Global Medical Genetics最新文献

{"title":"Corrigendum to \"Global comprehensive transcriptomic and proteomic analyses of murine terminal erythroid differentiation\" [Glob. Med. Genet. 12 (2025) 100083].","authors":"Xiao-Yue Tang, Jia-Huan Chen, Ran Yang, Hong Fan, Ke Yang, Tao Ding, Qiao-Chu Wang, Ye-Hong Yang, Yue Wu, Zhi-Yi Zhang, Chun-Mei Shi, Xue-Hui Liu, Jiang-Feng Liu, Xiang Lv, Jun-Tao Yang","doi":"10.1016/j.gmg.2026.100131","DOIUrl":"https://doi.org/10.1016/j.gmg.2026.100131","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1016/j.gmg.2025.100083.].</p>","PeriodicalId":40142,"journal":{"name":"Global Medical Genetics","volume":"13 3","pages":"100131"},"PeriodicalIF":2.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149041078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPI: A pan-cancer biomarker integrating genetic alterations, immune infiltration, and therapeutic response prediction.","authors":"Wei Hu, Yu Gao, Zimu Li, Zelei Du, Jincheng Tao, Anastasios A Politis, Fulvio Vincenzo Grilli, Alessandro Di Stefano, Xiefeng Wang, Junxia Zhang, Jianxing Yin","doi":"10.1016/j.gmg.2026.100127","DOIUrl":"10.1016/j.gmg.2026.100127","url":null,"abstract":"<p><p>Glucose-6-phosphate isomerase (GPI) is a key metabolic enzyme implicated in tumorigenesis, yet its pan-cancer role and clinical significance remain incompletely understood. This study aimed to systematically characterize GPI expression, genetic alterations, clinical relevance, and biological functions across cancers, and validate its pro-oncogenic effects.We employed bioinformatics tools (GEPIA2, SangerBox 3.0, cBioPortal, TIMER 2.0, etc.) to analyze GPI expression, genetic alterations, and clinical relevance across multiple cancer types. In vitro experiments were conducted to validate its pro-oncogenic effects in LGG cells.Bioinformatics analyses showed that GPI was upregulated in 29 cancers and downregulated in 3 cancers. High GPI expression was associated with advanced stage, metastasis and poor prognosis. Genetic alterations positively regulated GPI expression, which was linked to cancer stemness, RNA modification, metabolic pathways and tumor immune microenvironment, and could predict chemotherapy response. In vitro experiments confirmed that GPI overexpression promoted LGG cell proliferation, colony formation and invasion, while knockdown inhibited these phenotypes. The correlation between DNA repair and GPI expression is interconnected through metabolic and genetic instability pathways, requiring further investigation.GPI acts as a pan-cancer pro-oncogenic factor and a promising diagnostic, prognostic, and therapeutic biomarker. Further research on its molecular mechanisms, particularly with DNA repair, will inform novel cancer treatment strategies.</p>","PeriodicalId":40142,"journal":{"name":"Global Medical Genetics","volume":"13 3","pages":"100127"},"PeriodicalIF":2.1,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149041111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of core differentially expressed genes for respiratory syncytial virus infection.","authors":"Qing Deng, Zhaoying Li, Jie Deng, Xiaoli Jiang, Zhe Han, Hao Dong, Hui Liu, Yuxue Xu","doi":"10.1016/j.gmg.2026.100126","DOIUrl":"10.1016/j.gmg.2026.100126","url":null,"abstract":"<p><strong>Objective: </strong>Respiratory syncytial virus (RSV) is a highly contagious pathogen and the predominant cause of upper and lower respiratory tract infections. RSV-specific antiviral drugs are at an early stage, and clinical and experimental therapies targeting pathogenesis and immune pathways are limited, with challenging application.</p><p><strong>Methods: </strong>We systematically analyzed blood transcriptome data from 92 RSV patients and 47 healthy controls. Key functional genes were identified via differential expression analysis, weighted gene co-expression network analysis (WGCNA), core module identification, machine learning, protein-protein interaction (PPI) network analysis, and co-localization mapping. An independent cohort (28 patients, 8 controls) was used for validation. Immune-cell infiltration patterns influenced by key genes were assessed, and therapeutic targets were predicted. Quantitative real-time PCR (qRT-PCR) on clinical blood samples validated disease-associated core genes.</p><p><strong>Results: </strong>We identified eight functionally critical feature genes; seven (<i>IL1RN</i>, <i>RETN</i>, <i>GPR141</i>, <i>ARG1</i>, <i>SQRDL</i>, <i>SAMSN1</i>, and <i>MMP8</i>) were significantly upregulated (FDR < 0.01), while only <i>CD96</i> was downregulated. Immune-infiltration analysis showed a strikingly consistent association between these key genes and immune cells, except for <i>CD96</i>. Notably, <i>ARG1</i> and <i>RETN</i> shared a causal variant linked to lower respiratory tract infection pathology. Five candidate compounds with inverse regulatory effects on feature gene expression were predicted. qRT-PCR results validated <i>RETN</i> as the most critical core gene associated with RSV infection.</p><p><strong>Conclusion: </strong>This study systematically screened potential key genes via integrated bioinformatics and molecular validation, and identified <i>RETN</i> as a potential therapeutic target for RSV disease.</p>","PeriodicalId":40142,"journal":{"name":"Global Medical Genetics","volume":"13 3","pages":"100126"},"PeriodicalIF":2.1,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and regional distribution of TTN variants in toe walking: A descriptive cohort study.","authors":"David Pomarino, Amel Sidi Athmane, Bastian Fregien, Alexander Nazarkin, Kevin M Rostásy","doi":"10.1016/j.gmg.2026.100112","DOIUrl":"10.1016/j.gmg.2026.100112","url":null,"abstract":"<p><strong>Background: </strong>The TTN gene encodes titin, a key structural protein of the sarcomere. Variants in TTN are frequently identified in genetic testing, but their clinical interpretation remains challenging due to their high prevalence in the general population and frequent classification as variants of uncertain significance (VUS). Toe walking is often considered idiopathic; however, emerging evidence suggests a potential genetic contribution.</p><p><strong>Objective: </strong>To provide a descriptive analysis of TTN variants in children presenting with persistent toe walking, using a region-based approach to explore variant distribution and associated clinical features.</p><p><strong>Methods: </strong>This retrospective study included children with persistent toe walking following exclusion of known neurological, neuromuscular, and orthopedic causes. All patients underwent standardized clinical assessment and targeted next-generation sequencing using a 49-gene panel. TTN variants were grouped into predefined cDNA intervals (c.1-c.9000). Clinical and genetic data were analyzed descriptively.</p><p><strong>Results: </strong>Fifty-five patients carrying 43 TTN variants were included (mean age 7.3 years; 71% male). Variants were unevenly distributed, with clustering in the c.1001-2000 (22.4%) and c.3001-4000 (19.0%) regions. All variants were classified as VUS. A consistent clinical phenotype was observed across groups, including persistent toe walking, reduced ankle dorsiflexion, and a frequent positive foot drop test. Group-specific differences were noted but remained inconsistent and descriptive.</p><p><strong>Conclusions: </strong>TTN variants in children with toe walking show heterogeneous distribution but a largely consistent clinical presentation. No clear genotype-phenotype correlation was identified. These findings highlight the need for cautious interpretation of TTN VUS and further studies to clarify their clinical significance.</p>","PeriodicalId":40142,"journal":{"name":"Global Medical Genetics","volume":"13 2","pages":"100112"},"PeriodicalIF":2.1,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13276335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148296727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotypic and phenotypic spectrum of Galloway-Mowat syndrome in Kuwait.","authors":"Fares Alhammad, Nawal Y Ali, Sumaya Alkanderi, Reem M Elshafie, Laila Bastaki, Buthina Albash, Hind Alsharhan, Dana Marafi","doi":"10.1016/j.gmg.2026.100110","DOIUrl":"10.1016/j.gmg.2026.100110","url":null,"abstract":"<p><strong>Introduction: </strong>Galloway-Mowat syndrome (GAMOS) is a rare genetic disorder that is characterized by microcephaly and neurological and renal abnormalities. Ten types of GAMOS exist based on the underlying implicated gene. The purpose of this study was to investigate the phenotypic and genotypic spectrum of GAMOS in Kuwait.</p><p><strong>Methods: </strong>We queried the Kuwait Medical Genetic Center database for subjects with neuro-renal or neurological phenotypes and pathogenic variants in any of the ten known genes associated with GAMOS.</p><p><strong>Results: </strong>We identified eight subjects from five unrelated families with biallelic pathogenic <i>WDR73</i> variants and a diagnosis of GAMOS type 1 (GAMOS1). All subjects had global developmental delay, microcephaly, tone abnormalities and impaired activities of daily living. Renal features were observed in more than half of the subjects (5/8 subjects) and included proteinuria, nephrotic syndrome, and end-stage renal disease (ESRD). More than half of the subjects (5/8 subjects) died by 5-10 due to ESRD, including one of which who died due to unknown cause while the rest (ages 3-5 years) are still living with no renal features.Two possible founder variants were identified, including c.287 G>A;p.Arg96Lys in three unrelated families of Kuwaiti, Iraqi, and/or Syrian ancestry, and c.767 G>A;p.Arg256Gln in two unrelated families of Kuwaiti or Syrian ancestry.</p><p><strong>Conclusion: </strong>GAMOS1 is the most prevalent form of GAMOS in Kuwait, likely due to the presence of two <i>WDR73</i> regional founder variants. These findings contribute to the global understanding of GAMOS and highlight the important contribution of regional genetic studies in diverse populations to rare disease research.</p>","PeriodicalId":40142,"journal":{"name":"Global Medical Genetics","volume":"13 2","pages":"100110"},"PeriodicalIF":2.1,"publicationDate":"2026-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13265656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148266578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA methylation and exosomes in relation to type 2 diabetes in Black South Africans: A pilot study.","authors":"Buhle B Mbali, Laverdure T Piame, Sesethu Sehole, Hannibal T Musarurwa, Yandiswa Y Yako","doi":"10.1016/j.gmg.2026.100109","DOIUrl":"10.1016/j.gmg.2026.100109","url":null,"abstract":"<p><p>Type 2 diabetes (T2D) is a metabolic disorder characterised by hyperglycaemia, reduced insulin secretion, and increased insulin resistance, yet its mechanisms are not fully understood. While genetic predisposition contributes to the variable disease presentation across different ethnic populations, it does not fully explain the burden of T2D. Global 5-methylcytosine (5-mC) has emerged as an important regulator of gene expression, influencing disease pathogenesis through interactions with environmental factors. In parallel, circulating exosomes have attracted significant attention in research due to their role in mediating cell-to-cell communication and their capability to transport bioactive molecules, including methylated genomic DNA, that influence gene expression and metabolic pathways. The combined contribution of 5-mC and circulating exosome concentration to T2D pathogenesis in African populations remains poorly understood. A South African community case-control study of 40 T2D cases and 40 healthy controls quantified exosomes and 5-mC using their corresponding enzyme-linked immunosorbent assay. Associations of variables with T2D were evaluated using linear and logistic regression models. Serum exosome concentrations were positively correlated with global 5-mC (r = 0.269, p = 0.016). Global 5-mC levels were positively associated with triglycerides (r = 0.232, p = 0.038) and inversely correlated with weight in the diabetic group (r = -0.342, p = 0.038), while exosomes showed a sex-specific inverse association with diastolic blood pressure in males (r = -0.585, p = 0.028). However, neither biomarker independently predicted T2D after adjustment for confounders. These findings suggest a modest interplay between epigenetic modification and exosome signalling, warranting further investigation in larger studies.</p>","PeriodicalId":40142,"journal":{"name":"Global Medical Genetics","volume":"13 2","pages":"100109"},"PeriodicalIF":2.1,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13157153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147869772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"No significant increase in thrombotic risk following the widespread adoption of TPO-RAs in ITP: A comparative study.","authors":"Yun Wang, Huiyuan Li, Yunfei Chen, Xiaofan Liu, Rongfeng Fu, Wei Liu, Feng Xue, Lei Zhang, Renchi Yang","doi":"10.1016/j.gmg.2026.100107","DOIUrl":"10.1016/j.gmg.2026.100107","url":null,"abstract":"<p><p>In patients with primary immune thrombocytopenia (ITP), the risk of thrombosis associated with thrombopoietin receptor agonists (TPO-RAs) remains debated. This study compared the thrombosis occurrence in ITP patients before and after the launch of TPO-RAs in China, to explore the relationship between TPO-RAs and thrombosis in ITP patients. Data from 2005 to 2017 were obtained from an article published by the Blood Disease Hospital, Chinese Academy of Medical Sciences in 2018. The present study included 1915 hospitalized patients in the same center from January 2018 to February 2025. Among these, thrombosis events occurred in 33 cases (1.72%). The incidence of arterial thrombosis was higher than that of venous thrombosis. Male gender, age over 40 years old, hypertension, diabetes, smoking, and TPO-RAs were associated with thrombosis. Neither platelet count nor stage of ITP showed a significant effect on thrombosis risk. Although the utilization rate of TPO-RAs increased significantly after 2018, no corresponding significant change in thrombosis incidence was observed. These findings suggest that thrombosis in ITP patients results from the interplay of multiple risk factors. While the widespread use of TPO-RAs does not appear to increase the overall risk of thrombosis in ITP patients, caution is still advised when administering these agents to patients with pre-existing thrombosis risk factors.</p>","PeriodicalId":40142,"journal":{"name":"Global Medical Genetics","volume":"13 2","pages":"100107"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13091279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research on the imbalance of metal homeostasis and ferroptosis mechanisms in neurodegenerative diseases.","authors":"Peiyun Zhang, Wei Jin, Xinxuan Lyu, Shuaibo Zhu, Yanbing Lu, Yuzhen Chen, Lu Han, Ming Tao, Lihong Li","doi":"10.1016/j.gmg.2026.100108","DOIUrl":"10.1016/j.gmg.2026.100108","url":null,"abstract":"<p><strong>Objective: </strong>To investigate the associations between urinary and serum metal levels and neurodegenerative diseases (NGDs) as well as all-cause mortality, and identify research trends through bibliometric.</p><p><strong>Methods: </strong>This study first analyzed data from a large-scale national cross-sectional survey (2005-2018) involving 6288 participants. Multivariable regression models were used to assess the associations of urinary metals (Ba, Cd, Co, Cs, Mo, Pb, Sb, Tl, W) and serum metals (Fe, Cd, Pb, Hg) with the risk of neurodegenerative diseases (NGDs) and all-cause mortality. Subsequently, a bibliometric analysis was conducted on literature pertaining to \"metals\" and \"NGDs\" retrieved from the Web of Science Core Collection to identify research trends and key underlying mechanisms.</p><p><strong>Results: </strong>Epidemiological analyses revealed significant associations between several metals-such as Cd, Cs, Mo, Hg, and Pb-and either NGDs risk or all-cause mortality, with some exhibiting nonlinear patterns (<i>e.g.</i>L-shaped or inverted U-shaped relationships). Subsequent bibliometric analysis of 34,313 publications identified \"iron\" as a central hub keyword linking \"metal exposure\" to \"neurodegenerative diseases\". Mechanisms related to Fe-including \"oxidative stress\" and \"lipid peroxidation\"-emerged as research hotspot keywords. Notably, the cluster labeled \"ferroptosis\" demonstrated substantial scale in co-citation clustering. Research trajectories have evolved from broad pathological observations toward molecular-level investigations of the NLRP3 inflammasome, glutathione peroxidase 4 (GPX4), ultimately converged on the ferroptosis pathway.</p><p><strong>Conclusion: </strong>Exposure to multiple metals is significantly associated with the risk and prognosis of NGDs. Integrated bibliometric evidence highlights ferroptosis as the central mechanism bridging metal dyshomeostasis and neuronal injury, offering a cohesive evidence chain from population data to mechanistic insights.</p>","PeriodicalId":40142,"journal":{"name":"Global Medical Genetics","volume":"13 2","pages":"100108"},"PeriodicalIF":2.1,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13091291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147724310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and molecular characterization of giant axonal neuropathy due to a homozygous c.851 + 1G>A variant in <i>GAN</i>: A case report and literature review.","authors":"Emmanuel Rojas-Morales, Eduardo Esparza-García, María Teresa Magaña-Torres","doi":"10.1016/j.gmg.2026.100098","DOIUrl":"10.1016/j.gmg.2026.100098","url":null,"abstract":"<p><strong>Background: </strong>Giant Axonal Neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in the <i>GAN</i> gene, which encodes gigaxonin. The disease typically begins in childhood and is characterized by muscle weakness, gait disturbances, peripheral neuropathy, and distinctive kinky hair.</p><p><strong>Case description: </strong>We report the clinical, radiological, and molecular findings of a 7-year-old Mexican girl from Jalisco, Mexico, born to consanguineous parents, who presented with global developmental delay and absence of independent ambulation by age of seven. Additional features included kinky hair, broad forehead, blepharoptosis, depressed nasal bridge with a bulbous tip, high-arched palate, micrognathia, and generalized joint hyperlaxity. Given the phenotypic overlap with Noonan syndrome, <i>PTPN11</i> Sanger sequencing was initially performed, followed by a RASopathy gene panel; both analyses yielded negative results.</p><p><strong>Results: </strong>Whole-exome sequencing identified a homozygous splice-site variant in <i>GAN</i> c.851 + 1 G>A, which was confirmed by Sanger sequencing. Both parents were heterozygous carriers, consistent with parental consanguinity. According to ACMG/AMP guidelines (PVS1, PM2, PM3), the variant was classified as pathogenic. Additional studies, including brain magnetic resonance imaging, revealed peridentate hyperintensities compatible with gliosis or hypomyelination.</p><p><strong>Conclusion: </strong>The integration of clinical features, neuroimaging findings, and molecular analysis confirmed the diagnosis of giant axonal neuropathy type 1. This case underscores the clinical relevance of whole-exome sequencing in patients with overlapping syndromic features. Notably, the <i>GAN</i> c.851 + 1 G>A variant has previously been reported in at least five homozygous patients of Mexican ancestry, supporting a possible founder effect in this population.</p>","PeriodicalId":40142,"journal":{"name":"Global Medical Genetics","volume":"13 3","pages":"100098"},"PeriodicalIF":2.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13562385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148956921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanism study of novel compound heterozygous EOGT mutations leading to Adams-Oliver syndrome type 4.","authors":"Yufei He, Xiangyu Liu, Zongrui Shen, Tingting Xu, Fang Yang, Fu Xiong, Yuanling Xiao","doi":"10.1016/j.gmg.2026.100100","DOIUrl":"10.1016/j.gmg.2026.100100","url":null,"abstract":"<p><p>Adams-Oliver Syndrome Type 4 (AOS4) is a rare autosomal recessive disorder primarily characterized by aplasia cutis congenita and cranial defects. Pathogenic variants in several genes, including <i>DOCK6, ARHGAP31, EOGT, RBPJ, DLL4,</i> and <i>NOTCH1</i>, have been implicated in the etiology of AOS. In this study, we identified two novel compound heterozygous mutations in the <i>EOGT</i> gene (c.961 C>T, p.R321C and c.1115 G>A, p.R372Q) in a patient with AOS4. Both variants were predicted to be deleterious through structural and computational analyses, and these mutations are likely to impair enzymatic function without affecting subcellular localization. Given the established role of <i>EOGT</i> in O-GlcNAcylation and its regulatory relationship with Notch signaling, we further proposed that these mutations may disrupt Notch pathway activity through aberrant modification of Notch receptors, thereby contributing to the defective skin development observed in AOS4. These findings highlight a potential pathogenic mechanism for AOS4 and underscore the critical role of EOGT-mediated glycosylation in human development<b>.</b></p>","PeriodicalId":40142,"journal":{"name":"Global Medical Genetics","volume":"13 2","pages":"100100"},"PeriodicalIF":2.1,"publicationDate":"2026-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13058963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147647077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}