheral blood cultures induced with Mitomycin C. Mutational analysis using NGS, MLPA and Sanger sequencing. Genome-wide DNA methylation profiling was performed using Illumina Infinium Methylation EPIC 850k Bead Chip Array and gene expression was validated by qPCR. Global DNA methylation profiling revealed a significant hyper-methylation pattern in FA patients as compared to the controls. Pathway enrichment and gene ontology analysis revealed the hyper-methylated genes were associated with the mTOR, WNT, cell adhesion and non-homologous end joining pathways, while hypo-methylated genes were enriched in NF-kb, MAPK, Calcium and JAK-STAT signalling pathways. Validation of top candidate genes showed significant downregulation of FAM65B, NKAPL, ITGAM, CDIP1 and CDKN1b genes which are involved in tumour suppression, immune regulation and cell-cycle control. Protein-Protein interaction analysis demonstrated that these genes are indirectly linked through the p53 and TNF- α signalling axes, contributing to a pro-inflammatory microenvironment that may promotes the emergence of pre-leukemic clones in FA. These results suggest that aberrant DNA methylation may play a role in cancer predisposition in FA by silencing key regulatory genes and may represent as promising candidates for prediction of cancer progression.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147528483","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

The involvement of TNFRSF25 in age-related hearing loss. TNFRSF25在年龄相关性听力损失中的作用

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-03-26 DOI: 10.1007/s00439-026-02826-5

Marie Valerie Roche, Pei-Ciao Tang, Denise Yan, Michelle Rose De Marchena, Maria Camila Robayo, Clemer Abad, Yan Guo, Feng Gong, Katherina Walz, Xue Zhong Liu

{"title":"The involvement of TNFRSF25 in age-related hearing loss.","authors":"Marie Valerie Roche, Pei-Ciao Tang, Denise Yan, Michelle Rose De Marchena, Maria Camila Robayo, Clemer Abad, Yan Guo, Feng Gong, Katherina Walz, Xue Zhong Liu","doi":"10.1007/s00439-026-02826-5","DOIUrl":"10.1007/s00439-026-02826-5","url":null,"abstract":"Hearing loss is a prevalent sensory condition that affects the ability to perceive sounds. Hair cells play a vital role in hearing by converting mechanical sound vibrations into electrical signals that are transmitted to the brain. In humans, if damaged, these specialized sensory cells do not regenerate, leading to reduced sensitivity to sound, difficulty understanding speech, and deafness. The incidence of hearing loss increases with age, but it can also occur earlier due to genetic predisposition or environmental factors such as exposure to noise or ototoxic medications. Epigenetic mechanisms play a significant role in age-related hearing loss (ARHL) by regulating gene expression without changing the underlying DNA sequence. Aberrant DNA methylation patterns have been linked to ARHL. In this study, by performing an epigenome-wide association study in a cohort of 30 ARHL patients, we found a correlation between a specific CpG site methylation level proximal to the TNFRSF25 gene, with an impaired hearing threshold. Interestingly, Tnfrsf25 absence in mice cause ARHL, severe hair cell depletion, and degeneration of nerve fibers. Taking together these results suggests a crucial role of Tnfrsf25 expression in hearing maintenance.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13018069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147511839","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

A comprehensive and accessible model for co-segregation analysis in BRCA1, BRCA2, and PALB2 variant classification. BRCA1、BRCA2和PALB2变体分类中共分离分析的一个全面和可访问的模型。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-03-26 DOI: 10.1007/s00439-025-02816-z

Setareh Moghadasi, Ramin Monajemi, Merel E Braspenning, Maaike P G Vreeswijk, Mar Rodríguez-Girondo

{"title":"A comprehensive and accessible model for co-segregation analysis in BRCA1, BRCA2, and PALB2 variant classification.","authors":"Setareh Moghadasi, Ramin Monajemi, Merel E Braspenning, Maaike P G Vreeswijk, Mar Rodríguez-Girondo","doi":"10.1007/s00439-025-02816-z","DOIUrl":"10.1007/s00439-025-02816-z","url":null,"abstract":"Variants of uncertain significance (VUS) are genetic variations with unclear clinical implications, often complicating clinical management in genetic testing. The analysis of co-segregation of the variant with the disease in families has been shown to be a powerful tool for the classification of these variants. We present CAL-Leiden (Co-segregation Analysis via Likelihood ratio analysis-Leiden), a comprehensive co-segregation model facilitating the classification of variants in BRCA1, BRCA2 and PALB2 genes, which can be used as an important component of the ACMG/AMP (the American College of Medical Genetics and Genomics/ the Association for Molecular Pathology) classification guideline. CAL-Leiden includes an expanded range of cancer types, including pancreatic cancer, in addition to breast and ovarian cancer. The model operates on a multiple-cancers-per-individual framework, so that likelihood contributions account for all relevant cancers observed in a person, including contralateral breast cancer. The model integrates population incidence rates from the Netherlands, the United Kingdom and United States, along with penetrance data from the latest literature. A web-based platform has been developed, making the model accessible and practical for use in diagnostic labs: https://bioexp.net/cosegregation/ . We demonstrate the functionality of the tool with multiple pedigrees and compare its performance with alternative approaches. The features in CAL-Leiden collectively contribute to a more comprehensive and accurate assessment of variant pathogenicity, helping clinical laboratory specialists and researchers in classification of the variants of uncertain significance.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13018082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147511802","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

Human YTHDC2 mutations disturb RNA homeostasis of oocytes and early embryos. 人类YTHDC2突变扰乱了卵母细胞和早期胚胎的RNA稳态。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-03-21 DOI: 10.1007/s00439-026-02818-5

Wei Su, Yang Wang, Jiaqi Sun, Changlong Zhang, Changjian Yin, Ying Cui, Xiaolei Chen, Bohan Yang, Shigang Zhao, Keliang Wu, Ge Lin, Zi-Jiang Chen, Wei Zheng, Honghui Zhang, Han Zhao

{"title":"Human YTHDC2 mutations disturb RNA homeostasis of oocytes and early embryos.","authors":"Wei Su, Yang Wang, Jiaqi Sun, Changlong Zhang, Changjian Yin, Ying Cui, Xiaolei Chen, Bohan Yang, Shigang Zhao, Keliang Wu, Ge Lin, Zi-Jiang Chen, Wei Zheng, Honghui Zhang, Han Zhao","doi":"10.1007/s00439-026-02818-5","DOIUrl":"10.1007/s00439-026-02818-5","url":null,"abstract":"Oocyte and early embryo competence defects (OECD) are a kind of Mendelian genetic disorder. While numerous pathogenic variants have been identified, the underlying molecular mechanisms remain largely elusive. In this study, through whole-exome sequencing of infertile patients, we identified five novel biallelic mutations in YTHDC2, a locus previously implicated in primary ovarian insufficiency, in four families with OECD. Of note, two affected individuals presented with diminished ovarian reserve. To delineate the functional consequences of these variants, we overexpressed human mutant YTHDC2 in mouse growing oocytes at the GO2 stage (50–55 μm in diameter) with high Ythdc2 expression, and performed transcriptomic profiling. In parallel, we conducted single-cell RNA sequencing of human preimplantation embryo carrying YTHDC2 mutations. By integrating mouse Ythdc2 iCLIP-seq data, transcriptomes of GO2 oocytes, and human embryonic single-cell data, we demonstrate that YTHDC2 mutations disrupt RNA homeostasis, leading to progressive functional abnormalities during oocyte and early embryonic development. Furthermore, mutant YTHDC2 overexpressed in mouse zygotes significantly compromised early embryonic development, characterized by a marked reduction in blastocyst formation rates. Our study identifies YTHDC2 as a critical regulator of oocyte and early embryonic development and provides a novel target for clinical genetic diagnosis.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147493732","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

Polygenic scores and physical fitness prediction: a systematic review. 多基因评分和身体健康预测：系统综述。

IF 3.4 2区生物学

Human Genetics Pub Date : 2026-03-21 DOI: 10.1007/s00439-026-02820-x

Farzaneh Rami, Nazanin Vaziri, Amanda V Tyndall, David W Anderson, Marc J Poulin, Chad A Bousman

{"title":"Polygenic scores and physical fitness prediction: a systematic review.","authors":"Farzaneh Rami, Nazanin Vaziri, Amanda V Tyndall, David W Anderson, Marc J Poulin, Chad A Bousman","doi":"10.1007/s00439-026-02820-x","DOIUrl":"10.1007/s00439-026-02820-x","url":null,"abstract":"Polygenic scores (PGS) have emerged as a promising tool for understanding the genetic underpinnings of physical fitness traits, including aerobic fitness (also called cardiorespiratory fitness), muscular fitness and adiposity, and neuromotor performance (including agility/speed-related parameters). However, the predictive utility of PGS for physical fitness traits is unclear. To address this knowledge gap, we conducted a systematic review to critically evaluate the current body of literature on the association between weighted and unweighted PGS models, and various fitness-related phenotypes. Following PRISMA guidelines, we identified 67 studies published prior to May 2025 that examined 74 weighted and 39 unweighted PGS models in relation to cardiovascular, respiratory, muscular and adiposity, and/or neuromotor performance-related parameters. We classified body composition along with muscular fitness in the same category, because of the close correlation of these parameters. Our evaluation highlights key genetic components implicated in fitness traits, the methodological heterogeneity across studies, and the limitations of current PGS models. While PGSs offer insights into the genetic architecture of physical fitness, their practical application remains constrained by population specificity, polygenic complexity, and environmental interactions. We discuss the implications for personalized interventions and future research directions to enhance the predictive utility of PGS for physical fitness.","PeriodicalId":13175,"journal":{"name":"Human Genetics","volume":"145 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147493692","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