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PubMed2026

FBN1-related connective tissue disorders: unraveling cardiovascular, skeletal, and ocular complications through TGF-β signaling dysregulation and genotypic correlations.

Fibrillin-1 is an extracellular matrix glycoprotein essential for microfibril integrity, mediating cell-matrix interactions, providing structural support to tissues, and serving as a scaffold for elastogenesis. Pathogenic variants in the fibrillin 1 gene (FBN1) give rise to a spectrum of autosomal dominant connective tissue disorders collectively termed type-1 fibrillinopathies, which include Marfan syndrome, geleophysic dysplasia 2, acromicric dysplasia, Weill-Marchesani syndrome 2, marfanoid-progeroid-lipodystrophy syndrome, stiff skin syndrome, MASS syndrome, and isolated ectopia lentis 1. These disorders predominantly manifest cardiovascular, skeletal, and ocular abnormalities. Among these, aortic and valvular lesions are the principal and most life-threatening complications and therefore warrant the greatest clinical attention. Skeletal anomalies are diverse and can even be diametrically opposed across different phenotypes, while ectopia lentis represents the hallmark of ocular conditions. Notably, mutant fibrillin-1 disrupts microfibril structure and/or function, leading to dysregulated transforming growth factor-β (TGF-β) signaling, which is widely recognized as a central mechanism underlying type-1 fibrillinopathies. Although numerous pathogenic FBN1 variants have been identified, the knowledge of genotype-phenotype correlations remains limited in some specific regions. This review synthesizes the current understanding of the FBN1-related molecular mechanisms linking aberrant TGF-β signaling to distinct phenotypic outcomes and discusses how genetically engineered animal models and human induced pluripotent stem cell models advance mechanistic insights and facilitate therapy development. Additionally, clinical manifestations and genetic characteristics across all phenotypes are elaborated to facilitate diagnosis, treatment, and management of these complex disorders.

Cardiovascular complications↗
PubMed2026

The extracellular matrix in cancer-associated fibrosis: molecular mechanisms and clinical relevance.

The ECM is a dynamic component of the tumor microenvironment with a critical role in cancer progression, invasion, metastasis, immune exclusion, and response to therapy. Recent advances in proteomic analyses investigating the insoluble ECM fractions (termed "matrisome analysis"), along with single-cell RNA sequencing and spatial transcriptomics, have revealed cancer-specific patterns of ECM remodeling. These studies have identified a panel of recurrently upregulated ECM proteins, including annexin A1, fibrillin-1, fibronectin, periostin, and tenascin-C, actively contributing to tumor growth, invasion, angiogenesis, and immune exclusion. The expression of the cancer-associated ECM is largely driven by cancer-associated fibroblasts (CAFs), whose molecular diversity has been dissected through single-cell profiling and consolidated in emerging CAF atlases across cancers. By investigating the matrisome composition and CAF heterogeneity, these studies have unraveled the pivotal role of the stroma in shaping tumor biology. Based on these discoveries, ECM proteins and CAFs are now being explored as biomarkers and therapeutic targets. Future integration of multi-omics datasets with clinical outcomes will help to translate these insights into novel biomarkers for patient stratification and stroma-directed therapeutic interventions.

Humans↗
PubMed2025

Utility of genome sequencing and group-enrichment to support splice variant interpretation in Marfan syndrome.

PURPOSE: To quantify the impact of noncanonical FBN1 splice site variants in undiagnosed Marfan syndrome (MFS), a connective tissue disorder associated with skeletal abnormalities and familial thoracic aortic aneurysm disease (FTAAD). METHODS: A systematic analysis of ultrarare FBN1 variants was performed using genome sequencing data from the 100,000 Genomes Project. Variants were annotated with SpliceAI and the significance of enrichment among individuals with FTAAD was assessed using Fisher's exact test. Experimental validation used RNA sequencing, reverse transcriptase polymerase chain reaction, minigene constructs, and replication analysis was with data from UK Biobank. RESULTS: Using aggregate data for 78,195 individuals, we identified 13,864 singleton single-nucleotide variants in FBN1 of which 21 were predicted to affect splicing (SpliceAI > 0.5). Incidence of candidate splice variants in individuals recruited with FTAAD (9/703) was significantly elevated compared with that seen in non-FTAAD participants (12/77,492; odds ratio = 84, P = 9.7 × 10-14). Additional analysis uncovered a further 14 families harboring 11 different FBN1 splice variants. A total of 20 candidate splice variants in 23 families were identified, of which 70% lay beyond the ±8 splice regions. RNA testing confirmed the predicted splice aberration in 16 of 20 and for 9 of 20, pseudoexonization was the likely splicing anomaly. CONCLUSION: Our findings indicate that noncanonical splice variants may account for approximately 3% of families with undiagnosed FTAAD, highlighting the importance of incorporating analysis of introns and confirmatory RNA testing into genetic testing for Marfan syndrome.

Humans↗
PubMed2025

Genotype-first assessment of presentation and penetrance of neurofibromatosis type 1, autosomal dominant polycystic kidney disease, and Marfan syndrome within the All of Us research program cohort.

PURPOSE: Phenotype-based ascertainment of probands in studies of Mendelian disorders may exclude individuals with mild phenotypes or that lack health care access. We explore this premise in All of Us Research Program participants with pathogenic variation causal for 3 Mendelian conditions: autosomal dominant polycystic kidney disease (ADPKD), Marfan syndrome, and neurofibromatosis type 1 (NF1). METHODS: We identified All of Us Research Program participants with putatively pathogenic variation in NF1, FBN1, PKD1, and PKD2. Concept terms were extracted from electronic health records to assess participant diagnosis and phenotype. Variant annotation and participant surveys were evaluated to identify biological and social factors differentiating diagnosed and undiagnosed individuals. RESULTS: Large proportions of individuals with pathogenic variation in NF1, FBN1, or PKD1/PKD2 lack the associated diagnosis of NF1 (47%), Marfan syndrome (58%), or ADPKD (52%), respectively. Pathogenic variants in diagnosed individuals have greater inferred deleteriousness for NF1 and ADPKD, and undiagnosed individuals had less severe phenotypes compared with diagnosed individuals for all 3 conditions. CONCLUSION: A genotype-first ascertainment of individuals in genomic research allows for a more comprehensive assessment of Mendelian disease and removes biases that confound our understanding of the penetrance and presentation of these conditions.

Humans↗
PubMed2026

Losartan shows limited benefit in preclinical models of Geleophysic dysplasia.

Geleophysic dysplasia (GD) is a rare genetic disorder characterized by short stature, joint contractures, and cardiopulmonary complications, with early mortality, and linked to mutations in ADAMTSL2 (GD1), FBN1 (GD2), or LTBP3 (GD3) genes. These mutations are hypothesized to disrupt extracellular matrix (ECM) organization and enhance transforming growth factor beta (TGF-β) signaling. Losartan, an angiotensin II receptor blocker, has been proposed to mitigate TGF-β-mediated pathologies. In this study we tested the efficacy of losartan as a therapeutic drug for GD. We evaluated losartan's therapeutic potential using Adamtsl2 p.A165T mutant mice and patient-derived fibroblasts. Survival, growth, TGF-β signaling, and ECM protein expression were assessed. Losartan did not improve survival or growth in our mutant mice. Compared with control fibroblasts, patient-derived fibroblasts showed reduced basal TGF-β1 secretion. Consistent with this finding, transcriptomic analyses did not reveal activation of the TGF-β signaling pathway, and no differences in SMAD phosphorylation were observed between patient and control cells. Losartan treatment failed to modulate TGF-β signaling or ECM protein incorporation. These results suggest limited benefits of losartan in GD and challenge the notion of TGF-β dysregulation in GD pathogenesis, indicating a need for alternative targeted therapies.

Losartan↗
PubMed2025

Unraveling a novel FBN1 variant in Marfan syndrome with dilated aortic root manifestation.

BACKGROUND: Marfan syndrome (MFS) is a genetic disorder affecting connective tissue, with variable incidence rates. A significant portion of cases stems from novel genetic variants, while others inherit it from affected parents. OBJECTIVE: This study focuses on identifying the genetic cause of MFS in a specific family, using whole-exome sequencing (WES). METHODS: A 15-year-old male with confirmed MFS was examined, showing symptoms of palpitations and severe mitral valve regurgitation. WES was performed, followed by confirmation with Sanger sequencing. Variants were assessed for pathogenicity using bioinformatics tools and the American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: One potentially novel pathogenic variant was found in exon 14 of the FBN1 gene: c.1676delCinsAAT, p.Ala559GlufsTer21. In silico analysis suggested a deleterious impact on protein structure and function, supporting their pathogenic classification. CONCLUSION: The identification of this novel variant highlights the importance of the FBN1 gene in MFS, especially its cardiovascular manifestations. Early intervention can improve patient outcomes, while ongoing research holds promise for further advancements in treatment for Marfan syndrome.

Humans↗