Search Results (1,429)

Noonan syndrome (NS) is a paradigmatic rare, genetically heterogeneous, multisystem disorder belonging to the RASopathies family, caused by dysregulated RAS/MAPK signaling. It is characterized by distinctive craniofacial features, postnatal short stature, and a high prevalence of congenital cardiac defects, with pulmonary valve stenosis (PS) and hypertrophic cardiomyopathy (HCM) being the hallmark lesions. First described by Dr. Jacqueline Noonan in 1968, the molecular era began with the discovery of PTPN11 mutations in 2001, revolutionizing diagnosis, risk stratification, and understanding of pathogenesis. Strong genotype–phenotype correlations now guide prognosis and personalized management; for instance, RAF1 and RIT1 variants confer a high risk of severe, early-onset HCM, while PTPN11 is strongly linked to dysplastic PS. Cardiac involvement remains the central determinant of long-term outcomes, requiring continuous surveillance from the prenatal period through adulthood. Management is inherently multidisciplinary, addressing endocrine, hematologic, neurodevelopmental, and oncologic aspects. Recent consensus statements emphasize the critical need for structured transition from pediatric to adult care. Novelty arises from the potential of MEK inhibitors as targeted therapies for severe HCM and lymphatic complications. This review provides a comprehensive update on NS, integrating foundational clinical knowledge with contemporary molecular insights, advanced cardiologic management, and emerging frontiers in therapy and diagnostics, underscoring the necessity of a proactive, lifelong, and personalized care approach. Full article

Objectives: To characterize heterozygous pathogenic COCH variants in a French cohort with non-syndromic sensorineural hearing loss (NSHL) and assess genotype–phenotype correlations in autosomal dominant NSHL (DFNA9). Setting: National Reference Center for Genetic Hearing Loss, Necker–Enfants Malades Hospital, Paris, France. Methods: This retrospective observational study included 69 individuals from 20 unrelated families diagnosed with DFNA9 (2005–2025). All individuals underwent clinical and audiological evaluations and genetic testing via targeted COCH Sanger sequencing or next-generation sequencing (NGS) panels. Variants were interpreted according to ACMG guidelines. Audiometric profiles and vestibular data were collected. Results: Seven known pathogenic COCH variants were found in ten families, and ten novel likely pathogenic variants in the others. Variants in vWFA domains were associated with early or late onset, progressive, bilateral and symmetrical hearing loss. Three variants (p.Gln410Arg, p.Ile450Val, p.Cys542Arg) were associated with congenital or prelingual onset, an atypical DFNA9 presentation. Variants in the LCCL domain were associated with later-onset hearing loss and more frequent vestibular dysfunction. Vestibular abnormalities were observed in about half of early-onset cases. Conclusions:COCH-related hearing loss is a rare cause of autosomal dominant NSHL, with only 20 families identified over two decades within the French network. This study expands the mutational spectrum of COCH by reporting ten novel variants and supports a domain-specific genotype–phenotype correlation. These findings improve the understanding of DFNA9 variability and have direct implications for clinical diagnosis, prognosis, and genetic counseling. Full article

Background: Dystonia is a heterogeneous hyperkinetic movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures. Although numerous genes associated with dystonia have been identified, the genetic background remains unknown in many patients. Data on genotype–phenotype correlations in Polish populations remain limited. Objective: To analyze the clinical characteristics of patients with generalized dystonia and compare clinical features between individuals with and without genetically confirmed dystonia-causative variants in a Polish cohort. Methods: A retrospective analysis of patients diagnosed with generalized dystonia at a single neurological center was performed. Diagnosis was established according to MDS criteria. Genetic analysis included whole-exome sequencing, targeted NGS genetic panel, MLPA, Sanger sequencing and PCR_RFLP analysis. Clinical and demographic data were extracted from medical records. Clinical characteristics of individuals with and without causative variants were compared. Results: A total of 113 patients with generalized dystonia were included. Genetic variants were identified in 13 patients (11.5%). These included variants within the TOR1A, THAP1, SGCE, GCH1, NKX2-1, SLC2A1, KMT2B, PDHA1, MFN2, and GNAL genes. We found detailed clinical data of 46 patients included in the study. Our comparative analysis of patients with causative (n = 7) and without causative variants (n = 39) revealed no statistically significant differences in age of onset, initial symptom localization, treatment response, family history, or associated neurological features. Conclusions: In this cohort of Polish patients with generalized dystonia, we identified pathogenic variants in approximately 11.5% of cases. No significant clinical differences were observed between patients with genetically confirmed dystonia and those without identified variants. In this study, we report the first two Polish cases with DYT-GNAL variants. Further studies are required to reveal the clinical heterogeneity of dystonia and characterize dystonia subtypes. Full article

Heritable thoracic aortic diseases (HTAD) are inherited conditions that increase the risk of thoracic aortic aneurysms, dissections, and premature aortic rupture. Advances in human genetics and experimental models have transformed our understanding of these disorders from a phenotype-based classification system to a mechanism-based view involving extracellular matrix (ECM) architecture, transforming growth factor-β (TGFβ) signaling, and vascular smooth muscle cell contractility. Marfan syndrome, Loeys–Dietz syndrome, and nonsyndromic HTAD demonstrate how genetic mutations can disrupt the components that stabilize the aortic wall. These pathogenic mechanisms influence matrix organization, intracellular signaling, and the contractile machinery within the mechanically stressed proximal aorta. In this review, we summarize current mechanistic insights into the major forms of HTAD and discuss how new molecular and cellular concepts could influence surveillance, genetic counseling, and genotype-guided therapeutic strategies. Full article

Background/Objectives: As a global chromatin organizer, SATB1 is increasingly implicated in neurodevelopmental disorders (NDDs). This study aims to delineate the clinical and molecular characteristics of a novel de novo SATB1 variant in a patient presenting with epilepsy-dominant NDDs phenotypes. Methods: Triggered by the onset of seizures, trio-based whole-exome sequencing (Trio-WES) was performed to identify the genetic etiology. Subsequent sleep electroencephalogram (EEG) and magnetic resonance imaging (MRI) were then conducted to further characterize the patient’s clinical phenotypes. Pathogenicity was assessed through structural modeling and functional characterization. Nonsense-mediated mRNA decay (NMD) status, protein expression profiles, and subcellular localization were determined by reverse-transcription quantitative PCR (RT-qPCR), Western blotting, and immunofluorescence staining. The transcriptional regulatory impacts of the variant were quantified using dual-luciferase reporter system targeting known downstream regulatory elements. Clinical responses to antiepileptic intervention was also monitored. Results: We identified a novel de novo heterozygous pathogenic frameshift variant in SATB1 (NM_002971.5: c.1718_1719insCA; p.Val574Argfs*134) in a patient presenting with early-onset epilepsy, mild intellectual developmental disorder (IDD), speech delay, and dental anomalies. Functional assays demonstrated that the variant-derived transcript escaping NMD, yielding a truncated protein that forms irregular punctate aggregates within nuclei. Dual-luciferase assays revealed significantly increased transcriptional activity, indicating a loss of the protein’s innate transcriptional regulatory capacity. Clinically, treatment with sodium valproate (VPA) successfully stabilized seizures of the patient, markedly reducing both frequency and intensity. Conclusions: The study reports a novel SATB1 frameshift variant that exerts pathogenicity significant functional impairment by disrupting protein localization and transcriptional regulation. These findings expand the genetic spectrum of SATB1-related NDDs and underscore the efficacy of targeted antiepileptic management in genetic diseases. Full article

TANGO2-deficiency disorder (TDD) is a rare autosomal recessive condition characterised by neurodevelopmental delay, TANGO2 spells, life-threatening metabolic crises, and cardiac arrhythmias. Genotype–phenotype correlations remain poorly defined and the neurobehavioural profile of affected individuals is largely unexplored. We conducted a retrospective multicentre study of five Italian patients with genetically confirmed TDD, identified between June 2023 and May 2025. Clinical, neurophysiological, neuroimaging, genetic, and neurodevelopmental data were collected. Adaptive functioning, cognitive ability, and behavioural profiles were assessed using standardised instruments. All five patients carried biallelic TANGO2 mutations, including two previously unreported variants. Clinical severity ranged from an asymptomatic individual under preventive therapy to a fatal early-onset metabolic crisis. Marked intrafamilial variability was observed in two siblings sharing the same genotype. Systematic neurodevelopmental assessment revealed a spectrum of cognitive and adaptive outcomes, with attentional difficulties identified as a recurrent feature. No metabolic crises or TANGO2 spells were documented following initiation of B-vitamin and cofactor supplementation in surviving patients. This cohort expands the mutational and phenotypic spectrum of TDD and highlights the diagnostic value of TANGO2 testing in patients with neurodevelopmental delay or paroxysmal neurological episodes, even in the absence of metabolic crises. Early supplementation therapy may contribute to clinical stability, though prospective controlled studies are needed. Full article

Bacterial blight (BB), caused by Xanthomonas oryzae pv. Oryzae (Xoo), is one of the most devastating diseases in rice worldwide. Common wild rice (Oryza rufipogon Griff.) inhabiting the high-temperature and high-humidity environments of Hainan Island has evolved strong disease resistance through natural selection, representing a valuable genetic reservoir for resistance breeding. However, large-scale characterization of resistance phenotypes, resistance genes, and their combinations remains limited. In this study, we evaluated BB resistance in 1511 Hainan common wild rice accessions against three Xoo strains (HNX004, PXO99^A, and Z173) and analyzed the distribution of ten major known resistance genes (Xa1, Xa3, Xa4, xa5, Xa7, Xa10, xa13, Xa21, Xa23, and Xa27). Phenotypic evaluation revealed distinct strain-specific resistance patterns. Broad-spectrum resistance analysis (defined as moderate resistance or higher) revealed that 35 accessions (2.32%) were resistant to all strains, and 378 accessions (25.02%) showed resistance to two strains. Genotyping of known resistance genes revealed that, except for one accession, which lacked all tested genes but showed resistance to strain PXO99^A, all other accessions carried every tested gene except Xa21 and xa13. Interestingly, different Xoo strains exhibited distinct requirements for resistance genes, revealing a clear strain-specific resistance pattern. Notably, the number of resistance genes did not correlate with resistance level. Instead, specific complementary combinations, particularly Xa1 + Xa10 + Xa23 + Xa4 + Xa7, conferred the strongest broad-spectrum resistance. Our results demonstrate that gene quality and specific complementary combinations are more important than the absolute number of resistance genes. The identified resistant accessions and favorable gene combinations provide valuable resources for rice breeding programs. Full article

Carbapenem-resistant Pseudomonas aeruginosa is increasingly becoming a global health threat. However, although aquatic environments are key resistance reservoirs, data obtained from high-altitude ecosystems are scarce. Whole-genome sequencing of eight carbapenem-resistant P. aeruginosa isolates collected from aquatic environments in the Tibetan Plateau identified three sequence types (STs), with ST1420 predominating (62.5%, 5/8). Phylogenetic analysis revealed a close clustering of isolates with those from distant clinical settings, suggesting potential cross-habitat transmission. All studied strains were multidrug-resistant, exhibiting 100% resistance to imipenem, ceftriaxone, and trimethoprim–sulfamethoxazole. This included the PA6 strain, which showed multiple-antibiotic resistance. Eight strains harbored the intrinsic carbapenemase gene bla_OXA-50. The diverse virulence-gene profiles of strains PA2, PA4, and PA6 aligned with their high pathogenicity observed both in vitro and in vivo. However, virulence genotypes sometimes did not correlate with phenotypes, revealing the limitations of relying on static genetic information alone. This study highlights the aquatic environments of the Tibetan Plateau as reservoirs of carbapenem-resistant P. aeruginosa with substantial genetic diversity and divergent pathogenic potential, underscoring their public-health relevance. Full article

Background: Congenital sucrase–isomaltase deficiency (CSID) may mimic functional gastrointestinal disorders (FGIDs) and is likely underrecognized in pediatric practice. This study aimed to determine the frequency of sucrase–isomaltase (SI) gene variants among children with FGIDs and to evaluate genotype–phenotype associations and treatment-related quality-of-life outcomes. Methods: In this prospective cross-sectional study, children aged 0–18 years diagnosed with FGIDs according to Rome IV criteria were enrolled between May 2022 and January 2023. All patients underwent next-generation sequencing for SI gene variants. Clinical characteristics, FGID subtypes, and anthropometric data were recorded. Variant-positive patients received dietary sucrose restriction, and selected patients were treated with sacrosidase enzyme replacement. Symptom severity was assessed using the Numeric Rating Scale, and quality of life was evaluated with the Pediatric Quality of Life Inventory (PedsQL 4.0). Results: Among 290 children with FGIDs, SI gene variants were identified in 17 patients (5.9%). Variants were more frequently detected in children with irritable bowel syndrome–like symptoms. Clinical presentation was heterogeneous, and no consistent genotype–phenotype correlation was observed. Dietary intervention was associated with symptom improvement in compliant patients, while sacrosidase therapy led to significant improvements in both child- and parent-reported PedsQL scores. Conclusions: Sucrase–isomaltase deficiency is not uncommon among children with FGIDs and should be considered, particularly in those with IBS-like symptoms or diet-related complaints. Integrating genetic evaluation with targeted dietary and enzyme-based therapy may improve symptom control and quality of life in selected pediatric patients. Full article

The planet faces the critical interconnected challenges of climate change and antimicrobial resistance (AMR); these two crises mutually reinforce each other, threatening global health and ecosystem stability. This study conducts a systematic documentary analysis to map the convergence and identify the structural gaps between two key technological domains: artificial intelligence (AI) for climate action and molecular methods for AMR. The methodology was based on a corpus of 179 scientific documents indexed in Scopus (2010–2025), analyzed with data science tools to identify trends, collaborations, and impact. Quantitative results revealed clear leadership by the United States, accounting for 37.4% of publications, followed by China (26.8%); this leadership reflects the concentration of high-throughput molecular surveillance infrastructure and data science clusters essential for monitoring the environmental resistome. In terms of scientific impact, Spain showed the highest average, with 32.8 citations per article. The most influential work, a review on food security and sustainability, accumulated 275 citations. Network analysis identified authors such as Zhu, Yongguan, with 240 citations in total, as central nodes in international collaborations. Thematically, metagenomics and machine learning emerged as mature and interconnected research cores. This analysis confirms a solid yet still fragmented relationship between the two fields. The analysis reveals that, while metagenomic tools dominate the current literature, a gap persists in correlating genotypic resistance potential with functional phenotypic expression under changing climatic stressors. The results confirm a solid yet still fragmented foundation, highlighting the need for hybrid platforms that transition from descriptive bibliometrics to functional integration for designing systemic solutions. Future work should prioritize the development of hybrid platforms, such as intelligent biosensors, and collaborative governance frameworks that accelerate effective responses to these dual crises. Full article

We present a neonatal case of Wiedemann–Steiner syndrome (WSS) with a de novo, previously reported KMT2A missense variant (c.3464G>A; p.Cys1155Tyr; NM_001197104.2), and provide a focused literature review of this specific variant. WSS (OMIM#605130) is a rare neurodevelopmental disorder caused by heterozygous variants in the KMT2A gene, which encodes a histone H3 lysine K4 (H3K4) methyltransferase involved in transcriptional regulation. Clinically, the syndrome is characterized by developmental delay, distinctive facial features, short stature, hypertrichosis, and neurological manifestations such as hypotonia and seizures. In this single-patient report, we describe additional clinical findings, including interstitial lung disease and hypertrophic pyloric stenosis requiring surgical intervention. These may represent rare manifestations of WSS that require confirmation in further reports before a formal expansion of the phenotypic spectrum can be established. Most pathogenic KMT2A variants arise de novo and are typically nonsense or frameshift; however, missense variants have also been reported and may have complex functional consequences. Haploinsufficiency is considered the primary pathogenic mechanism, leading to the disruption of chromatin modification and transcriptional regulation. While emerging genotype–phenotype correlations are being identified, considerable variability remains. Given the single-patient nature of this study, these observations should be considered hypothesis-generating and require confirmation in additional cases. Full article

Cutaneous lichen amyloidosis (CLA) is a rare dermatological condition characterized by amyloid deposition in the skin, presenting as pruritic, hyperkeratotic papules. Although most cases are sporadic, CLA has been associated with multiple endocrine neoplasia type 2A (MEN2A), a hereditary syndrome caused by germline alterations in the RET proto-oncogene. In MEN2A, CLA is typically localized to the interscapular region and linked to RET codon 634 variants, whereas generalized forms are rare. We report a male patient with MEN2A and a generalized form of CLA that preceded the diagnosis of primary hyperparathyroidism (PHPT) and medullary thyroid carcinoma (MTC). Genetic testing using Sanger sequencing identified an ultra-rare heterozygous RET variant, p.Y806C, in exon 14, currently classified as a variant of uncertain significance (VUS). This variant has not been previously described in association with MEN2A. This case may contribute to understanding genotype–phenotype correlations in MEN2A and suggests that atypical or generalized CLA may be an early clinical clue warranting consideration of RET genetic testing. Full article

Background/Objectives: Acute intravascular hemolysis is associated with the release of labile heme, which contributes to systemic inflammation and organ dysfunction. Galectin-3 (Gal-3) is a known modulator of inflammatory responses. However, its specific role in heme-induced organ injury remains to be fully elucidated. Methods: We used a phenylhydrazine (PHZ)-induced model of acute hemolysis in wild-type (WT) and Gal-3 knockout (KO) mice to investigate the influence of Gal-3 on tissue alterations and the inflammatory response. Results: Despite equivalent levels of hemolysis and anemia in both genotypes, Gal-3 deficiency was associated with reduced injury in the liver, kidneys, and pancreas. In WT mice, Gal-3 was associated with a pro-inflammatory splenic microenvironment. Conversely, Gal-3 KO mice exhibited a shift toward an immunoregulatory phenotype, characterized by an increased frequency of CD4 + CD25 + FoxP3+ regulatory T cells and IL-10+ macrophages. This shift correlated with preserved organ architecture and a more controlled inflammatory profile. Conclusions: Our findings suggest that Gal-3 may act as a mediator of heme-induced systemic inflammation. By influencing the splenic immune microenvironment and promoting a regulatory phenotype, the absence of Gal-3 appears to alleviate multi-organ stress, suggesting its potential as a target for modulating complications during acute hemolytic crises. Full article

Background/Objectives: Bruck syndrome type 2 (BS2) is an ultra-rare autosomal recessive disorder within the osteogenesis imperfecta (OI) spectrum caused by biallelic pathogenic variants in PLOD2, which encodes lysyl hydroxylase 2 (LH2), an enzyme essential for bone-specific collagen cross-linking. Marked clinical heterogeneity complicates diagnosis, particularly in patients with atypical or incomplete presentations. We aimed to further delineate the clinical and molecular spectrum of PLOD2-associated disease. Methods: In this descriptive case series, we performed clinical, radiological, and molecular evaluations of four patients from three unrelated families, including two previously reported siblings. Molecular testing comprised targeted next-generation sequencing or whole-exome sequencing, followed by Sanger sequencing for variant confirmation and familial segregation analysis where feasible. Results: Four PLOD2 variants (NM_182943.3) were identified: homozygous c.1885A > G (p.Thr629Ala) in two siblings; c.8dup (p.(Cys4MetfsTer35)) and c.2222G > A (p.(Gly741Glu)) in one patient; and homozygous c.2027A > C (p.(Tyr676Ser)) in one infant. Three variants were previously unreported. Two missense variants remained classified as variants of uncertain significance, and the phase of the two heterozygous variants detected in one patient could not be established because a paternal sample was unavailable. Clinical severity was variable: age at first fracture ranged from 3 months to 4 years, and cumulative fracture burden ranged from 3 to multiple recurrent fractures. One 10-year-old patient had a severe OI-like phenotype without congenital contractures. Older patients showed additional axial and pelvic involvement, including craniovertebral junction abnormalities and acetabular protrusion. Conclusions: This case series broadens the range of clinical presentations observed in PLOD2-associated disease and indicates that severe bone fragility may occur in the absence of congenital contractures. These findings support inclusion of PLOD2 in the differential diagnosis of patients with unexplained bone fragility and progressive skeletal deformities. Additional well-characterized cases and functional studies are needed to refine genotype–phenotype correlations and clarify the clinical significance of newly identified variants. Full article

Background/Objectives: DDX3X syndrome (MIM#300958) is a neurodevelopmental disorder associated with intellectual disability, language impairment, and a characteristic neurobehavioral phenotype that predominantly affects females. Although dysmorphic features have been reported, a consistent facial phenotype and clear genotype–phenotype correlations have not been established. Methods: We conducted an observational, ambispective, descriptive study including patients aged 0–18 years with a molecular diagnosis of DDX3X. Clinical, standardized facial images, neurobehavioral, neuroimaging, and molecular data were collected. Automated facial analysis was performed using Face2Gene after algorithm training. Results: Of 11 identified patients, 9 were included (8 females); 8 variants were de novo and 4 novel. Two variants of uncertain significance underwent in silico analysis. Frequent facial features included thin upper lip (9/9), tapered chin (8/9), long uniform eyebrows (8/9), short neck (8/9), and long face (6/9). After training, Face2Gene identified DDX3X syndrome in 92% of cases within the top 5 suggestions, supporting its utility as a diagnostic aid. All females had intellectual disability and language disorder; 66% presented sleep disturbances and aggressive behavior. Neuroimaging revealed ventricular dilatation (5/9) and corpus callosum hypoplasia (3/9). Loss-of-function variants were associated with greater clinical severity. Conclusions: This series suggests a recognizable facial phenotype of DDX3X syndrome and supports a possible genotype–phenotype correlation. Further studies are needed to confirm these findings. Full article