Search Results (14,656)

Background/Objectives: L-2-hydroxyglutaric aciduria (L2HGA) is a rare autosomal recessive neurometabolic disorder marked by developmental delay, intellectual disability, and progressive movement abnormalities. Variants in RYR1 can cause congenital myopathies, but data on the co-occurrence of variants in populations are limited. The aim of this study was to characterize the clinical and genetic basis of the neurometabolic and neuromuscular abnormalities and to investigate the potential interaction between the identified variants. Methods: Patients with complex, previously undiagnosed clinical presentations underwent neurological evaluation, including brain magnetic resonance imaging, electromyography, biochemical testing, and whole-exome sequencing (WES). Identified variants were analyzed in silico and confirmed by Sanger sequencing in the patient and her parents. Three cases were reviewed, and one of these patients exhibited developmental delay, hypotonia, intellectual disability, and progressive motor dysfunction. Biochemical tests revealed markedly elevated urinary 2-hydroxyglutaric acid levels, consistent with L2HGA. Results: WES identified a homozygous likely pathogenic variant in L2HGDH (c.589_590insGGC, p.Q197insG), confirming the molecular diagnosis of L2HGA. In addition, a heterozygous missense variant in RYR1 (c.7268T>A, p.M2423K), classified as a variant of uncertain significance, was detected and was inherited from her mildly affected father. The L2HGDH variant explains the neurometabolic phenotype of the patient, whereas the RYR1 variant remains of uncertain significance, and its clinical contribution cannot be clearly established. Conclusions: To our knowledge, this case illustrates the co-occurrence of a likely pathogenic L2HGDH variant and a heterozygous RYR1 variant of uncertain significance. The findings expand the mutational spectrum of L2HGA and underscore the value of comprehensive genomic testing in complex neurometabolic and neuromuscular disorders. Full article

Background/Objectives: Phylogenetic relationships within Triplophysa remain unclear due to limited molecular data and complex traits. Mitochondrial genomes are robust markers for teleostean phylogeny and molecular evolution. This study aims to provide Triplophysa brevicauda mitochondrial genome and molecular evidence for its phylogenetic position and high-altitude adaptation. Methods: The complete mitochondrial genome of T. brevicauda was assembled via Illumina NovaSeq 6000 paired-end sequencing. Genomic characteristics were analyzed, with phylogenetic reconstruction based on complete mitochondrial genomes and selective pressure analyses for adaptive evolution. Results: The 16,570 bp circular genome encodes 13 PCGs, 22 tRNAs, two rRNAs, and a D-loop. All PCGs start with ATG (except cox1) and terminate with TAA, TAG, or incomplete Triplophysa Phylogenetic analysis supports four Triplophysa clades, with T. brevicauda sister to Triplophysa nujiangensa. Purifying selection is pervasive, with elevated non-synonymous rates in atp8, nad2, nad4L, nad6, and positive selection in nad2/nad5. Conclusions: Positive selection in nad2 and nad5 may relate to T. brevicauda’s plateau adaptation. This study provides valuable mitochondrial resources, supporting further research on Triplophysa’s phylogeny and high-altitude adaptive evolution. Full article

Background: Cell division plays a crucial role in plant growth and development. Cyclin-dependent kinase inhibitors (ICK/KRP) negatively regulate the cell cycle, thereby affecting cell elongation and organ development. This study aimed to systematically identify and characterize the ICK/KRP gene family in pepper, and to explore their roles in growth, development, and stress responses. Methods: Bioinformatics approaches were used for genome-wide identification, chromosomal localization, collinearity analysis, sequence characterization, promoter element prediction, and tissue-specific expression profiling of pepper ICK genes. Phylogenetic analysis was performed with homologs from Arabidopsis, tomato, maize, and rice. Quantitative real-time PCR and virus-induced gene silencing (VIGS) were applied to validate gene expression patterns and gene function, respectively. Subcellular localization assays were also conducted. Results: A total of six ICK genes were identified in pepper. They were classified into three subfamilies and distributed on different chromosomes, with one pair showing evidence of duplication. All ICK/KRPs contain the conserved Motif 1 (amino acid sequence: KIPTTREIEEFFATAEKQQQRRFIEKYNFDPVNEKPL) and were predicted to localize to the nucleus. Promoter analysis revealed cis-acting elements associated with plant development, stress responses, and hormone signaling. Expression pattern analysis indicated tissue-specific divergence and significant induction/repression under temperature stress. qRT-PCR results were consistent with transcriptome data, and expression differences were observed in materials with different stigma lengths. Subcellular localization confirmed that Caz03g38750.1 and Caz12g03790.1 proteins localize to both the nucleus and plasma membrane. Silencing of CazICK1 significantly repressed stigma elongation and altered stigma morphogenesis. Conclusions: The six pepper ICK/KRP genes display distinct diversity in distribution, structure and expression, and function in plant growth, development and stress adaptation. This work not only lays a solid basis for exploring the cell cycle regulatory network of pepper and contributes to relevant theoretical research, but it also identifies key gene resources for improving stigma traits. It has great potential for application in molecular breeding to promote high yield and efficient hybrid seed production in pepper. Full article

Background: Strychnos madagascariensis Poir (Loganiaceae) is a drought-tolerant indigenous fruit tree of East and southern Africa, valued for its food, medicinal, and socio-economic contributions to rural communities. Despite its importance as a candidate food crop, intraspecific morphological and genetic diversity had not previously been characterized, and no simple sequence repeat (SSR) markers had been developed for this species, leaving breeders and conservation planners without the basic diversity baseline needed to prioritize material for domestication. Methods: This study assessed vegetative and reproductive trait variation, variance components, and broad-sense heritability, and SSR-based genetic diversity among 27 morphologically defined S. madagascariensis morphotypes at Bonamanzi Game Reserve, KwaZulu-Natal, South Africa. Three trees were measured per morphotype (81 trees total), over two growing seasons. Genetic diversity was characterized in one representative tree per morphotype using seventeen newly developed SSR loci, the first such markers reported for this species, and analyzed with population structure (STRUCTURE version 2.3.4), PCA, and Nei’s genetic distance. Results: Twenty-seven morphotypes were identified based on leaf colour, shape, hairiness and size, dominated by grey (41%), elongated (59%), less hairy (48%), and medium-sized (>50–90 mm) leaves. Fruit diameter and mass showed the highest inter-morphotype variation (r = 0.949) and also the highest broad-sense heritability (H² = 55.3% and 47.8%, respectively), indicating strong genetic control of these traits and their suitability as targets for selective breeding. Environmental variance exceeded genotypic variance for most traits. A total of 144 alleles were identified across 17 SSR loci (mean 4.24 alleles/locus; mean PIC = 0.31). Population structure gave a preliminary, tentative signal of two genetic clusters (K = 2) with substantial admixture, which we interpret cautiously, given the limited sampling depth. Conclusions: This is the first study to characterize intraspecific morphological variation in S. madagascariensis and the first to develop SSR markers for the species. The results provide a preliminary, single-site framework for conservation genetics and crop improvement that should be validated with larger, multi-site samples. Grey morphotypes GyEvH1, GyEvH2, GyEvH3, GyRlH1 and GyEH2 combined consistent fruiting performance with favourable fruit-trait values and are proposed as priority candidates for further evaluation in domestication and breeding programmes. Full article

Single-cell RNA sequencing (scRNA-seq) has emerged as a transformative technology for resolving cellular heterogeneity and deciphering gene regulatory networks in complex tissues. Despite challenges such as incomplete genome annotation, technical variability across platforms, and limitations in robust cell-type annotation, scRNA-seq has substantially advanced our understanding of the developmental processes, physiological regulation, and disease responses in pigs, an economically and biomedically important species, thereby providing insights into traits of agricultural and translational relevance. By profiling transcriptomes at the single-cell resolution, scRNA-seq enables the identification of rare cell populations, dynamic cellular states, and lineage trajectories that are critical for reproduction, growth, immunity, and metabolic homeostasis. Recent porcine scRNA-seq studies have generated high-resolution cellular atlases spanning embryos, reproductive organs, immune tissues, skeletal muscle, and the gastrointestinal tract, revealing cell-type-specific regulatory mechanisms associated with reproductive performance, muscle accretion, adipogenesis, immune competence, and intestinal functionality. This review summarizes the fundamental principles and analytical strategies of scRNA-seq, highlights its major applications in porcine biology and production, and discusses current challenges as well as future perspectives for integrating single-cell technologies into livestock science. Full article

Background/Objectives: The expansion of direct-to-consumer (DTC) genetic testing has generated civilian genomic databases containing tens of millions of profiles, some of which may be available, under specific conditions, for criminal investigations. Meanwhile, artificial intelligence (AI) is reshaping forensic genetics through applications such as kinship inference, DNA mixture deconvolution, probabilistic phenotyping, and the prioritization of investigative leads. This review examines the scientific, legal, and ethical implications of the convergence between DTC genetic databases, forensic investigative genetic genealogy (FIGG), and AI-assisted forensic analysis. Methods: This article presents a multidisciplinary narrative review at the intersection of forensic genomics, FIGG, artificial intelligence, genomic data governance, and bioethics, with particular attention to French, European, and international regulatory frameworks. Results: Six major dimensions structure the field: (i) the current state of forensic genomic technologies, including STRs, SNPs, and next-generation sequencing; (ii) the contribution of AI to forensic genetics and FIGG; (iii) the governance of large-scale genomic data; (iv) regulatory fragmentation across jurisdictions; (v) the principal bioethical tensions raised by the forensic use of DTC genetic databases; and (vi) future governance needs and operational recommendations. Across these dimensions, three findings emerge. First, genealogical matches and AI-supported outputs should be understood primarily as investigative leads rather than autonomous judicial evidence. Second, the relational nature of genomic data exposes non-consenting relatives to potential forensic scrutiny, thereby challenging traditional models of individual consent and privacy. Third, the absence of harmonized standards for validation, transparency, and oversight remains a major obstacle to legal certainty, judicial admissibility, and public legitimacy. Conclusions: The forensic use of DTC genetic databases should not be understood as a purely technical extension of conventional DNA profiling. It reflects a broader transformation in the relationship between genomic knowledge, criminal investigation, and fundamental rights. Its long-term legitimacy and operational viability will depend on the combined strength of scientific reliability, legal proportionality, ethical safeguards, and meaningful democratic oversight. Full article

Background/Objectives: Single-stranded oligonucleotides (ssODNs) are used as donor templates for therapeutic gene editing by CRISPR-Cas9 cleavage and homology-directed repair (HDR). Although ssODN sequence fidelity is critical to the safety and efficacy of editing, standard quality control methods cannot resolve individual nucleotide errors. Methods: We performed deep sequencing of ssODNs from three manufacturers and amplicons from edited hematopoietic stem/progenitor cells. Results: We find that synthesis errors are present in all ssODNs tested at rates that vary more than two-fold among manufacturers, at positions that are dependent on sequence context. These synthesis errors are propagated into the genome by HDR at frequencies proportional to their abundance in the ssODN. In our sickle cell mutation correction protocol, the most prevalent SNEs are predicted to produce benign β-globin variants, while the less frequent frameshift deletions are predicted to generate β-thalassemia-like alleles. Conclusions: Current quality control standards are insufficient to detect these errors, and deep sequencing of ssODNs should be incorporated into regulatory submissions for clinical gene editing programs. Full article

Objectives: The aim of this study was to report novel ABCA4 variants detected in a cohort of 259 patients with ABCA4 retinopathy with the intention of improving the diagnostic accuracy for ABCA4 retinopathy and expanding its genetic spectrum. Methods: We retrospectively reviewed 259 patients with ABCA4 retinopathy, comprising 190 patients from the Oxford Cohort and 69 patients from other centres with a clinical diagnosis of ABCA4 retinopathy who were referred for genetic testing. Patients with a phenotype consistent with ABCA4 retinopathy who had a novel ABCA4 variant were included. Phenotyping in the Oxford Cohort included clinical evaluation, retinal imaging, and electrodiagnostic testing. Genetic testing was performed using next-generation sequencing (NGS) and Sanger sequencing. In silico analysis was used to investigate the pathogenicity of novel variants. Results: Eleven novel variants were detected in 12/259 patients, with one variant detected in two unrelated patients. These variants included three missense, four truncating, three splice-site variants, and one exon deletion. The variants were distributed across eight exons and three introns of ABCA4. In silico analysis and phenotype correlation supported the potential pathogenicity of the novel variants. Phenotypes ranged from mild isolated flecks with preserved retinal architecture to extensive chorioretinal degeneration. Conclusions: Despite over 2200 ABCA4 variants being reported to date, a further 11 novel ABCA4 variants were identified in 259 patients using NGS panel-based sequencing and MLPA. The variants were located across the whole ABCA4 gene, emphasising the necessity to sequence the whole gene. Our reporting of these variants expands the known genetic spectrum of ABCA4 retinopathy, contributing to accurate diagnosis in this patient group and the identification of suitable patients for recruitment to potential therapeutic interventions. Full article

Background/Objectives: The genes encoding HSPA1A, HSPA1B, and HSPA1L, located in the MHC class III region at 6p21.3–22.1, a region implicated in susceptibility to schizophrenia, are critical regulators of neurodevelopmental processes and contribute to synaptic neuroprotection. This study investigated whether the HSPA1A, HSPA1B, and HSPA1L genes are associated with schizophrenia. Methods: We sequenced the coding regions of HSPA1A, HSPA1B, and HSPA1L from 100 patients with schizophrenia to identify genetic variants. Further, we conducted a genetic association analysis of three SNPs (rs9469057, rs142416335, and rs2075800) in the HSPA1L gene in 519 patients with schizophrenia and 1492 healthy controls from the Taiwan Biobank. We analyzed the function of the HSPA1L protein via immunoblotting. Results: We identified 17 coding variants, including 8 missense and 9 synonymous mutations, in 100 patients with schizophrenia. Three variants (HSPA1L^p.Ala8Pro, HSPA1L^p.Ala8Thr, and HSPA1L^p.Glu602Lys) in the HSPA1L gene did not exhibit any significant differences in allele or genotype frequencies between patients and control subjects. Notably, one ultra-rare missense mutation, HSPA1L^p.Val262Met, was not documented in the control sample in Taiwan BioBank. Immunoblotting revealed HSPA1L^p.Val262Met mutant with decreased protein expression in SH-SY5Y cells compared with the wild type. Conclusions: While common variants in the HSPA1A, HSPA1B, and HSPA1L genes do not seem to be significant genetic risk factors for schizophrenia in this cohort, the ultra-rare mutation, HSPA1L^p.Val262Met, significantly reduces protein expression. These preliminary findings suggest that a potential loss-of-function or reduced expression of the HSPA1L gene may be a predisposing factor contributing to schizophrenia vulnerability in certain individuals. However, the finding should be replicated in other independent samples. The in vitro and in vivo impacts of the associated mutation at the HSPA1L gene on the pathophysiology of schizophrenia are worthy of future investigation. Full article

Background/Objectives: Sex estimation is a cornerstone of research and practice in bioarchaeology and forensic anthropology. However, morphological and metric methods are often hampered by population-specific variation, subjectivity in assessment, and taphonomy. This study compares morphological analysis and ancient DNA (aDNA)-based sex assessment in a 19th-century Portuguese sample to evaluate the accuracy of osteological (anthropological) criteria. Methods: This study analysed 37 skeletons from the Venerável Ordem Terceira da Nossa Senhora do Carmo burial grounds in Porto. Sex estimation was based on (1) the bioanthropological assessment of morphological traits of the os coxae and the skull (2) through aDNA analysis using a multi-marker approach, including real-time PCR (qPCR) targeting autosomal loci, the amelogenin locus, a Y-chromosomal INDEL, and Y-STRs. aDNA was extracted via a non-destructive protocol. Results: Whilst anthropological analysis was possible on all 37 individuals, estimation of sex through aDNA analysis was possible for 26 individuals. A 20% discordance rate was found between morphological and aDNA results. Many individuals morphologically classified as “possible female” or “indeterminate” were genetically identified as male. Genetic analysis resolved most cases that biological anthropologists concluded were “indeterminate”. Conclusions: The high discordance in the Carmo sub-sample may indicate reduced skeletal sexual dimorphism, with males exhibiting skeletal traits typically associated with females, suggesting a sample-specific reduction in sexual dimorphism likely influenced by environmental, nutritional, and/or genetic stressors. A limitation of this study is its small sample size: only 26 of 37 individuals yielded usable genetic results, and only a portion of these individuals provided sufficient data for a direct comparison between morphological and genetic data. Nevertheless, these findings highlight the risk that applying generalised osteological standards relying solely on morphology can lead to systematic misclassification, emphasising the need for a critical, multidisciplinary approach to sex estimation. Full article

Arrhythmogenic cardiomyopathy (ACM/ARVC) is an inherited myocardial disease characterized by progressive fibro-fatty replacement, ventricular arrhythmias, and an increased risk of sudden cardiac death. In addition to mutations in desmosomal genes, growing evidence suggests that microRNAs (miRNAs) actively contribute to disease pathogenesis by regulating key processes such as fibrosis, cell adhesion, and cardiac remodeling. This systematic review analyzed the main miRNAs identified in studies of human cardiac tissue and animal models of ARVC. Materials and Methods: Studies based on human myocardial tissue analysis (including autopsy and biopsy samples) and animal models of arrhythmogenic cardiomyopathy were included, using RNA sequencing, small RNA sequencing, miRNA arrays, and RT-qPCR. Studies on circulating miRNAs and narrative reviews were excluded. miRNAs were analyzed in relation to their functional pathways and their role in disease pathogenesis. Results: The synthesis of studies on human and animal cardiac tissue reveals a consistent miRNA signature associated with arrhythmogenic cardiomyopathy. MiR-21-5p and miR-29b-3p are associated with fibrosis and extracellular matrix remodeling, whereas miR-133a-b and miR-130a are linked to cardiomyocyte integrity loss and desmosomal dysfunction. A second group of miRNAs, including miR-217-5p, miR-708-5p, and miR-135b, regulates key pathways such as Wnt/β-catenin and Hippo signaling, contributing to structural remodeling and loss of cellular identity. Furthermore, downregulation of miR-499-5p is associated with mitochondrial dysfunction and cellular vulnerability, while the miR-142-3p, miR-182-5p, and miR-183-5p clusters contribute to differential molecular signatures compared with other cardiomyopathies. Overall, miRNAs converge on three main pathogenic axes: myocardial fibrosis, desmosomal impairment, and remodeling of cellular signaling pathways. Conclusions: The available evidence indicates that arrhythmogenic cardiomyopathy is regulated by a coordinated network of miRNAs that actively drives myocardial damage progression. These miRNAs represent not only biomarkers but also functional mediators of disease, suggesting potential diagnostic and therapeutic applications based on tissue-specific molecular signatures, including in post-mortem settings. Full article

Objective: This umbrella review aimed to evaluate the strength and consistency of evidence linking genetic variants to dental caries susceptibility. Methods: An umbrella review was conducted, following PRISMA 2020 guidelines. A comprehensive literature search was performed across six databases. Eligibility criteria included systematic reviews and meta-analyses of human subjects. Study selection, data extraction, and methodological quality assessment were performed systematically, with quality evaluated using the AMSTAR-2 tool. Multilevel meta-analyses were conducted to assess variant-specific and grouped genetic effects. Results: The search identified 29 eligible systematic reviews and meta-analyses for inclusion. The multilevel meta-analysis showed statistically significant associations for polymorphisms in TAS2R38 rs713598 (OR = 0.26, 95% CI: 0.09–0.73) and VDR Cdx-2 rs11568820 (OR = 0.66, 95% CI: 0.46–0.95), both indicating lower odds of dental caries, while MBL2 rs1800450 was associated with increased odds (OR = 1.48, 95% CI: 1.03–2.14). However, pooled effects across the main gene categories, including tooth development and mineralization, salivary composition and function, immune and inflammatory response, taste perception, and signaling, were not statistically significant. Findings were heterogeneous across studies. Conclusions: Current evidence on the association between genetic variants and dental caries susceptibility remains limited and inconsistent, providing insufficient support for the use of genetic markers in risk assessment or personalized prevention. The significant single-nucleotide polymorphism (SNP) associations identified in this review are hypothesis-generating and require validation in larger and more diverse populations using standardized caries definitions and gene–environment approaches. Full article

Generative artificial intelligence (AI) is transforming biological and medical research and data analysis. Beyond analyzing existing information, these models can learn complex patterns and generate new data such as realistic protein sequences, genetic variants, or clinical notes. In molecular biology, language-like sequence models can read and generate DNA, RNA, and amino acid sequences to predict genetic variant effects, design new proteins, and explore molecular functions. In medicine, large language models (LLMs) trained on biomedical literature and electronic health records (EHRs) can summarize clinical findings, identify patterns, and provide decision support for clinicians and healthcare providers. Additionally, synthetic data generation can help protect patient privacy and augment existing disease datasets. While these advances make tasks that were previously impractical possible at scale, they also carry major risks, including producing convincing but incorrect results, reflecting hidden biases in the training data, and underperforming when real-world conditions change. Full article

Background/Objectives: White–Sutton syndrome (WHSUS; OMIM 616364) is a rare neurodevelopmental disorder caused by pathogenic variants in the POGZ gene and characterized by developmental delay, intellectual disability, speech impairment, autism spectrum features, and dysmorphic traits. Although most reported cases are sporadic, inherited forms are exceptionally rare. We describe a familial case of WHSUS involving an affected mother and two children carrying a heterozygous POGZ nonsense variant, highlighting marked intra-familial phenotypic variability and expanding the clinical spectrum of the disorder. Methods: Clinical evaluation included multidisciplinary assessments. Genetic testing was performed using clinical exome sequencing (CES) with a virtual neurodevelopmental disorder (NDD) gene panel, followed by Sanger confirmation and segregation analysis in family members. The POGZ transcript reference NM_015100.3 was used for variant nomenclature and verified with the Mutalyzer tool. CNV detection from NGS data was performed using the Alissa CNV caller (Agilent) and visualized via IGV; the Xp11.22 microduplication was confirmed by chromosomal microarray (aCGH) and parental segregation analyses. Results: CES identified the heterozygous pathogenic POGZ variant c.1522C>T (p.Arg508*) in the female proband (III₆), an infant presenting with global developmental delay, hypotonia, speech impairment, gait abnormalities, and characteristic dysmorphic features. Segregation analysis demonstrated maternal inheritance and confirmed the presence of the variant in her affected brother (III₄), who also carries a de novo 1.79 kb microduplication at Xp11.22, while the maternal grandparents tested negative, indicating a de novo origin in the mother. The mother exhibited an attenuated phenotype, including mild neuropsychiatric and gastrointestinal manifestations. The variant is predicted to undergo nonsense-mediated decay (NMD), consistent with a moderate clinical presentation; however, experimental validation was not performed. Conclusions: This report documents a rare familial occurrence of WHSUS with highly variable expressivity. Our findings broaden the phenotypic and molecular characterization of POGZ-related disorders and emphasize the importance of comprehensive segregation studies and early genomic diagnosis. While experimental data link POGZ deficiency to DNA repair defects, no longitudinal clinical studies have demonstrated increased cancer risk in WHSUS; therefore, formal malignancy screening guidelines cannot be established at present, and this issue deserves future study in larger cohorts or registries. Full article

High levels of low-density lipoprotein cholesterol (LDL-c) have been recognized as the main causal factor of atherosclerotic cardiovascular disease (ASCVD) and are influenced by both genetic and environmental factors. Among genetic determinants, Familial Hypercholesterolemia (FH) is the most common monogenic disorder, caused by rare high-impact variants in genes involved in LDL uptake. Other monogenic causes of hypercholesterolemia include sitosterolemia, cerebrotendinous xanthomatosis and lysosomal acid lipase deficiency (LALD). However, monogenic disorders only account for a small proportion of inherited hypercholesterolemia. In many individuals, increased LDL-c levels are caused by the contemporary presence of different single-nucleotide polymorphisms (SNPs) with a moderate/low impact. These SNPs could be summarized through polygenic risk scores (PRS) that attribute relative weight to each of these. Another genetic determinant of hypercholesterolemic phenotypes is high levels of lipoprotein(a)—Lp(a). Lp(a) is an LDL particle modified by the binding of apolipoprotein(a)—apo(a)—which represents an independent risk factor for ASCVD. Lp(a) levels are mainly genetically determined by variation in the number of kringle IV type 2 (K-IV₂) repeats, as well as by several SNPs, and remain stable throughout life. The aim of this narrative review is to report an updated overview of the genetic mechanisms underlying hypercholesterolemia, including monogenic disorders, PRS and Lp(a), focusing on their potential repercussion in clinical practice by the integration into cardiovascular risk stratification beyond traditional clinical assessment. This integration could lead to a more comprehensive and individualized approach to cardiovascular prevention, with emerging perspectives including the possible use of artificial intelligence (AI). Full article