Congenital contractural arachnodactyly (CCA) is a rare autosomal dominant connective tissue disorder, and FBN2 is its only known causative gene. CCA is characterized by joint contractures, arachnodactyly, scoliosis, and crumpled ears. Due to its rarity, phenotypic diversity, heterogeneity, and clinical overlap with conditions such as Marfan syndrome (MFS), the diagnosis remains challenging, and genetic screening plays a critical role in facilitating accurate diagnosis. We recruited a CCA family with three patients across three generations and detected their genetic etiology. The proband exhibited the Marfanoid habitus with a height of 121 cm (> + 3 SD), a weight of 16 kg (-2 SD ∼-1 SD), arachnodactyly, and long bone overgrowth. He had joint contractures in the 2nd ∼ 5th fingers of bilateral hands and 2nd and 5th toes of the left foot. His mother and grandmother also presented arachnodactyly and arachnodactyly. They were confirmed to be affected with CCA. A novel heterozygous missense variant in the exon 30 of FBN2 (NM_001999.4: c.3916T > G, p.Y1306D) was identified by whole-exome sequencing. The variant was classified as "likely pathogenic" according to the American College of Medical Genetics and Genomics guidelines and standards. Bioinformatics predictions revealed that the variant altered the hydrophobicity, extended an intrinsically disordered protein region, disrupted a benzene ring structure on a β-sheet, and modified the surface charge of the fibrillin-2 partial region. We descripted a CCA family and identified a novel FBN2 variant. Our findings extended the variant spectrum of FBN2, contributing to the genetic counseling and molecular diagnostics for CCA.
Emotional intelligence (EI) has emerged as a critical neurocognitive construct linking affective processing, social behavior, and adaptive functioning. This integrative narrative review synthesizes multidisciplinary findings to map the biological underpinnings of EI across genetic, epigenetic, neuroanatomical, and neurophysiological domains. Drawing on evidence from neuroimaging, molecular genetics, neurochemistry, and brain connectivity studies, the review suggests EI as a product of dynamic interactions between prefrontal-limbic circuits, neurotransmitter systems, and environmentally sensitive regulatory mechanisms. Key brain structures, including the prefrontal cortex, amygdala, anterior cingulate cortex, and insula, operate within coordinated networks that support the recognition, regulation, and social cognition of emotions. Neurotransmitters such as dopamine, serotonin, oxytocin, and gamma-aminobutyric acid (GABA) modulate the emotional reactivity and cognitive control essential to EI. Epigenetic modifications further explain the lifelong plasticity of emotional capacities in response to experience. Anchored in the process model of emotion regulation and the social brain hypothesis, this review provides a cohesive neuroscientific framework for EI. It outlines its translational implications in education, healthcare, and affective computing. By consolidating current advances, this review may help inform precision interventions and policy initiatives aimed at enhancing emotional resilience, empathy, and psychological well-being.
In non-endemic settings, imported malaria poses diagnostic challenges due to non-specific presentations and lack of immunity, especially in visiting friends and relatives (VFRs). Focusing on the Western Friuli (Italy) observatory, this work aims to optimize triage by identifying early severity predictors. Through the analysis of clinical parameters, paediatric cerebral cases, and host genetics - including an illustrative case of HbS/β-thalassaemia - we evaluate the drivers of Plasmodium falciparum progression to improve patient management. This retrospective study (2016-2025) analysed symptomatic malaria cases in the Friuli Occidentale Health Authority, combining epidemiological data with illustrative clinical cases. Diagnosis was confirmed via microscopy and molecular methods. Using WHO/AMCLI criteria, we evaluated admission parameters, including procalcitonin (PCT), C-reactive protein (CRP), and platelet count, to identify predictors of severe malaria, adopting a ≥2% parasitaemia threshold. Diagnostic accuracy was assessed via multivariable logistic regression and ROC analysis. Of the 124 malaria cases (P. falciparum 88.71%), 90.32% were VFRs, primarily from West Africa; only 12% reported adequate prophylaxis. Severe malaria occurred in 19.35% (24/124), including two cerebral malaria (CM) cases, with no fatalities. Severity fluctuated significantly, peaking at 60% (6/10; 95% CI 26.2%-87.8%) in 2025. Multivariable analysis identified parasitaemia ≥2% (aOR 8.44; 95% CI 2.41-29.58; p=0.001) and PCT (aOR 1.23; 95% CI 1.06-1.42; p=0.007) as the only independent severity predictors. PCT outperformed CRP (AUC 0.84 vs 0.73); at a 5.10 ng/mL cut-off, PCT demonstrated a 95.9% negative predictive value (NPV), effectively identifying low-risk patients. CM Case 1 (2017): A 5-year-old male with HbS/β-thalassaemia (VFR, from Ghana) admitted for P. falciparum malaria (9.5% parasitaemia) and severe anaemia, evolving into CM (loss of consciousness, seizures, BCS score 0); successfully treated with IV artesunate, antiepileptics, and blood transfusions, without sequelae. CM Case 2 (2022): A 3-year-old male (VFR, from Burkina Faso) with P. falciparum malaria (12.6% parasitaemia) evolving into CM (altered state of consciousness, EEG signs of cerebral distress, retinal haemorrhage, BCS score 2); resolved with IV artesunate and antiepileptics without sequelae. Imported malaria remains a critical challenge due to unpredictable severity trends and non-specific onset of CM. PCT, combined with parasitaemia, outperformed CRP and platelet count as an independent predictor of severity. High PCT levels should serve as a "red flag" for immediate triage and parenteral therapy. Integrating PCT into clinical guidelines is essential for effective risk stratification and preventing life-threatening complications in non-endemic settings.
Kissing can be observed across the animal kingdom. This presents an evolutionary puzzle, since the fitness benefits of kissing are unclear. We use a non-anthropocentric approach to define kissing as a non-agonistic interaction involving directed, intraspecific, oral-oral contact with some movement of the lips/mouthparts and no food transfer. Using this definition we collate basic observational data across the Afro-Eurasian primates and employ Bayesian phylogenetic methods to reconstruct the evolutionary history of kissing. We find that kissing occurs in most extant large apes, and likely also occurred in Neanderthals (Homo neanderthalensis), first evolving in the ancestor to this group ~21.5-16.9 mya. Additionally, we highlight various life history variables that correlate reasonably, but not perfectly, with kissing across the apes (multi-male mating systems, non-folivorous diets, and premastication). With a major caveat about the quantity of available data at present, we hope that our results provide a useful starting point for further research into the adaptive function of kissing that highlights hypothesis generation and testing within a phylogenetic framework.
Candida albicans is a common opportunistic pathogen. Genotyping based on the 25S rDNA and mating type locus (MTL) allows for epidemiological and genetic profiling. This study aimed to characterize the genotypes and mating types of C. albicans isolates from various clinical sources in Iran. Ninety-four isolates from clinical samples (saliva, urine, vaginal swabs, and skin scrapings) were cultured on CHROMagar Candida and identified by standard phenotypic methods. Genotyping was performed using CAINT primers, and mating type analysis was conducted using MTLa1 and MTLα1 primers. In this study, 94 isolates of C. albicans from various sources were analyzed. Genotype A was the most frequent (65%), followed by genotypes C (24.5%), B (9.6%), and D (1.1%). Most isolates (97.9%) were heterozygous at the MTL locus, only two isolates homozygous (α/α). Genotype A and MTL-heterozygous strains were predominant among C. albicans isolates, suggesting a consistent molecular pattern across different clinical sources and regions.
Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases, lacking efficient therapies. Direct correction of mtDNA mutations may offer a cure for such diseases. We propose a novel strategy based on double-stranded DNA (dsDNA) oligonucleotide delivery into mitochondria and intrinsic microhomology-mediated end joining (MMEJ) for mtDNA editing. This strategy enables the introduction of multiple predefined nucleotide changes in mtDNA. For this, the presence of MMEJ activity in the human mitochondrial lysates was confirmed. Forty-nine bp DNA oligonucleotide duplexes, fused to an RNA hairpin previously identified as a mitochondrial import signal, were delivered into the mitochondria of cultured human cells. Delivery of these donor dsDNA molecules, homologous to an ND4 site of mtDNA and bearing designed nucleotide changes, led to a low but statistically significant introduction of the intended nucleotide changes into mtDNA. Donor dsDNA delivery combined with the CRISPR-mito-AsCas12a system also resulted in a statistically significant number of an expected concomitant change of five nucleotides distributed across a 16 nt ND4 site of the mitochondrial genome. The proposed strategy may become an efficient mtDNA editing tool suitable for the correction of near-homoplasmic mutations, such as Leber's hereditary optic neuropathy (LHON)-associated mutations in the ND4 gene of mtDNA.
The objective of this case report is to describe the challenging surgical procedure of a rare, massive retroperitoneal leiomyoma and administration of postoperative circulation reconstruction, while addressing the patient's significant perioperative psychological distress. A 52-year-old woman presented with fever and oliguria for 1 week. She presented with a giant pelvic and abdominal mass measuring 48×48×25 cm3. After multidisciplinary preparation and rectification of the mentioned detrimental symptoms, she underwent transabdominal resection with total hysterectomy and bilateral salpingo-oophorectomy. To prevent hemodynamic instability during tumor removal, a warm water bag was applied in situ during slow lifting of the mass. The 40-kg massive retroperitoneal neoplasm resulted in that the right kidney and ureter were displaced toward the abdominal midline. Throughout the tumor resection procedure, the upper one-third segment of the ureter was inadvertently transected, and a ureteral stent was placed. Postoperative pathological examination confirmed a spindle cell tumor in the right adnexal region, accompanied by hyaline degeneration and infarction, consistent with degenerative changes of leiomyoma. To reduce the risk of postoperative volume redistribution, we carried out rigorous management intraoperatively and postoperatively. Meanwhile, the patient's Hamilton Anxiety Scale (HAMA) score decreased from 21 preoperatively to 9 postoperatively, with a reduction rate exceeding 50%, confirming a marked psychological therapeutic effect. This case emphasizes the critical role of multidisciplinary collaboration in the management of complex retroperitoneal masses and suggests that active clinical intervention can still yield favorable outcomes for patients with untreated conditions. It is worth emphasizing that psychological intervention is of great significance during her initial consultation, and empathetic and encouraging methods might be able to help her face this illness and receive treatment earlier.
The treatment of HIV infection has entered a dichotomous phase, as established oral regimens are now sharing the landscape with long acting injectable combination therapies. By looking at the new antiretrovirals in the pipeline it is apparent that the future of HIV treatment will be largely covered by long-acting regimens, with an increasing shift toward injectable formulations allowing much less frequent administration; in parallel, the development of novel once-daily oral combinations, as well as oral long acting therapies is expected to further expand treatment options. However, the current HIV-infected population still includes a large proportion of patients with a variety of immunovirological conditions whose weaknesses require the currently available strongest option, such as a triple oral regimen including a 2nd generation integrase strand-transfer inhibitor (INSTI) like the co-formulation containing Bictegravir (BIC), Emtricitabine (FTC) and Tenofovir alafenamide (TAF). Further to a proportion of newly diagnosed HIV infections at an advanced disease stage still exceeding 50%, many are the patients whose history may include a late start of treatment, virologic failures and a suboptimal immune recovery. BIC/FTC/TAF is the point of arrival of decades of antiretroviral research and has the pharmacologic characteristics to guarantee the therapeutic success in most patients with difficult-to treat infections. Properties like intrinsic potency, strong genetic barrier and forgiveness of BIC/FTC/TAF are unique among currently available antiretroviral regimens and make this single tablet combination as the gold standard for comparative studies of new therapeutic solutions. The main clinical-pharmacologic features of BIC/FTC/TAF are here analysed with the intention to focus on some key advantages this regimen may offer whenever the individual conditions are less than ideal for other regimens.
In some crosses, the hybrid progeny perform better than their parental inbred lines in terms of beneficial traits (e.g., greater biomass, faster development), a phenomenon known as hybrid vigor or heterosis. While classical genetic paradigms explain much of its basis, how these interactions translate into specific molecular frameworks remains a significant challenge. Mounting evidence indicates that epigenetic regulation-encompassing chromatin states, histone modifications, DNA methylation, and small RNAs-reshapes the hybrid transcriptional landscape. While many studies provide compelling correlations between epigenetic remodeling and heterotic phenotypes, a definitive mechanistic synthesis remains elusive due to the complexity of distinguishing cause from consequence. This review integrates current knowledge of these multilayered regulatory systems, emphasizing the redundant and hierarchical nature of epigenetic interactions that sustain the heterotic state. We highlight the transition from descriptive profiling to functional validation, and discuss how emerging tools such as targeted epigenome editing for recreating optimal hybrid methylotypes may finally bridge the gap between epigenetic variation and hybrid vigor.
This study presents a genetic analysis of three-generation family exhibiting terminal 19p13.3 duplication resulting from a maternal balanced translocation, t (19; 21) (p13.3; p12). Additionally, we reviewed previously reported cases with similar aberrations. Peripheral blood or amniotic fluid samples from six family members were comprehensively analyzed using G-banding, N-banding, fluorescence in situ hybridization (FISH), and copy number variation sequencing (CNV-seq). Furthermore, a genomic mapping analysis was performed on 23 cases of terminal 19p13.3 duplication, combining our findings with those from previously reported cases. The results demonstrated that the maternal balanced translocation resulted in three offspring inheriting the 19p13.3 terminal duplication. The proband presented with typical clinical features such as intrauterine growth restriction, microcephaly, intellectual disability, developmental delay, and facial abnormalities, in addition to precocious puberty, autism spectrum disorder (ASD) features, and a shortened lingual frenulum. The precocious puberty phenotype is postulated to be associated with the KISS1R gene within the duplicated region. Genomic mapping identified a minimal overlapping region (MOR) of approximately 313 kb (chr19:3,223,850-3,536,224), encompassing four OMIM genes (CELF5, NFIC, DOHH, FZR1) and two protein-coding genes (SMIM24, SMIM44). This study clarifies the genetic mechanism of pure terminal 19p13.3 duplication in offspring resulting from a parental balanced translocation involving D/G group chromosomes. It also defines a novel critical region based on case samples with 19p13.3 terminal duplication, providing new insights into the genotype-phenotype correlations associated with terminal pure 19p13.3 duplications.
This study aimed to enhance glucose oxidase (GOX) production in Pichia pastoris GS115 using a novel dual-promoter system, combining the constitutive glyceraldehyde-3-phosphate dehydrogenase promoter (pGAP) in pGAPZαA with the methanol-inducible Alcohol oxidase 1 promoter (pAOX1) in PIC9. The GOX gene from Aspergillus niger (ATCC 9029) and a transcription factor, general control nonderepressible 4 (GCN4) gene from P. pastoris were co-expressed to mitigate oxidative stress, thereby improving cell viability and enzyme yield. The recombinant construct pGAPZαA-GOX-GCN4 was transformed into P. pastoris GS115 and P. pastoris GS115-PIC9 via electroporation. Expression conditions under various temperatures and pH treatments were optimized. We examined glucose oxidase expression by inducing methanol at concentrations of 100% and 5% in BMMY (Buffered Methanol-complex-medium). The highest enzyme levels were observed at pH 6.0, 34°C, and 5% methanol induction. Enzyme validation was performed using SDS and Western blotting. Co-expression of GCN4 significantly enhanced GOX production, achieving 16.65 μg/mL (333 U/mL) in P. pastoris GS115-PIC9-pGAPZαA-GOX-GCN4(2), a 377.4-fold increase over the control, and 11.03 μg/mL (220.6 U/mL) in P. pastoris GS115-PIC9-pGAPZαA-GOX-GCN4(3), a 249.65-fold increase. The results demonstrate that GCN4's stress mitigation amplifies the synergy between constitutive and inducible promoters. The dual-promoter strategy offers a robust platform for recombinant protein production.
This study aims to elucidate the potential bidirectional genetic relationship between frailty and preeclampsia (PE), which currently remains unclear. We performed a bidirectional two-sample Mendelian randomization (MR) analysis to assess the causal link between the frailty index (FI) and PE. Summary statistics for FI were sourced from the IEU Open GWAS project (ebi-a-GCST90020053). For PE, two independent datasets were employed: one from IEU Open GWAS (ebi-a-GCST90018906) and another from the FinnGen R12 release (finn-b-O15_PREECLAMPS), to improve robustness and generalizability. The primary analysis used the inverse variance weighted (IVW) method, supported by MR-Egger, weighted median, simple mode and weighted mode methods. Sensitivity analyses were performed using Cochrane's Q test, the MR-Egger intercept test, the MR-PRESSO global test and leave-one-out analysis. Genetically predicted FI conferred an increased odds of PE, as robustly demonstrated by the IVW method in both independent datasets: ebi-a-GCST90018906 (OR = 3.027, 95% CI [1.445, 6.343], P = 0.003]) and finn-b-O15_PREECLAMPS (OR = 1.561, 95% CI [1.013, 2.404], P = 0.043). Conversely, PE also showed a significant causal effect on FI in the FinnGen dataset (OR = 1.047, 95% CI [1.031, 1.064], P < 0.001). These results indicate that higher genetically predicted frailty is a risk factor for PE and PE may in turn contribute to the exacerbation of frailty. The robustness of these associations was supported by consistent findings across multiple sensitivity analyses. This study provides suggestive genetic evidence for a potential bidirectional relationship between frailty and PE. The forward-direction findings, with frailty as the exposure and PE as the outcome, were consistently supported across two independent datasets, while the reverse-direction findings, with PE as the exposure and frailty as the outcome, were dataset-dependent and require further validation. Frailty may represent a promising target for obstetric risk stratification, pending confirmation in pregnant populations.
Starch biosynthesis in rice (Oryza sativa) is precisely regulated in an organ-specific manner, but the molecular mechanism operating this pathway in root-tip columella cells has remained unclear. Here, we elucidated the starch biosynthetic pathway in rice root tips using CRISPR/Cas9-mediated mutagenesis, Lugol's iodine staining, expression analysis, anatomical validation, and quantitative analysis of starch and soluble sugar contents. Systematic genetic screening revealed that disrupting genes encoding individual large (AGPL) or small (AGPS) subunits of ADP-glucose pyrophosphorylase (AGPase) did not affect columella starch accumulation, indicating functional redundancy. Expression profiling and double-knockout analysis demonstrated that starch biosynthesis in columella amyloplasts specifically requires the plastidic AGPase subunits OsAGPL1, OsAGPL4, OsAGPS1, and OsAGPS2a, whereas cytosolic AGPase subunits are dispensable for this pathway. Subunit-specific disruption further showed that OsAGPS2a, but not OsAGPS2b, is essential for starch formation in columella cells, establishing the exclusive requirement for plastidic AGPase function in this tissue. We also show that glucose-6-phosphate (Glc-6-P) import into columella amyloplasts is mediated by Glc-6-P/Phosphate Translocator 1 (OsGPT1), whereas OsGPT2 paralogs do not appear to contribute to this process. Loss of OsGPT1 function markedly diminished, but did not completely abolish, starch accumulation. These changes were accompanied by lower soluble sugar levels, suggesting that disrupting plastidic starch biosynthesis impairs sink strength in root-tip tissues. Analysis of resin-embedded sections confirmed that starch deposition is restricted to columella amyloplasts and is dependent on plastidic AGPase and OsGPT1 function. Together, our results define a complete plastidic starch biosynthetic pathway in rice root-tip columella cells and establish this tissue as a distinct, locally specialized metabolic sink within the organ-specific carbon partitioning network of rice.
RNA interference (RNAi) regulates gene expression through small RNAs that act via Argonaute-containing RNA-induced silencing complexes (RISCs). We previously found that short RNAs with G-rich 6mer seeds (e.g., GGGGGC and G5C) can kill cells by targeting C-rich 3' UTR seed matches in essential survival genes (SGs), a mechanism termed death induced by survival gene elimination (DISE). To assess therapeutic potential, we systemically delivered two DISE-inducing sRNAs, sG5C and sCAG (based on CAG trinucleotide repeats), using lipopolyplexes (LPPs) composed of low-molecular-weight polyethyleneimines and lipids. In mouse ovarian and prostate cancer models and a rat hepatocellular carcinoma model, LPP-delivered small RNAs (sRNAs) markedly reduced or eliminated tumors without harming normal tissues. Predicted SG targets were engaged in tumors. Transcriptomic analyses across 10 major human cancers showed that many sG5C-targeted SGs are consistently upregulated in tumors and increase with stage, revealing a therapeutic window. These results support LPP-delivered DISE-inducing sRNAs as a promising pan-cancer therapy.
Retrieval-augmented generation (RAG) is rapidly emerging as a transformative paradigm for large language models (LLMs), especially in high-stakes domains like oncology that demand precision, factual grounding, and up-to-date knowledge. By pairing LLMs with external knowledge repositories, RAG systems explicitly ground model outputs in relevant retrieved documents, helping to reduce hallucinations and ensure responses reflect current evidence. In oncology, where clinical knowledge evolves continually with new research and drug approvals, RAG offers a way to integrate the latest data (e.g., trial results, guidelines, genomic databases) into decision-making. This review synthesizes the technical foundations of RAG, including its architecture and key components, and examines current applications in oncology such as clinical decision support, patient education, radiology reporting, pathology analysis, and genomics-driven precision medicine. We highlight recent studies that demonstrate RAG's potential-for instance, improving treatment recommendations by incorporating genetic profiles and literature, and enhancing diagnostic accuracy by integrating guidelines. We also discuss emerging developments like multimodal RAG (combining text with imaging or other data), ensemble model approaches, and new explainability tools that trace model outputs to sources. Finally, we critically analyze the limitations and challenges of deploying RAG in healthcare, including computational costs, retrieval errors, noise or conflicts in retrieved information, and ethical and regulatory considerations. While RAG-based systems show promise in augmenting oncologists' expertise with timely knowledge, careful implementation, high-quality curation of knowledge bases, and human oversight will be crucial for safe and effective adoption in clinical practice.
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No prior meta-analysis has systematically assessed efficacy and safety of C-type natriuretic peptide (CNP) analogs within the context of evolving understanding of FGFR3 biology and achondroplasia natural history. To evaluate the safety and efficacy of CNP analogs in children with achondroplasia and contextualize clinical outcomes and natural history. Systematic review of randomized control trials and real-world studies evaluating the safety and efficacy of CNP analogs (vosoritide and navepegritide) in children aged <18 years with genetically confirmed achondroplasia was performed. Coprimary outcomes of interest were adverse events (AEs) and changes from baseline in annualized growth velocity (AGV) at the end of the trials. Secondary outcomes included changes from baseline in height Z-score, standing height, and upper-to-lower body segment (ULS) ratio. Eleven studies (N = 542) were included, of which 4 RCTs (n = 326) with low overall risk of bias were meta-analyzed. Overall and serious AE rates were comparable between CNP analogs and placebo, except for higher relative risks of injection site reactions (1.65), urticaria (4.04), and swelling (3.57). C-type natriuretic peptide analogs significantly increased mean differences in AGV (1.36 cm/year; 95% CI: 1.05-1.68; P < .00001) and standing height (1.24 cm; 95% CI: 0.47-2.01; P = .002), without short-term effect on ULS ratio. Real-world studies demonstrated sustained growth benefits with infrequent serious AEs or treatment discontinuations. C-type natriuretic peptide analogs provide slight but statistically meaningful improvements in linear growth in children with achondroplasia with acceptable short-term safety profile. Long-term studies are needed to define optimal timing of therapy on adult height, functional outcomes, and achondroplasia-related complications.
The causal relationship between gut microbiota and lactose intolerance (LI) remains elusive due to confounding factors in observational studies. This study aims to decipher the bidirectional causal link between specific gut bacterial taxa and LI by integrating genetic inference with experimental validation. We employed a two-sample bidirectional Mendelian Randomization (MR) analysis using summary statistics from the MiBioGen Consortium (gut microbiota) and the FinnGen study (LI). Robustness was assessed via inverse-variance weighted (IVW), MR-Egger, and sensitivity analyses. To validate the genomic findings, we established a lactose-intolerant rat model induced by a high-lactose diet and analyzed cecal microbiota composition using 16S rRNA high-throughput sequencing. MR analysis identified significant causal associations: the class Deltaproteobacteria, genus Bilophila were identified as potential risk factors for LI, whereas the genus Paraprevotella and Blautia exhibited protective effects. Notably, reverse MR analysis suggested that LI genetically influences host gut microbiota, particularly suppressing carbohydrate metabolism and blooming Bifidobacterium. Experimental sequencing in rats corroborated these findings, showing a distinctive alteration in microbial structure, specifically an increased abundance of Bifidobacterium and a depletion of Blautia in the high-lactose group, consistent with the genetic inference. This study provides robust evidence for a causal interplay between gut microbiota and LI. The convergence of genetic and experimental data highlights specific taxa, particularly Bifidobacterium and Blautia, as potential biomarkers or therapeutic targets. These findings offer new insights into the microbial etiology of metabolic disorders and suggest microbiota-targeted strategies for LI management.
COG5-related congenital disorder of glycosylation (COG5-CDG) is a rare autosomal recessive metabolic disorder with variable neurologic and ophthalmologic involvement. We report two siblings presenting with optic atrophy, macular atrophy, and neurodevelopmental delay; these three phenotypic manifestations have not, to our knowledge, been combined together in previously described individuals with COG5-CDG. The genetic disorder was only diagnosed through whole genome sequencing (WGS) after panel-based exome testing was unrevealing. Both siblings presented with early-onset severe visual impairment, bilateral optic atrophy, central macular atrophy, sensory nystagmus, and strabismus in the setting of global developmental delay. Additional features included polymicrogyria and hypotonia (Case 1) and microcephaly and autism spectrum disorder (Case 2). After repeated non-diagnostic inherited retinal gene panels, clinical quad WGS identified compound heterozygous variants in COG5 in both siblings: a paternally inherited pathogenic frameshift variant (c.1415dup) and a maternally inherited deep intronic variant (c.417 + 4779A>G) with high SpliceAI-predicted splicing impact. Visual function has remained relatively stable over 5 years of follow-up. These cases expand the phenotypic spectrum of COG5-CDG to include concurrent optic nerve and macular involvement with neurodevelopmental impairment and highlight the essential role of WGS in diagnosing complex neuro-ophthalmologic presentations when targeted genetic testing is nondiagnostic.
[This corrects the article DOI: 10.3389/fpls.2026.1754820.].