Search Results (20,619)

Background: Immunotherapy efficacy in esophageal squamous cell carcinoma (ESCC) is often limited by an immunosuppressive tumor microenvironment (TME). NLRC5, a key regulator of MHC-I antigen presentation, exhibits context-dependent roles in tumor immunity; however, its function in ESCC remains unclear. This study aimed to systematically investigate the expression pattern, prognostic value, and immunological role of NLRC5 in ESCC. Methods: An integrated analysis of bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) data was performed using multiple cohorts, including The Cancer Genome Atlas, Gene Expression Omnibus, and an in-house ESCC cohort. Differential expression, survival analysis, immune infiltration estimation, and functional enrichment analyses were conducted to elucidate the role of NLRC5 in the tumor microenvironment. Results: NLRC5 was significantly upregulated in ESCC and its high expression independently predicted poor patient survival. Although NLRC5 expression was associated with increased CD8⁺ T cell infiltration, it was paradoxically accompanied by features of T-cell exhaustion and elevated expression of multiple immune checkpoints. Moreover, NLRC5-high tumors were enriched in transcriptional programs related to PANoptosis, indicating an additional immunosuppressive mechanism within the TME. Conclusions: NLRC5 is not only a prognostic biomarker but also a key modulator of an immune-active yet functionally suppressed tumor microenvironment in ESCC. These findings highlight NLRC5 as a potential therapeutic target for restoring effective antitumor immunity. Full article

Boule is the ancestral member of the Deleted in Azoospermia (DAZ) family and is pivotal for gametogenesis and male fertility in most animals. However, there is a dearth of information on molluscan boule. Here, we identified a counterpart (Pcbol) from the genome of Pomacea canaliculata, which has emerged as a cosmopolitan alien species and notorious pest that causes devastating damage to aquatic biodiversity, freshwater ecosystems and crop production in invaded ranges. This study aimed to investigate the biological roles of Pcbol in male reproduction and to decipher the molecular mechanisms underpinning its modulation via dsRNA-delivered RNA interference (RNAi). The bioinformatic analysis showed that the Pcbol genomic sequence is 12,934 nt in length, harboring an open reading frame of 294 nt that encodes 97 aa residues, with an RRM domain evolutionarily conserved among molluscan orthologues. Spatiotemporal expression profiling indicated the predominant abundance of Pcbol in adult males and testis tissues. dsPcbol, injected at a dose of 4 μg/per snail for 5 days, yielded optimal silencing at both transcript and translation levels of Pcbol, as revealed by qRT-PCR and Western blotting. Immunofluorescence echoed a pronounced reduction in Pcbol signal intensity following RNAi. In addition to the arrested reproductive gland phenotype, the number of sperm cells substantially dwindled upon dsPcbol treatment relative to the dsGFP control. In biochemical and fecundity assays, Pcbol depletion triggered a significant decrease in Te/SP/Arg content and suppressed the number of deposited eggs and hatchability. Furthermore, spermatogenic genes like CDC25/TSSK1/SPATA17/DDX4/Dmrt2/Sox2/Kelch10/SPO11 displayed considerable downregulation post Pcbol silencing, with molecular docking predicting a strong affinity between CDC25 and Pcbol. These molecular modules may interact with Pcbol to mediate knockdown effects on spermatogenesis dysfunction. Collectively, our findings not only confirmed that boule was indispensable for spermatogenesis and male fertility in a mollusk, but also highlighted the Pcbol-based male sterile technique (MST), which can be incorporated into precision pest management (PPM) strategies for sustainable control of P. canaliculata. Full article

Mitochondria regulate nuclear genomes and their own genetic material, primarily to provide energy in eukaryotes. Currently, high-throughput sequencing technologies are being used to resolve the mitochondrial genomes of various edible fungi. However, the application of pan-genomes for the analysis of edible mushroom mitochondrial genomes remains unexplored. In this study, we conducted a comparative mitochondrial genome analysis of 31 Hypsizygus marmoreus strains (four newly sequenced monotypes and 27 public datasets), ranging from 98,284 to 111,087 bp. This variation was determined to be primarily driven by dynamic changes in non-coding regions, particularly intronic polymorphisms in the cox1 gene. Further, transfer RNA (tRNA) secondary structures exhibited atypical globular and elongated conformations alongside copy number variations. Additionally, codon usage showed a pronounced A/T bias, whereas core respiratory chain genes demonstrated an evolutionary pattern of strong purifying selection. Furthermore, the 31 mitochondrial genomes of H. marmoreus were found to harbor eight gene rearrangement patterns and five genetic clusters, and the pan-genome analysis (220,364 bp, 217 nodes) captured abundant single-nucleotide polymorphisms (SNPs), insertions/deletions (InDels), and structural variations. This study provides breeding-relevant genetic markers and a genomic framework for H. marmoreus germplasm classification, genetic improvements, and the molecular breeding of stress-resilient varieties. Full article

Ammopiptanthus nanus (Fabaceae) is a Class II nationally protected endangered evergreen shrub in China and is endemic to the arid regions of Central Asia. To assess how contrasting ex situ management histories are associated with sequence-variant retention at an ecologically relevant gene, we analyzed a 594 bp coding fragment of the antifreeze protein gene (AnAFP) in one wild population and two ex situ collections maintained under active versus passive management contexts. Only two variable sites were detected across 75 individuals, both represented by single-base indels near the 5′ end of the coding region. The wild population contained both rare variants, the actively managed ex situ collection retained one of them at low frequency, and the passively maintained collection was monomorphic across the analyzed fragment. Rarefaction analysis indicated that the absence of variation in the passive collection is unlikely to be explained by sample-size disparity alone at this targeted locus. Because only one locus was analyzed, these results are interpreted as locus-specific patterns rather than evidence of genome-wide diversity change. Nevertheless, the observed pattern is consistent with reduced retention of rare sequence variants in the passive ex situ collection and with the possibility that a narrow founder base, together with the absence of subsequent genetic supplementation, contributed to this outcome. These results support the view that ex situ conservation of A. nanus may benefit from maximizing founder representation, maintaining sufficiently large managed collections, and combining neutral marker approaches with targeted monitoring of ecologically relevant loci. Targeted loci such as AnAFP should, however, be regarded as complementary indicators rather than stand-alone proxies for broader genetic diversity or adaptive potential. Full article

Nitrogen is essential for plant growth. Reliance on synthetic nitrogen fertilisers, however, is costly and contributes to soil degradation. Utilising nitrogen-fixing bacteria as biofertilisers may offer a sustainable alternative, reducing fertiliser costs and environmental impact. In this study, we attempted to isolate nitrogen-fixing bacteria from 14 seed batches of warm-season pasture grasses and successfully isolated bacteria from three of these batches. Whole genome sequencing confirmed the presence of the nif operon within all three isolates. Two seed batches of Cenchrus clandestinus (Hochst. ex Chiov.) Morrone from which nif-containing bacteria were isolated, along with two ‘nif’-negative C. clandestinus seed batches, were used in nitrogen-limiting growth assays. This was done to evaluate the effect of the presence of seed-associated nitrogen-fixing bacteria within a seed batch on nitrogen-limited plant growth and the associated plant microbiome composition, using 16S amplicon sequencing of root and shoot samples. Initial plant growth assays revealed significantly reduced root length between plants grown from seed batches harbouring nitrogen-fixing bacteria and those without, under limiting nitrogen availability, but no resulting shoot biomass reduction was observed. The plant microbiomes of these nif-positive seed batches were also statistically similar to each other, compared to the nif-negative seed batch plants. Plant microbiomes of all four C. clandestinus seed batches were significantly different from their original seed microbiomes, showing shifts in community composition. This study demonstrates the presence of potential nitrogen-fixing bacteria associated with warm-season pasture grass seeds at low abundance and reveals differences in plant-associated bacterial community composition between seed batches harbouring and lacking these bacteria. Full article

Background/Objectives: Among cotton species, Gossypium barbadense produces the strongest fibers. Examining cytoskeletal dynamics in single epidermal cells of G. barbadense ovules offers a direct approach to investigating fiber quality. Microtubules are major cytoskeletal components whose organization and dynamics are precisely regulated by microtubule-associated proteins (MAPs). However, information on the TPX2 family remains limited, and characterizing its features in G. barbadense is critical to clarifying the role of TPX2 family members in fiber strength formation. Methods: Using the Arabidopsis thaliana TPX2 sequence as a reference, 40, 49, 26, and 26 TPX2 family members were identified in the genomes of G. barbadense, Gossypium hirsutum, Gossypium arboreum, and Gossypium raimondii, respectively. We further analyzed the expression pattern of GbTPX2-35 and validated its function via virus-induced gene silencing (VIGS). Results: In G. barbadense, GbTPX2-35 (Gbar_D11G59825.1) was significantly upregulated in fiber samples of the parental lines at 25 days post-anthesis, and this expression pattern was further validated in G. barbadense lines with extreme fiber strength phenotypes. Next, VIGS-mediated silencing of GbTPX2-35 downregulated the transcript levels of cellulose synthase and microtubule-related protein genes, a finding further validated by mature fiber strength phenotypic data. Conclusions: This study preliminarily validated a pathway in which GbTPX2-35 regulates fiber strength by coordinating cellulose biosynthesis with microtubule cytoskeleton dynamics, providing valuable candidate genes and theoretical support for molecular breeding of high-strength cotton fibers. Full article

Background: Public catering is an underexplored One Health interface where structurally complex food-transport equipment may sustain reservoirs of antimicrobial-resistant bacteria. We investigated Escherichia coli from reusable institutional catering food-transport containers, focusing on a difficult-to-clean pressure-relief/ventilation valve compartment. Our objectives were to quantify phenotypic resistance using applied clinical breakpoints, assess inhibitor-synergy outcomes in ESBL confirmatory testing, and contextualize inhibitor-positive isolates by whole-genome sequencing (WGS). Methods: E. coli was isolated from containers sourced from 17 institutions and three central kitchens using ISO 16649-2. Minimum inhibitory concentrations (MICs) were determined by broth microdilution. Extended-spectrum β-lactamase (ESBL) confirmatory testing used cefotaxime/ceftazidime ± clavulanate; inhibitor positivity was defined as a ≥3 two-fold MIC decrease in the presence of clavulanate in isolates meeting CLSI screening thresholds. Inhibitor-positive isolates underwent WGS and CARD-based resistome profiling. Results: Resistance was most frequent to colistin (10, 10.8%), followed by doxycycline (8, 8.6%), florfenicol (7, 7.5%), enrofloxacin (4, 4.3%), and gentamicin (3, 3.2%). Third-generation cephalosporin resistance by clinical breakpoints was uncommon (cefotaxime: 2, 2.2%; ceftazidime: 1, 1.1%). Inhibitor-positive ESBL confirmatory phenotypes occurred in 30 isolates (32.3%), which were sequenced. WGS identified 45 resistance-associated genes across inhibitor-positive isolates but detected no classical ESBL genes; all carried chromosomal ampC/ampH alongside ubiquitous efflux-associated determinants. All WGS isolates belonged to phylogroup A, with serotype O154:H9 (20, 66.7%) and ST5549 (17, 56.7%) predominating. Conclusions: Institutional catering food-transport containers can harbor AMR E. coli, with colistin as the most frequent resistance phenotype and frequent inhibitor-positive ESBL confirmatory profiles that, in this set, were not explained by classical ESBL gene carriage. Integrating phenotype, WGS resistomics, and lineage structure supports targeted hygiene surveillance and risk-informed One Health monitoring in mass catering systems. Full article

Background: Sulfate transporters (SULTRs) are integral membrane proteins responsible for sulfate uptake, translocation, and plant adaptation to abiotic stresses. However, knowledge regarding the SULTR gene family in the economically important crop, Brassica rapa (Chinese cabbage), limited. The aim of this study is to conduct a genome-wide identification and functional characterization of BrSULTR genes and to explore their potential functions under abiotic stress. Methods: We identified 19 BrSULTR genes in the B. rapa genome by performing homology searches with Arabidopsis thaliana SULTR sequences as queries. Subsequent bioinformatics analysis included phylogenetic classification, chromosomal localization, gene structure, conserved motif dissection, cis-regulatory element prediction, and protein–protein interaction (PPI) network analysis. Tissue-specific expression profiles of BrSULTRs were assessed using publicly available transcriptome data. Furthermore, their expression dynamics under salt (150 mM NaCl) and low-temperature (4 °C) stress were investigated by integrating transcriptomic, proteomic, and qRT-PCR data. Results: The 19 identified BrSULTR members were phylogenetically categorized into four subfamilies and were mapped unevenly across seven chromosomes. Promoter analysis identified an array of cis-regulatory elements associated with development, hormone response, and stress response. Expression profiles revealed distinct tissue-specific patterns in roots, stems, leaves, flowers, and siliques. Under salt stress, BrSULTR13 was significantly upregulated, while BrSULTR9 and BrSULTR11 were significantly suppressed under low-temperature stress. PPI network projection indicated that the Arabidopsis homologs of BrSULTR5 may physically interact with stress-regulating enzymes such as APS and APR. Conclusions: Our work presents a comprehensive genomic and functional overview of the BrSULTR gene family in B. rapa. The results underscore the potential functions of BrSULTRs, highlighting their involvement in sulfate transport and abiotic stress responses. These insights establish valuable insights and a foundation for further research aiming at improving stress tolerance in B. rapa through the manipulation of sulfur metabolism pathways. Full article

Background: Retinal and optic nerve disorders are a leading cause of irreversible visual impairment worldwide. Advances in molecular genetics—including next-generation sequencing, genome-wide association studies, and gene-based therapeutic technologies—have reshaped understanding of both inherited and complex retinal diseases. However, translating genetic discovery into sustained clinical benefit remains biologically and practically constrained. Methods: A structured literature search was conducted using PubMed and Scopus to identify relevant studies published between 2015 and 2025. The search focused on molecular genetics, epigenetic modulation, mitochondrial biology, and translational applications in inherited retinal dystrophies and selected complex retinal diseases, prioritizing high-impact original research and systematic reviews addressing diagnostic innovation and therapeutic development. Results: Inherited retinal dystrophies represent the most advanced model of precision ophthalmology, with diagnostic yields approaching 70–80% in well-characterized cohorts. Gene augmentation and genome-editing strategies have demonstrated proof-of-concept efficacy, yet clinical benefit depends on residual cellular viability, delivery efficiency, and durability of expression. Emerging platforms include AAV-mediated gene transfer, in vivo CRISPR-based editing, RNA-directed splice modulation, and mitochondrial-targeted approaches. Persistent barriers include unresolved non-coding and structural variants, variant interpretation uncertainty, and endpoint selection in clinical trials. In contrast, complex retinal diseases such as glaucoma, age-related macular degeneration, and pathological myopia reflect polygenic susceptibility interacting with environmental and aging-related factors. Although polygenic risk scores refine probabilistic prediction, their utility is limited by ancestry bias and incomplete predictive performance. Epigenetic and mitochondrial mechanisms further modulate disease expression but remain largely non-actionable in routine practice. Conclusions: Retinal genetics has progressed from gene discovery to early therapeutic implementation. Future advances will depend on improved variant detection, functional validation, biomarker-guided staging, and integration of genomics with imaging and longitudinal modeling to achieve durable and equitable precision ophthalmology. Full article

Urachal carcinoma is a rare and aggressive malignancy for which standardized management remains limited, particularly in patients with locally advanced and node-positive disease. We report the case of a 34-year-old woman with urachal adenocarcinoma involving the bladder dome and radiographically suspicious pelvic lymph nodes who underwent robot-assisted partial cystectomy with urachal resection and extended bilateral pelvic lymph node dissection. Because there was no clinical, radiologic, or intraoperative evidence of umbilical involvement, the umbilicus was preserved after preoperative counseling and intraoperative confirmation of a negative proximal margin. Final pathology demonstrated a 4.5 cm enteric-type urachal adenocarcinoma, pT3a pN2 (2/17), with lymphovascular invasion, perineural invasion, and negative surgical margins. Immunohistochemistry and DNA- and RNA-based next-generation sequencing showed microsatellite stability, mismatch-repair proficiency, low tumor mutational burden, and no actionable genomic alteration. Given the absence of an established adjuvant standard, the multidisciplinary tumor board selected adjuvant FOLFOX as a non-standard postoperative strategy based on the overall clinicopathologic context. The patient remained continent, experienced no postoperative complications or treatment-limiting toxicity, and showed normalization of carcinoembryonic antigen and carbohydrate antigen 19-9 levels. This case provides a carefully contextualized example of transparent surgical reasoning and restrained multidisciplinary management in a rare malignancy with limited prospective evidence. Full article

Lumpy skin disease virus (LSDV) is a large DNA capripoxvirus that causes LSD, a disease that has major economic impact. Since 1989, several sporadic outbreaks were reported in Israel, with the latest outbreaks in 2012, 2019 and 2023. Although considered genetically stable, LSDV shows a high degree of genetic recombination events and genetic variations. In particular, in-frame nonsense mutations were suggested to act as one of the main evolutionary drivers of outbreaks. Whole-genome sequencing of LSDV isolates from the 2019 and 2023 outbreaks was used for genomic analysis using various bioinformatics tools to characterize the genomic evolution, recombination events and micro-evolutionary forces shaping LSDV in Israel by comparing isolates. Comparative genomic analysis revealed substantial nucleotide substitutions in the 2019 and 2023 isolates relative to the 2012 isolate. Specifically, increased nucleotide mismatches, inter-genic deletion, enhanced APOBEC editing signatures and elevated codon usage. Additionally, numerous mutations were recognized, leading to structural disruptions in specific viral proteins and possible RNA instability. In conclusion, this analysis supports that nucleotide substitutions, codon selection pressure and APOBEC-associated editing had driven local microevolution of LSDV during the years between outbreaks despite the absence of clinical indications and major vaccination campaigns. Furthermore, genomic evidences of recombination events between the 2012 and 2019 isolates suggests that these processes may have contributed to the emergence of the variant identified during the 2023 outbreak. Full article

Cutaneous adnexal carcinomas (CACs) comprise a diverse group of malignant tumors that show morphological differentiation toward one of the four main adnexal structures in normal skin: hair follicles, sebaceous glands, sweat-apocrine glands, and sweat-eccrine glands. These tumors can arise sporadically or may be associated with rare genetic syndromes. A total of 276 CACs cases underwent hybrid capture-based comprehensive genomic profiling (CGP) to assess all classes of genomic alterations (GA). Sequencing data were used to determine microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), genomic ancestry, and COSMIC mutational signatures. PD-L1 expression was evaluated by immunohistochemistry (TPS; Dako 22C3). Statistical analyses were performed using Fisher’s exact test, with false discovery rate correction via the Benjamini–Hochberg method. Sequencing was performed on primary cutaneous tumors in 131 cases (47.4%) and on local recurrence or metastatic site biopsies in 145 cases (52.5%). Across all groups, there was a male predominance (64–81%) and similar mean ages (59–63 years), with apocrine (APO) tumors occurring in older patients than eccrine (ECC) tumors (72 vs. 62 years; p = 0.001). Histologically, 173 tumors (62.7%) were sweat gland-derived (SWT), 55 (19.9%) sebaceous gland-derived (SEB), 14 (5.1%) hair follicle-derived (HRF), and 34 (12.3%) unclassified (UNK). Among SWT tumors, 150 (86.7%) were eccrine and 23 (13.3%) apocrine. SWT tumors included digital papillary adenocarcinomas (DPA, 6.9%), mucinous carcinomas (MC, 6.3%), porocarcinomas (POR, 11.0%), spiradenocarcinomas (SPR, 8.1%), syringoadenocarcinomas (SRNG, 5.8%), and 77 (44.5%) unclassified cases. The number of GA per tumor was highest in SEB compared with SWT tumors (7.9 vs. 4.9; p = 0.005) and lowest in DPA (2.1 vs. 5.0 in non-DPA; p = 0.03). No differences in ancestry distribution were observed. Compared with SWT tumors, SEB tumors exhibited higher frequencies of RB1 (38.2% vs. 8.1%; p < 0.0001) and TP53 alterations (76.4% vs. 43.4%; p = 0.0002), suggesting potential neuroendocrine differentiation. MC tumors showed significantly higher PTCH1 alterations than non-MC tumors (36.4% vs. 1.8%; p = 0.044). MSI-high status was most frequent in SEB tumors compared with all other groups (15.7% vs. 1.2%; p = 0.005), and gLOH > 16% was also more common in SEB than SWT tumors (19.6% vs. 7.2%; p = 0.081). The MMR signature occurred more frequently in SEB than SWT tumors (32.0% vs. 2.1%; p = 0.005). Mean TMB was elevated across most CACs types, ranging from 10.4 mutations/Mb in HRF to 38.8 mutations/Mb in MC, with the exceptions of APO (2.7 mut/Mb; p = 0.001) and DPA (1.4 mut/Mb; p = 0.003). PD-L1 expression was generally low and did not differ significantly between SWT and SEB tumors (37.0% vs. 33.3%; NS). Given the limited data on CAC treatment, this study provides a catalog of commonly observed GA. SEB tumors exhibited the highest frequency of genomic alterations. Prospective clinical trials are needed to determine the prognostic and predictive value of CAC-specific biomarkers for immune checkpoint inhibitor (ICI) response, which is essential for integrating novel therapies into the evolving treatment landscape. Full article

Anthrax is a zoonotic infectious disease characterized by high lethality and transmissibility. Its spores are highly stable and can persist in the environment for long periods. Furthermore, the overuse or improper use of antibiotics may contribute to bacterial resistance, complicating anthrax treatment. Phages can efficiently target and lyse Bacillus anthracis (B. anthracis), significantly reducing pathogen contamination and transmission risks in soil, water, and other environmental media. Compared to traditional chemical disinfectants and antibiotics, phages enable precise pathogen elimination while minimizing ecological disruption. In this study, two phages infecting B. anthracis, vB_BanM-JC307 (JC307) and vB_BanS-YL5 (YL5), were isolated and characterized. Both phages belong to the class Caudoviricetes. Genome sequencing revealed that JC307 and YL5 have sequence lengths of 148,323 bp and 74,568 bp, respectively. Phylogenetic analysis indicates that JC307 is located in the same evolutionary branch as the Nachito phage of the Herelleviridae family, while YL5, although grouped with the Basilisk-like phages, forms an independent branch. As these two phages have been observed to exhibit lytic activity against all nine tested strains of B. anthracis, they could serve as auxiliary tools for pathogen diagnosis and assist in ecological management of anthrax-contaminated areas. Full article

Transcriptome atlases can be used to examine the spatiotemporal dynamics of gene expression, thereby enabling the generation of genome-wide resources for understanding complex biological processes. In the silkworm Bombyx mori, transcriptomes serve as crucial datasets for elucidating the mechanisms underlying economically important traits. In this study, we integrated 832 transcriptome datasets across all developmental stages and tissues and performed whole-genome-scale transcriptome sequencing (RNAseq) on five critical tissues from silkworm strains Xian8 and 9211. We identified 5773 and 3323 housekeeping genes expressed across all developmental stages and tissues, respectively, and these genes were primarily enriched in cellular signaling, transport, structural organization, DNA repair, and RNA processing pathways. We also identified 27 stage-specific genes and 58 tissue-specific genes, providing candidate markers for future single-cell and spatial transcriptomics. A large number of alternative splicing events were detected from 832 NGS samples, indicating the critical roles of alternative splicing in silkworm development. Interestingly, only 10 long-read full-length transcriptome samples from Xian8 and 9211 yielded results comparable to the NGS in terms of novel genes and alternative splicing events, and these multi-tissue comparative analyses also revealed significant differences in alternative splicing patterns, underlining the necessity of long-read sequencing for such research. These datasets not only advance functional genomics research in Lepidoptera but also provide molecular signatures for silkworm strain-specific comparisons and association analyses with differential phenotypes. Silkworm pan-transcriptomics, by analyzing multidimensional transcriptional regulatory networks and gene-expression dynamics, can facilitate multidisciplinary integration and accelerate the breeding of high-yield and high-quality silkworm varieties. Full article

Introduction: Spondyloenchondrodysplasia with immune dysregulation (SPENCDI) is a rare autosomal recessive disorder caused by biallelic variants in the tartrate-resistant acid phosphatase 5 (ACP5) and characterized by variable skeletal, immunological, and neurological manifestations. Because early skeletal abnormalities may be subtle, diagnosis can be challenging in infancy. Materials and methods: We conducted a detailed clinical, immunological, radiological, and molecular evaluation of an infant with early-onset cytopenia, recurrent infections, seizures, and developmental delay. Genomic analysis was performed using whole exome sequencing (WES) and copy number variation sequencing (CNV-seq). In addition, we performed a structured narrative review of published ACP5-related SPENCDI cases to summarize the clinical spectrum and the currently reported use of Janus kinase (JAK) inhibitors. Results: Genomic analysis identified an ACP5 stop-gain variant (c.311G>A; p.Trp104*) with an apparently homozygous signal on WES. Re-evaluation of the copy-number data demonstrated an overlapping heterozygous 19p13.2–p13.13 deletion encompassing ACP5, indicating biallelic ACP5 defects consisting of a sequence variant on one allele and deletion of the other allele. Clinically, the patient showed prominent extra-osseous manifestations, including impaired T- and NK-cell cytotoxicity, before the emergence of definite radiographic skeletal abnormalities. Our literature review showed that skeletal abnormalities were repeatedly documented across published ACP5-related SPENCDI reports, although radiographic changes were often subtle and could be preceded by immune manifestations. Reported use of JAK inhibitors suggests potential benefit for immune dysregulation in selected patients, whereas the neurological response remains uncertain. Conclusions: This study reports a novel ACP5 variant and expands the known phenotypic spectrum of SPENCDI. SPENCDI should be considered in children with unexplained immune dysfunction and developmental delay, and suggestive neuroimaging findings, even when overt skeletal deformities are absent. Early genetic testing and targeted skeletal imaging may facilitate diagnosis. Full article