Search Results (159)

Background: Pathogenic variants in the NEXMIF gene have been linked to a broad neurodevelopmental phenotype, encompassing autism spectrum disorder, intellectual disability, and epilepsy. Among epileptic manifestations, Jeavons Syndrome was observed in 24% of affected females in the largest cohort of NEXMIF-related disorders reported to date, but long-term adult outcomes remain poorly documented. Methods and Results: We report a 25-year-old Italian woman with drug-resistant Jeavons syndrome in which the combined approach of next-generation sequencing and chromosomal microarray analysis allowed us to identify, after a 13-year diagnostic odyssey, a de novo ~350 Kb microdeletion at Xq13.2q13.3 encompassing the entire NEXMIF coding region, with no other OMIM genes involved. To our knowledge, this is the first reported case of a patient harboring a deletion restricted to the entire coding sequence of the NEXMIF gene. The patient presented with moderate intellectual disability and seizure onset at age 10 years. Her epilepsy proved refractory to multiple antiseizure medications. Video-EEG/polygraphic monitoring at age 23 years confirmed epilepsy with eyelid myoclonia, demonstrating characteristic eyelid myoclonia with absences triggered by eye closure. Conclutions: This case provides a detailed clinical description of an adult patient useful for genetic counseling regarding adult outcomes and prognostic expectations. Furthermore, this study underscores the diagnostic value of chromosomal microarray analysis alongside next-generation sequencing in individuals with intellectual disability and drug-resistant epilepsy, in order to expedite the diagnostic pathway and enable timelier and more appropriate patient management. Full article

Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disorder with marked clinical heterogeneity, frequently leading to delayed diagnosis. We describe a 71-year-old woman with lifelong episodic inflammatory symptoms beginning in infancy, including recurrent fevers, lymphadenopathy, and gastrointestinal and mucocutaneous manifestations, later evolving into intermittent arthralgia, myalgia, and fatigue. A unifying diagnosis was established when genetic testing identified two missense pathogenic MVK variants consistent with compound heterozygous MKD, supported by elevated serum IgD levels and a characteristic clinical phenotype. This case illustrates the essential role of molecular genetic testing in resolving prolonged diagnostic odyssey, in guiding surveillance for complications such as AA amyloidosis, and enabling targeted therapeutic strategies. Full article

Life evolved under a persistent 1 g field that is continuous, ubiquitous, and directionally structured. Here, we synthesize evidence across evolutionary biology, mechanobiology, and genome architecture to propose gravity as a mechanical boundary condition that helped canalize the emergence of complex multicellularity. Order-of-magnitude considerations indicate that gravity-derived hydrostatic loads can fall within force/pressure regimes relevant to nuclear and chromatin mechanosensitivity when transmitted through adhesion–cytoskeleton–LINC–lamina coupling. Comparative genomic and imaging frameworks suggest that complex animals increasingly rely on volumetric genome organization (packing domains and higher-order 3D architectures) that supports durable transcriptional memory and stable differentiated cell identities. Integrating these concepts with altered-gravity experiments, we argue that microgravity and hypergravity perturb chromatin topology and region-level transcription in rapid, largely reversible patterns consistent with a mechanically defined 1 g reference state. We advance a boundary-condition thesis: gravity is not a sole driver but a stable reference that likely contributed to the evolvability and long-term robustness of mechanogenomic architectures required for high-dimensional differentiation and tissue homeostasis. Full article

Background: Kleefstra syndrome (KS) is a rare neurodevelopmental disorder caused by haploinsufficiency of EHMT1; it is characterized by global developmental delay, intellectual disability, hypotonia, distinctive facial features, and variable congenital anomalies. Autistic features, behavioral abnormalities and severe speech impairment are frequently reported. However, molecularly confirmed cases of KS from Africa remain extremely limited, largely due to restricted access to genomic diagnostic infrastructures. Methods: We describe a 15-month-old patient from Rwanda presenting with neonatal hypotonia, global developmental delay, short stature, and characteristic dysmorphic facial features. Comprehensive clinical evaluation was performed, followed by trio-based exome sequencing to identify the underlying genetic cause of this neurodevelopmental disorder. Results: Exome sequencing identified a de novo heterozygous frameshift variant in EHMT1 (NM_024757.5: c.2871dup; p. Phe958Leufs*219), confirming the diagnosis of KS. Conclusions: This report presents the first molecularly confirmed case of KS in Rwanda. It highlights additional clinical features like bilateral 5th toe clinodactyly, short stature and absence of obesity in KS. There is a need to further delineate the study of EHMT1 and investigate the natural history of KS across different populations for optimal patient management and to reduce diagnostic odyssey. The diagnostic utility of exome sequencing for neurodevelopmental disorders needs to be strengthened, with strong emphasis on expanding genomic medicine to help diagnose rare diseases in resource-limited settings. Full article

Food waste poses significant environmental, economic and public health challenges. The black soldier fly (Hermetia illucens) larvae (BSFL) represent a promising solution for organic waste valorisation, converting substrates into protein-rich biomass for animal feed and organic fertiliser. However, the use of food waste as an insect substrate remains prohibited in the European Union due to regulatory and safety concerns. This study evaluated the suitability of heterogeneous food waste for BSFL rearing under industrial conditions by comparing larval performance on a standard Gainesville diet (control) and a blend derived from local restaurant waste (test). The 14-day bioconversion assay assessed bioconversion rate (BCR), feed conversion ratio (FCR), survival rate, average growth rate, and nutritional composition. Compared with the control, the test group showed significantly improved (p < 0.001) BCR (18.34% vs. 11.02%), FCR (5.48 vs. 9.09 kg/kg), survival (69.29% vs. 51.30%), and growth (8.38 vs. 6.59 mg/day). Larvae reared on food waste also exhibited significantly higher protein (19.70% vs. 16.80%), fat (13.70% vs. 7.20%), ash (6.97% vs. 3.51%), carbohydrates (7.00% vs. 3.60%), and fibre (5.20% vs. 2.90%). Overall, heterogeneous food waste is a suitable substrate for BSFL, supporting agrifood sustainability; however, future research should focus on standardisation of these substrates. Full article

Interest in the genomic sequencing of healthy newborns has raised a discussion on whether this technology should be introduced into existing newborn screening (NBS) programs. This qualitative study explores a multi-stakeholder perspective on the future of genomic sequencing in NBS. Semi-structured interviews were conducted with 26 professionals involved in NBS or in clinical genome sequencing in the Netherlands. Participants highlighted opportunities such as the possibility to use one test for a wide range of genetic conditions, reducing diagnostic odyssey, expanding the scope of NBS, and increasing program efficiency. Challenges were raised regarding genetic variant interpretation, expected increased parental anxiety, data privacy issues, difficulties with information provision, and high costs. Three areas of tension between participants’ perspectives were identified: screening strategy, screening performance, and roles and responsibilities. It was emphasized that implementing genomic sequencing should not risk reducing the current high NBS participation, and that enhancing knowledge, communication, and collaboration between all stakeholders is needed. Although most participants did not believe genomic sequencing as a first-tier test is currently desirable and feasible, they acknowledged it has a role to play in the future of NBS. Future decision-making should consider the potential impact on the participation rate, program quality, and balancing benefits and harms. Full article

Metastatic colorectal cancer (mCRC) accounts for 90% of CRC-related mortality. This review synthesizes insights from comparative genomics tracing evolutionary trajectories from primary tumor to disseminated disease. Multi-region sequencing reveals metastatic seeding often occurs early—before clinical detection—challenging linear progression models. The metastatic bottleneck reduces clonal diversity while enriching for dissemination-competent traits including SMAD4 loss, PTEN inactivation and metabolic reprogramming. Organ-specific adaptation yields distinct molecular signatures: liver metastases exhibit Wnt hyperactivation and TGF-β-driven immune suppression; peritoneal tumors display mucinous features; brain metastases show HER2 enrichment. The immune microenvironment evolves toward immunosuppressive configurations, with Microsatellite instability high (MSI-H) tumors acquiring B2M or JAK1/2 mutations. Circulating tumor DNA (ctDNA) enables real-time tracking of clonal dynamics, detecting molecular residual disease months before radiographic progression. Therapeutic resistance follows predictable evolutionary trajectories—from RAS/BRAF mutations to EGFR ectodomain alterations, HER2/MET amplifications and lineage plasticity—with metastasis-specific mechanisms including microenvironmental protection and cellular dormancy. The clinical future lies in interception: leveraging liquid biopsies for early detection, targeting both tumor-intrinsic vulnerabilities and permissive metastatic niches and adapting therapy dynamically to anticipate resistance. Understanding this genomic odyssey is essential for transforming mCRC into a controllable chronic condition. Full article

Background: Niemann–Pick type C is a lysosomal storage disorder that results from pathogenic variants in the NPC1 gene or in some cases from NPC2 pathogenic alterations. The disease presents a remarkable clinical variability that in some cases resembles common diseases, often resulting in a diagnostic odyssey or at least delaying proper diagnosis. In addition, the NPC1 gene is highly polymorphic, and consequently, when missense variants are identified after gene sequencing, accurate classification of their pathogenicity is essential to ensure appropriate access to available therapies and to provide reliable genetic counseling. Objectives: To get insights into the pathogenicity of a novel variant in NPC1, p.Cys800Ser, we created stable cell lines expressing this variant, in parallel with cell lines expressing the NPC1 wild-type and NPC1 pathogenic variants. Methods: We leveraged an isogenic cell line in which the NPC1 gene was knocked down and subsequently infected it with retroviruses carrying NPC1-WT and NPC1 variants C-terminally fused with an mNeonGreen tag. Three different NPC1 variants were included in this study: two known pathogenic variants, p.Ala1035Val and p.Pro1007Ala, and the novel p.Cys800Ser, whose significance was unknown. Results: We observed in the stable cell line expressing NPC1 p.Cys800Ser that the mutated NPC1 protein is transported to the lysosome similarly to the p.Pro1007Ala variant and affects lysosomal distribution. Conclusions: Using this approach, we could analyze the pathogenicity of each variant separately and these cell lines could be used for personalized medicine-based approaches and multi-omic studies. Full article

This article rereads Odysseus’s encounter with the Sirens in the Odyssey through the lens of sound, arguing that the episode stages a foundational tension between knowledge and alterity in Western thought. Drawing on Emmanuel Levinas’s notion of the “temptation of temptation,” the essay shows how Odysseus’s famous stratagem—hearing the Sirens while bound to the mast—models a form of mediated proximity that allows sound to be collected without ethical exposure. Close readings of Homeric Greek, especially the Sirens’ claim to knowledge of ὅσσα γένηται, reveal that their song gestures not merely toward retrospective epic knowledge but toward natality and coming-into-being, a dimension Homer pointedly withholds. By placing the Sirens alongside early colonial soundscapes and modern reflections on cartography, the article argues that Western listening practices privilege mastery over vulnerability. Against this tradition, the Sirens’ unheard song marks a suppressed alternative: listening as openness, risk, and ethical relation. Full article

Genetic variation in ATP Binding Cassette Subfamily C Member 6 (ABCC6) can cause both pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI). There are 930 distinct missense variants in ABCC6 reported, 87% of which are of uncertain clinical significance (VUS). New approaches are needed to mechanistically interpret and classify these VUS. We developed 3D protein models of ABCC6 in three functionally relevant conformations to calculate the structural effects of variants. We also used three-dimensional (3D) hotspot detection and developed a mechanistic ontology for critical structure-based functions of ABCC6, enabling us to categorize genomic variants. We identified two 3D hotspots and six specific functions of ABCC6 which variants impact. From this, we propose a mechanism for pathogenicity for 41% of VUS according to their impacted function. We propose that 33 of these variants could be reclassified as Likely Pathogenic with the addition of these structure-based evidence. The mechanistic information we present will guide future research to better address calcification disorders and understand genetic variants. This work emphasizes the benefits of thorough, holistic, and protein-based approaches to genetic interpretation. Further, our VUS reclassification approach will improve the diagnosis of ABCC6-driven diseases, shortening diagnostic odysseys. We believe that computational structural genomics approaches will soon take prominence in genomics data interpretation and variant classification. Full article

The global population continues to rise, placing increasing pressure on the agri-food sector and leading to the accelerated generation of urban organic waste, factors that collectively intensify climate stress and environmental instability. Insects are recognised for their remarkable capacity to transform substrates into valuable products, with the black soldier fly larvae (BSFL) emerging as one of the most efficient and widely utilised species for this purpose. Beyond recycling organic matter, BSFL can also mitigate microbial contamination, effectively reducing bacterial and fungal loads in waste substrates. Understanding and manipulating the genome could provide tools to improve BSFL bioconversion process and contribute to sustainability. In this review, we provide an overview of recent advances in black soldier fly genomics and genome-editing technologies. Although research in this subject remains limited, recent studies have clarified its origin, characterised its genome, and established the foundation for targeted genetic improvements to enhance by-product conversion, nutrient recovery, and environmental sustainability. Full article

Following a pot trial with annual ryegrass (Lollium multiflorum Lam. (Pooideae: Poaceae)), where the effect of chemical fertilization was compared with organic fertilization with Black Soldier Fly larvae frass (BSFF), obtained by bio-digestion of cattle production effluents, and with mixed fertilization in proportions of 25%, 50%, and 75% of BSFF, the effect on crop production and soil fertility was tested in three soils of different textures, namely, sandy soil (Gleyic podzol), calcareous soil (Haplic calcisol), and clay soil (Haplic fluvisol). On top of the previous experimental device, a second year of testing was carried out with sowing of the same crop, but without any fertilizer input in all the residual soils for the different further modalities. With regard to the second sowing cycle production, the results are supportive of the expectation that fertilization with BSFF has a superior capacity for soil fertility resilience (assessed in terms of the ability to maintain or even increase soil production in the following year, in the absence of any fertilizer application) in all the soils tested in this experiment, with a significantly greater difference in the treatment corresponding to fertilization with only BSFF compared to the exclusively chemical treatment, in all the soils tested. Furthermore, BSFF, preferably as a mixed fertilizer (in a proportion until 75%), is shown to be a promising alternative for Gleyic podzol in the production of ryegrass as in the resilience and promotion of soil productivity. As far as more fertile soils are concerned (as in the case of Haplic calcisol and Haplic fluvisol), BSFF has not proved promising in terms of immediate crop production. Full article

Folded, arcuate terrains on the surface of Mars provide insight into the volcanic properties of surface materials and emplacement dynamics. This research focused on the analysis of folded terrains in the chaotic-terrain Avernus Colles region, located near Elysium Planitia, using images from the Mars Odyssey Orbiter and altimetry data from the Mars Orbiter Laser Altimeter (MOLA). The combined data revealed areas of deformation, which is inferred to be the result of compressions and possibly collapse from the late Amazonian period. We identified and measured 19 distinct folds, with morphometric wavelengths ranging from 0.7 to 1.75 km. These measurements were applied to a simple two-layer regolith model to better understand the folding patterns observed. The model suggests that these folds could have formed with an upper viscous boundary layer less than 0.55 km thick and strain rates approximately 10⁻⁷ s⁻¹. These strain rates indicate that the deformation of the terrains likely occurred over a relatively short period of time, ranging from 16 to 38 days. By studying these deformation patterns, we can enhance our understanding of the volcanic history and surface processes on Mars, offering insight into the planet’s geologic evolution and material properties. Full article

Drawing inspiration from Stanley Kubrick’s iconic science fiction masterpiece, this study posits that the future of joint health is not confined to a singular trajectory but is instead shaped by our collective efforts towards pioneering initiatives that transcend present-day boundaries. From its inception to the horizon of 2050, the trajectory of arthroplasty presents a compelling narrative of medical innovation, socioeconomic challenges, and sustainability pursuits. This Perspective addresses the growing osteoarthritis epidemic, emphasizing the urgent need for prevention and early-intervention strategies to reduce disease progression in the context of imminent critical-raw-material scarcity and the transition to a carbon-free economy. This transition, aiming for Net Zero by 2050, may unintentionally lead to financial instabilities and healthcare disruptions—driven by supply-chain fragility and rising costs—and could thereby exacerbate inequities in access to elective joint replacement. The illustrative scenarios and conditional comparative trends presented here highlight potential co-occurring clinical, economic, and material risks under business-as-usual (BAU) assumptions. These multifaceted complexities warrant the development of coordinated strategies. By examining current trends and future challenges, this paper therefore calls for a holistic approach to the green transition that promotes multidisciplinary dialogue and policy alignment to ensure an ethical, equitable, and sustainable future for resilient arthroplasty services amid ongoing decarbonization initiatives. Full article