Pathogenic variants in five established leptin-melanocortin pathway genes (LEP, LEPR, MC4R, PCSK1, POMC) are associated with severe early-onset obesity and are targets for emerging treatments. However, these variants are rare in these patients, suggesting the involvement of additional genes interacting with this pathway. Next-generation sequencing (NGS) analysis was performed in 395 patients with severe obesity, including 213 children (mean BMI: 56.3 kg/m2; BMI-z-score: 4.6). The analysis targeted 20 genes, including the 5 established genes. Rare genetic variants were assessed for pathogenicity using prediction algorithms, genetic databases, and literature review. Phenotypic data were retrospectively collected, focusing on obesity severity, age of onset, familial history, eating behavior disorder, neurodevelopmental and endocrine-associated diseases, and obesity complications. Pathogenic heterozygous variants were identified in 34 patients (8.6%), 18 of them harboring pathogenic variants in the 15 additional genes. In adults, early-onset obesity was more frequent in potentially pathogenic variants carriers than in non-carriers (83.3% vs. 55.0%, p = 0.04). No differences were observed in the other phenotypic characteristics. This supports the relevance of expanded genetic testing in severe obesity. Early-onset obesity remains a key clinical feature to guide genetic investigation and identify patients who may benefit from early personalized care and targeted treatments.

BackgroundHepatocyte nuclear factor 1β (HNF1B) pathogenic variants constitute a major genetic contributor to congenital anomalies of the kidney and urinary tract (CAKUT), with patients simultaneously exhibiting distinct extrarenal features. Among these clinical manifestations, renal disease progression is crucial for long-term outcomes, needing comprehensive evaluation.MethodsUsing the Chinese Children Genetic Kidney Disease Database (2017–2024), we analyzed 26 pediatric HNF1B cases to characterize renal phenotypes and genotype correlations.ResultsAll patients exhibited abnormal renal phenotypes at diagnosis: renal cysts (50%) and multicystic dysplastic kidney (MCDK) (37.5%). Genetic analysis revealed 16 patients (61.5%) had a 17q12 deletion including the HNF1B gene, while the remaining carried HNF1B intragenic pathogenic variants, including a novel c.1390-1405dup. Comparing phenotypic trajectories, 17q12 deletion cases showed earlier renal phenotype onset (median age: 0 vs. 1 year 11 months, p = 0.121), while HNF1B variants showed faster renal function deterioration (latest eGFR: 85 vs. 45.6 mL/min/1.73 m², p = 0.11). Three of five CKD 5 children underwent kidney transplantation before 15; one developed reversible tacrolimus-induced hyperglycemia.ConclusionOur results suggest a potential trend wherein the 17q12 deletion may be associated with a higher prevalence of developmental renal anomalies, while HNF1B pathogenic variants might correlate with an increased risk of tubular dysfunction, indicating possible distinct genotype-phenotype correlations. Based on these observations, we recommend that affected families receive tailored clinical management, including prenatal counseling, genotype-specific monitoring, and regular renal function assessment.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12882-025-04616-z.

CD33 drives cutaneous melanoma: mendelian randomization confirms causality, multi-omics and in vitro experiments reveal M2 macrophage polarization-mediated progression.

Congenital nephrotic syndrome (CNS) and infantile nephrotic syndrome (INS) are disorders of podocytes in the slit diaphragm. CNS manifests during the first three months of life, and INS between 3-12 months, with severe proteinuria due to mutations in the NPHS1 and NPHS2 genes. This study aimed to establish specific genotype-phenotype characteristics of CNS and INS in the North American population. Eleven Pediatric Nephrology Research Consortium (PNRC) sites retrospectively reviewed charts of 36 patients born between 1998-2019 who had CNS or INS and underwent genetic testing. The genetic database confirmed the variant's pathogenicity. NPHS1 mutations were more frequently seen in CNS patients, while variant mutations in the WT1 and NPHS2 genes were more common in the INS group. Like c.2335-1 G > A splice mutation, the frequent compound heterozygous mutations of the NPHS1 gene were associated with more severe proteinuria (112.4 ± 135.6 vs. 53.9 ± 57.3). Additionally, NPHS1/WT1 and NPHS1/NPHS2 digenic inheritance featuring biallelic or tri-allelic hits were associated with patient transplantation, regardless of the disease onset. Identification of compound heterozygous mutations in the NPHS1 gene as an indicator of an aggressive course of CNS in infants. This finding could lead to earlier and targeted interventions of patients, through a precision therapeutic approach IMPACT: Variations at splice sites, particularly the c.2335-1 G > A mutation, alongside compound heterozygous mutations in the gene NPHS1 and digenic inheritance involving both NPHS1/WT1 or NPHS1/ NPHS2 with a triallelic hit, have been linked to a more severe progression of Congenital Nephrotic Syndrome (CNS) in infants. The presence of a variant involving the digenic inheritance of the NPHS1 gene among children in North America suggests earlier indicators for the severity of the kidney disease. This knowledge can transform the management of Congenital Nephrotic Syndrome in children's healthcare settings, and lead to the development of early diagnosis biomarkers for the disease.

Beyond the Diagnosis: Evaluation of Quality-of-Life Measures in Representing the Clinical Characteristics of SLC6A1-Related Neurodevelopmental Disorder.

Forensic biobank; towards comprehensive forensic genetic frequency database for the Kenyan population.

Familial Searching utilising the National Forensic DNA Database of South Africa (NFDD-ZA) to aid in the identification of Missing Persons and Unidentified Human Remains.

Nationwide study on forensic genetic analyses in criminal cases in Denmark.

Morphological and molecular identification of Eimeria spp. (Apicomplexa: Eimeriidae) in dairy cattle, Bos taurus from intensive dairy cattle farms in some areas of China.

Introduction: Periodontitis is a common chronic inflammatory disease that can lead to tooth loss. Conventional treatments face limitations due to microbial resistance and side effects. Qingwei San, a traditional Chinese medicine formula, is widely used for oral inflammation, but its mechanisms remain unclear. Methods: Active components of Qingwei San were retrieved from the TCMSP database and filtered according to pharmacokinetic criteria, while disease-related targets were obtained from multiple genetic databases. Intersecting targets were identified and incorporated into a drug-component-target-disease network constructed in Cytoscape, with protein-protein interactions analyzed through the STRING database. Gene Ontology and KEGG enrichment analyses were conducted to determine biological functions and signaling pathways. A Random Forest (RF) model was applied to evaluate the relative importance of intersecting genes. High-importance genes were cross-referenced with PPI hubs to identify core targets for molecular docking. Results: The study identified 46 active compounds and 600 associated targets, with 114 overlapping genes linked to periodontitis. Network and topological analyses revealed 24 core targets, with TNF, IL6, IL1B, and TP53 being the most significant. The RF model achieved an AUC of 0.967, identifying ten core targets (TNF, IL1B, IL6, TP53, CXCL8, MMP9, CASP3, MAPK3, PTGS2, and JUN) consistent with network findings. Enrichment analyses highlighted pathways including lipid metabolism and atherosclerosis, AGE-RAGE signaling, and TNF signaling. Molecular docking demonstrated strong binding affinities, particularly between quercetin and IL6/TNF, as well as kaempferol and IL1B. Conclusion: Qingwei San alleviates periodontitis through multiple bioactive compounds, notably quercetin, kaempferol, and paeoniflorin, which target core genes and regulate key inflammatory pathways. These findings provide a theoretical foundation for its clinical use and warrant further experimental validation.

Chlamydia pecorum is a widespread zoonotic pathogen infecting livestock and wildlife, with recent reports of severe human infection. To assess its epidemiological threat, we investigated its prevalence, genetic diversity, and evolutionary dynamics in livestock from western China. Rectal swabs (n = 1322) were collected from cattle and sheep across four provinces in western China in 2024–2025. Samples were screened by Nested PCR, and positives were characterized by ompA genotyping and multilocus sequence typing (MLST). Overall, 18.9% of samples tested positive for C. pecorum. ompA analysis defined 33 sequence similarity-based clades (17 unique to the region), while MLST revealed 114 sequence types (111 novel). Discordance between ompA and MLST trees highlighted recombination and complex evolutionary trajectories. These findings demonstrate both a high prevalence and marked genetic heterogeneity of C. pecorum in western Chinese livestock, with numerous unique local clades and sequence types highlighting its ongoing evolution and zoonotic potential. Therefore, this study provides a foundational genetic database and has prompted the creation of a One Health surveillance network, which are essential for precise source-tracing and early detection to mitigate zoonotic spillover risk.

Exome sequencing (ES) and genome sequencing (GS) are essential for diagnosing rare genetic disorders, yet a significant number of patients remain without a definitive diagnosis after the initial analysis. Reanalysis of existing ES and GS data has emerged as a clinically indispensable practice, offering the potential to solve previously unresolved cases by leveraging rapid advances in genomic knowledge and technology. This review comprehensively addresses the growing importance, clinical utility, methodologies, and challenges of ES and GS data reanalysis. The increase in diagnostic yield from reanalysis is driven by several key factors: the continuous discovery of new gene-disease associations, ongoing updates to clinical and population genetic databases like ClinVar and gnomAD, the refinement of bioinformatic pipelines, and the application of advanced analytical techniques. Reanalysis has been shown to provide an additional diagnostic yield ranging from 3% to 15% across various disease cohorts, including neurodevelopmental, renal, and cardiovascular disorders. A significant portion of these new diagnoses stems from the reclassification of variants of uncertain significance, which often leads to direct and meaningful changes in clinical management, including targeted surveillance and tailored therapies. The reanalysis of ES and GS data is no longer a supplementary activity but a fundamental component of modern genomic medicine, transforming genomic testing from a one-time event into a continuous diagnostic process. To fully realize its potential, the development of standardized guidelines is crucial to address financial, logistical, and ethical barriers and to facilitate the equitable integration of reanalysis into routine clinical care.

Guyuan cattle, a transitional breed between northern and central Chinese cattle, are known for their climbing ability and disease resistance. However, the genomic resources of indigenous Chinese cattle breeds, including Guyuan cattle, remain largely unexplored. We first assembled the Guyuan cattle genome, named Guyuan_Btau_1.0, using PacBio HiFi sequencing. Guyuan_Btau_1.0, with a total size of 2.86 Gb, was anchored to 30 chromosomes (29 autosomes plus one X), achieving a contig N50 of 85.27 Mb and a scaffold N50 of 107.67 Mb. Additionally, we sequenced the genomes of 10 Guyuan cattle using Oxford Nanopore sequencing, which detected 65,273 structural variations (SVs) with lengths of 40.37 Mb and 4,849 shared SVs with lengths of 3.15 Mb. Across the shared SVs, we identified, visualized, and validated a 1,290 bp deletion in the second intron of IGF2BP2 gene in the genomes of 10 Guyuan cattle relative to ARS-UCD1.2. Overall, this study enriches the genetic resource database of indigenous Chinese cattle and provides new foundational data for the breeding and genetic improvement of Guyuan cattle.

McArdle disease (also known as glycogen storage disease type V) is a rare metabolic myopathy that is caused by myophosphorylase deficiency, leading to impaired glycogenolysis in skeletal muscles. This study explored the clinical, histopathological, and genetic landscape of McArdle disease in a regional cohort from Turkey, emphasizing diagnostic and management challenges. A retrospective analysis was conducted on 350 muscle biopsies performed between 2013 and 2024 in a tertiary care center. Seven patients (2.1 %) were diagnosed with McArdle disease. The clinical features included exercise intolerance (100 %), muscle pain (75 %), and the second wind phenomenon (62.5 %). Two patients presented with acute renal failure due to rhabdomyolysis with myoglobinuria, leading to metabolic acidosis. Histopathological findings revealed glycogen accumulation in subsarcolemmal vacuoles and absent myophosphorylase activity in all cases. Genetic analysis identified five distinct PYGM pathogenic variants, including c.808C>T (p.Arg270Ter) and c.2262del (p.Lys754fs). These findings highlight the phenotypic and genetic heterogeneity of McArdle disease. McArdle disease remains underdiagnosed due to its variable clinical presentation and limited access to advanced diagnostic tools. This study underscores the importance of a multidisciplinary approach that integrates clinical assessment, muscle biopsy, and molecular analysis. Increased awareness and training among healthcare providers are critical for early recognition and intervention. Future research should focus on expanding genetic databases and exploring targeted therapies to improve outcomes in this challenging condition.

The Bioinformation and DNA Data Bank of Japan Center (https://www.ddbj.nig.ac.jp/) continues to serve as a global core infrastructure for biological information as part of the International Nucleotide Sequence Database Collaboration. In 2024, we reinforced data quality and transparency through mandatory metadata standards, including sampling geolocation and date, aligning with international debates on Digital Sequence Information. Our repositories expanded across multiple omics layers, and our secure environment for analysis of personal genome provides tools and precomputed data on personal genomes archived at the Japanese Genotype-phenotype Archive. International collaboration was advanced through metadata harmonization with the Korea Bioinformation Center and the China National Genomics Data Center, which strengthened regional data resilience and integration. Inside Japan, we began a new collaboration with the Japan Institute of Health Security\, which facilitated the systematic release of pathogen genomes via the Pathogens.jp portal. To support these expanding activities, our high-performance computing infrastructure was renewed with 14 000 CPU cores, 50 PB Lustre storage, and newly deployed GPU nodes. These updates enable both AI-driven analyses and cost-efficient large-scale genome reanalysis.

Zooplankton are fundamental components of marine trophic networks and served as bioindicators of environmental changes. Assessing their genetic diversity is essential for biodiversity assessment, ecosystem monitoring, and evidence-based conservation strategies. The conventional morphological identification methods are limited in detecting cryptic species and lack phylogenetic resolution, necessitating the use of molecular approaches. Hence, this review synthesises the recent advancements in genomic tools for investigating marine zooplankton genetic variability, encompassing techniques such as DNA barcoding and metabarcoding, complete mitochondrial genome analysis, as well as environmental DNA profiling. We systematically evaluated the advantages of each method, the application of genetic markers, and their effectiveness in species identification, population genetics, and evolutionary studies. The genetic methods have greatly improved taxonomic resolution, revealed hidden biodiversity, and offered deeper insights into the population structure and community dynamics of marine zooplankton in response to human-induced pressures. Despite these achievements, several challenges persist, including incomplete genetic reference databases, sequencing errors, and the lack of standardised protocols. Accordingly, future research should prioritise the expansion of comprehensive genetic libraries, the refinement of bioinformatics pipelines, and the integration of multi-marker approaches to deepen our understanding of marine zooplankton genetic variation and ecological interactions. Continued improvement in these molecular methodologies will be important for the effective conservation of marine biodiversity, the mitigation of environmental fluctuation impacts, and the promotion of sustainable fisheries management.

The increasing severity and frequency of mass bleaching events has placed shallow-water tropical coral reefs at risk of significant decline in the coming decades. The association of endosymbiotic dinoflagellates (Family: Symbiodiniaceae) with corals is regulated by local environmental conditions along with evolutionary history and plays a leading role in bleaching sensitivity and recovery. Resolving temporal and spatial dynamics of coral-Symbiodiniaceae associations is therefore essential for accurate bleaching risk predictions. Here, we investigated temporal patterns in dominant Symbiodiniaceae across the Greater Caribbean region, which is heavily impacted by human activities, disease and climate change. Using records derived from genetic databases, we considered Symbiodiniaceae dominance from 1994 to 2009, with a particular focus on and around the 2005 mass bleaching event. From the 4 Symbiodiniaceae genera recorded ( Symbiodinium , Breviolum , Cladocopium and Durusdinium spp.), we identified genera-specific responses to ocean heating and bleaching stress. Generalist symbiont representatives were dominant only during periods of sustained environmental stability. In contrast, during and immediately after bleaching saw the emergence and subsequent persistence of Durusdinium spp.—an invasive genus in the Caribbean with high thermal tolerance but which induces negative impacts on coral physiology and calcification. In post-bleaching recovery years, a regional-scale bet-hedging strategy was adopted allowing thermal tolerance to be maintained, but poised for a more physiologically beneficial symbiosis if/when environmental conditions become favourable. Our regional-scale, multi-year perspective gives support for local-/colony-scale tuning of coral-Symbiodiniaceae relationships, and highlights how continued warming and bleaching stress will enable Durusdinium spp. invasion to persist, with knock-on implications for future coral reef development.

Geneticists frequently use loss-of-function (knockout) mutations to reveal the effects of a gene's dysfunction at the organismal level, observed as the mutant phenotype. This strategy is facilitated by creation of large, searchable collections of knockout mutants in an organism of interest. Paramount among such resources in maize is the UniformMu National Resource, a large collection of genetic stocks carrying mutations generated by insertions of Robertson's Mutator (Mu) transposons. The name UniformMu refers to the phenotypic uniformity of the W22 inbred genetic background in which Mu insertion mutants were created. This community resource continues its pivotal role in providing seeds containing beneficial knockout and knockdown mutations in targeted genes, which can be used to elucidate gene function. The resource offers an invaluable complement to other functional genomics approaches aimed at bridging the gap between genome sequences and plant performance in the field. Several key features are central to the success of the UniformMu National Public Resource. First, mapped insertions are linked to seed stocks that are readily available through the Maize Genetics and Genomics Database (MaizeGDB) and the Maize Genetics Cooperation Stock Center. Second, a uniform inbred background facilitates analysis of mutant phenotypes, by providing uniform wild-type controls. Third, mutant alleles are reliably heritable and consistently recovered in stated lines. Finally, lines are stable, with no continuing transposition of Mu insertions. The collective effort of the maize community allows UniformMu to provide readily accessible knockout and knockdown mutant seeds, as well as, ultimately, highly sought evidence for gene function in planta.

Chronic kidney disease (CKD) affects 9.1% globally and is associated with significant morbidity and mortality. While up to 10% of CKD cases yield a genetic diagnosis with hundreds of implicated genes included in some genetic test panels, the results often yield many variants of uncertain significance (VUS). We sought to report genetic testing outcomes in a cohort of 228 patients who received genetic testing for kidney disease phenotypes from 2020-2023 at Geisinger, a regional health system in Pennsylvania. We report on diagnostic yield, management changes, and VUS resolution. A multidisciplinary approach was undertaken to resolve VUS. All cases were reviewed with ≥2 nephrologists and a genetic counselor. VUS with potential clinical relevance, based on known gene-disease associations, were investigated through comprehensive review of genetic databases, consultations with ClinGen variant classification expert panels and genetic testing laboratories, functional assays for Alport syndrome VUS, and case-control analyses using data from a large exome sequencing study (Geisinger MyCode DiscovEHR) linked to electronic health records. Out of 228 patients in this study, 34% had a positive (pathogenic [P] or likely pathogenic [LP]) result, 52% had a VUS result only, and 14% had a negative result. Overall, the mean number of VUS reported was 4.0 (SD 3.1) per patient. After multidisciplinary review of variants, 42 potentially relevant VUS were re-examined by our team. Utilizing MyCode biobank data with available functional analysis we were able to recommend upgrading 10 VUS to LP, which was consistent with genetic laboratories' decisions to upgrade 5 variants over the course of the study. In addition, our data supported downgrading 10 VUS to likely benign. Genetic testing resulted in direct management changes for 69 (88.5%) positive patients and provided a better understanding of patients' diagnoses. Genetic testing also had familial implications in 86 (37.7%) of patients. In conclusion, a multidisciplinary approach using biobank data integrating exome sequencing and electronic health records, functional testing, and collaboration with genetic testing laboratories can support the reclassification of clinically significant VUS, potentially maximizing the clinical utility of genetic testing with important diagnostic, prognostic, and management implications.

Rare variants in CFI and CFH genes are associated with AMD. This study aimed to compare the incidence of late AMD in carriers of these variants to a reference cohort using a long follow-up cohort (LF-cohort) and to examine short-term AMD progression in a short follow-up cohort (SF-cohort). This cohort study included two groups: the LF-cohort, observed for more than five years retrospectively and the SF-cohort, observed for one year prospectively, with patients attending in-hospital visits. One hundred twelve AMD patients with rare CFH/CFI or variants were invited from the European Genetic Database. The LF-cohort's outcome was the incidence of late AMD per 100 person-years compared to a matched reference cohort. In the SF-cohort, geographic atrophy (GA), retinal sensitivity, and visual acuity were measured. The LF-cohort included 28 patients (median [interquartile range {IQR}] age, 71.3 [24.3] years; 18 females [64%]) with an incidence rate of 6.2 per 100 person-years which was higher than the reference cohort (1.8 per 100 person years (P = 0.01)). The SF-cohort consisted of 44 patients (median [IQR] age 70.5 [16.5] years; 29 (65% female). Mean annual GA growth (SD) was 0.22 mm (0.13) in 19 eyes of 12 patients. Retinal sensitivity changed for late-staged eyes (right eye: 17.2 dB to 15.7 dB, P = 0.03; left eye 17.3 dB to 16.4 dB, P = 0.06) whereas visual acuity did not. Carriers of rare CFI or CFH variants show a higher incidence of late AMD. These patients may benefit from personalized gene therapy and complement inhibition in future trials.