Variants of uncertain significance (VUS) in genes implicated in thoracic aortic aneurysm (TAA) present clinical challenges due to ambiguous pathogenicity and low patient representation. This study investigates the pathogenic potential of missense VUS in the ROBO4 gene, previously associated with vascular integrity and ascending aortic aneurysm. Clinical and genetic data from five patients with heterozygous ROBO4 VUS and thoracic aortic aneurysms or dissections were analyzed. Computational tools including AlphaFold2, AlphaMissense, REVEL, PolyPhen-2, SIFT, FATHMM, MutationTaster2, GranthamMatrix, and PhastCons were utilized to predict pathogenicity and structural impacts. Patients exhibited varying severities of aortic pathology, from elective aneurysm repairs to extensive familial aneurysmal histories. Structural modeling revealed significant differences in residue positions and biochemical properties, particularly for extracellular domain variants affecting critical beta-sheet structures involved in vascular stability. Notably, patient-specific predictions aligned computational evidence with clinical severity, suggesting potential genotype-phenotype correlations. For example, a variant (Q44P) showed strong pathogenic predictions coinciding with severe familial presentations. These computational predictions, validated by clinical data, highlight a novel and efficient workflow for evaluating VUS pathogenicity, informing precision medicine, and guiding counseling for aortic degenerative diseases. Ultimately, we demonstrate the value of integrating computational modeling with clinical data to decipher the pathogenic significance of genetic variants in cardiovascular diseases.
{"title":"Leveraging in-silico deep learning and computational analyses to predict the pathogenicity of ROBO4 variants of uncertain significance in aortic aneurysm and dissection patients.","authors":"Chanseo Lee, Irbaz Hameed, Michela Cupo, Ely Erez, Harris Ahmad, Jaihyoung Lee, Shiv Verma, Waleed Saeed, Asad S Fatimi, Roland Assi, Prashanth Vallabhajosyula","doi":"10.1186/s12872-025-05357-5","DOIUrl":"https://doi.org/10.1186/s12872-025-05357-5","url":null,"abstract":"<p><p>Variants of uncertain significance (VUS) in genes implicated in thoracic aortic aneurysm (TAA) present clinical challenges due to ambiguous pathogenicity and low patient representation. This study investigates the pathogenic potential of missense VUS in the ROBO4 gene, previously associated with vascular integrity and ascending aortic aneurysm. Clinical and genetic data from five patients with heterozygous ROBO4 VUS and thoracic aortic aneurysms or dissections were analyzed. Computational tools including AlphaFold2, AlphaMissense, REVEL, PolyPhen-2, SIFT, FATHMM, MutationTaster2, GranthamMatrix, and PhastCons were utilized to predict pathogenicity and structural impacts. Patients exhibited varying severities of aortic pathology, from elective aneurysm repairs to extensive familial aneurysmal histories. Structural modeling revealed significant differences in residue positions and biochemical properties, particularly for extracellular domain variants affecting critical beta-sheet structures involved in vascular stability. Notably, patient-specific predictions aligned computational evidence with clinical severity, suggesting potential genotype-phenotype correlations. For example, a variant (Q44P) showed strong pathogenic predictions coinciding with severe familial presentations. These computational predictions, validated by clinical data, highlight a novel and efficient workflow for evaluating VUS pathogenicity, informing precision medicine, and guiding counseling for aortic degenerative diseases. Ultimately, we demonstrate the value of integrating computational modeling with clinical data to decipher the pathogenic significance of genetic variants in cardiovascular diseases.</p>","PeriodicalId":9195,"journal":{"name":"BMC Cardiovascular Disorders","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-04DOI: 10.1186/s12872-026-05571-9
Omer Abdalhaleem Omer Ahmed, Mahmood Abbas, Ali Abdelhaleem Omar Ahmed, Mamdoh Abbas Ali Ibrahim, Mugtaba Eltag Mohammed Abakar, Elhaitham Yasir, Mohamed Elfatih Esameldin Edris, Reem Abdelhaleem Omar Ahmed, Rana Abdelhaleem Omar Ahmed, Mojahid Babkir, Mohamed Adil Mubarak Abdulaziz, Henry A Sota, Collins Gilbert, Ahmed Ashraf Eissa
{"title":"Direct oral anticoagulants versus vitamin K antagonists for postoperative atrial fibrillation after cardiac surgery: a systematic review and meta-analysis of randomized controlled trials.","authors":"Omer Abdalhaleem Omer Ahmed, Mahmood Abbas, Ali Abdelhaleem Omar Ahmed, Mamdoh Abbas Ali Ibrahim, Mugtaba Eltag Mohammed Abakar, Elhaitham Yasir, Mohamed Elfatih Esameldin Edris, Reem Abdelhaleem Omar Ahmed, Rana Abdelhaleem Omar Ahmed, Mojahid Babkir, Mohamed Adil Mubarak Abdulaziz, Henry A Sota, Collins Gilbert, Ahmed Ashraf Eissa","doi":"10.1186/s12872-026-05571-9","DOIUrl":"https://doi.org/10.1186/s12872-026-05571-9","url":null,"abstract":"","PeriodicalId":9195,"journal":{"name":"BMC Cardiovascular Disorders","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-04DOI: 10.1186/s12872-026-05566-6
Guijian Liu, Kuan Cheng, Ye Xu, Yang Pang, Yunlong Ling, Qingxing Chen, Wenqing Zhu, Junbo Ge
{"title":"Comparative analysis of Chinese large language model performance on atrial fibrillation questions.","authors":"Guijian Liu, Kuan Cheng, Ye Xu, Yang Pang, Yunlong Ling, Qingxing Chen, Wenqing Zhu, Junbo Ge","doi":"10.1186/s12872-026-05566-6","DOIUrl":"https://doi.org/10.1186/s12872-026-05566-6","url":null,"abstract":"","PeriodicalId":9195,"journal":{"name":"BMC Cardiovascular Disorders","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-04DOI: 10.1186/s12872-026-05552-y
Øyvind Næss, Huong Nguyen Thu
{"title":"Unobserved individual-level variation in cardiovascular mortality in birth cohorts born before and after 1945.","authors":"Øyvind Næss, Huong Nguyen Thu","doi":"10.1186/s12872-026-05552-y","DOIUrl":"https://doi.org/10.1186/s12872-026-05552-y","url":null,"abstract":"","PeriodicalId":9195,"journal":{"name":"BMC Cardiovascular Disorders","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-04DOI: 10.1186/s12872-026-05581-7
Hong Wang, Zhihong Ma, Siqi Ge, Junping Tian
{"title":"Association of triglyceride-glucose index with carotid atherosclerosis in the general population: a case-control study of 14,535 participants.","authors":"Hong Wang, Zhihong Ma, Siqi Ge, Junping Tian","doi":"10.1186/s12872-026-05581-7","DOIUrl":"https://doi.org/10.1186/s12872-026-05581-7","url":null,"abstract":"","PeriodicalId":9195,"journal":{"name":"BMC Cardiovascular Disorders","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-02-04DOI: 10.1186/s12872-026-05587-1
Xiang Fang, Ruhui Liu, Jing Zeng
{"title":"Early-onset hypertension associated with a CACNA1H variant of uncertain significance: a case report and literature review.","authors":"Xiang Fang, Ruhui Liu, Jing Zeng","doi":"10.1186/s12872-026-05587-1","DOIUrl":"https://doi.org/10.1186/s12872-026-05587-1","url":null,"abstract":"","PeriodicalId":9195,"journal":{"name":"BMC Cardiovascular Disorders","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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