Search Results (10,963)

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

The growing availability of genomic resources is changing how genetic diversity is studied in Vitis vinifera L. At the same time, it has become increasingly clear that a single reference genome cannot fully represent the complexity of a species characterised by high heterozygosity, clonal propagation and a long history of diversification. Recent grapevine pangenomes, super-pangenomes and graph-based resources have revealed forms of variation that are often overlooked in conventional reference-based analyses, including structural variants and gene presence–absence variation. Rather than providing another inventory of available datasets, this review examines how continued reliance on a single reference genome may influence the interpretation of grapevine diversity and what can be gained from a broader pangenomic perspective. Drawing on recent studies in grapevine and other crops, we discuss how these approaches are beginning to improve the representation of genetic diversity, uncover biologically relevant variation and strengthen links between genomic information and adaptive traits. We also examine the challenges that still limit their practical use, particularly the integration of genomic resources with functional studies and breeding programmes. In the end, the value of pangenomics will probably depend not only on generating additional genomic resources, but also on how effectively these can be translated into tools that support grapevine conservation, climate adaptation and varietal improvement. 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

Aim: The aim of this study was to correlate single-nucleotide polymorphisms (SNPs) in the FTO and MC4R genes with body composition (BC) in populations with various levels of physical activity, and to investigate associations of SREBF1 methylation with the level of physical activity (PA) and BC. Methods: Fifty-six participants aged 18–65 years old with no underlying medical conditions were included in the study and were classified into sedentary/light PA (SLPA), moderate PA (MPA) and vigorous PA (VPA) groups using the International PA questionnaire (IPAQ). Anthropometric measures such as age, gender, body mass index (BMI) and body fat percentage (BFP) were recorded at the time of recruitment. Venous blood samples were collected during participant recruitment and DNA was extracted. Genotyping assays were performed for SNPs in FTO (rs9939609) and MC4R (rs17782313) using Taqman^® RT qPCR and TaqMan Genotyper software 1.7.1. Methylation analysis assay for CpG sites in the SREBF1 gene was performed on 56 samples using PyroMark^® Q48 Autoprep (Qiagen,Venlo, Netherlands). The results were statistically analysed to identify any associations between FTO/MC4R genotypes and the level of PA, and between SREBF1 methylation status and the level of PA. This is the first study to investigate links between PA and quantitative methylation of SREBF1. Results: According to IPAQ guidance, the 56 participants were classified into SLPA n = 14, MPA n = 11 and VPA n = 31. The correlation analysis revealed that the FTO rs9939609 ‘A’ risk allele had a significant negative association with BFP in the VPA group (p = 0.0387); the MC4R rs17782313 ‘C’ risk allele had a significant positive association with BMI in the VPA group (p = 0.0256). In the SREBF1 pyrosequencing analysis, higher levels of methylation were observed in the VPA group (p = 0.07). Conclusions: We concluded that SNPs associated with obesity identified in FTO rs9939609 and MC4R rs17782313 could help to predict the molecular effects of PA. A high frequency of FTO risk variants in the cohort was observed and the VPA group could help maintain a healthy BFP. Full article

Environmental exposure to persistent and non-persistent endocrine-disrupting chemicals (EDCs), including per- and polyfluoroalkyl substances (PFAS), polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), polycyclic aromatic hydrocarbons (PAHs), dioxins, phthalates, and bisphenols, has been increasingly associated with elevated cardiovascular disease (CVD) risk. Emerging evidence suggests the importance of gene–environment interactions in modulating individual susceptibility to EDC-related cardiovascular effects. This review summarizes current knowledge by synthesizing the main classes of EDCs, evaluating the evidence linking them to cardiovascular outcomes, and highlighting how genetic variability may modulate EDC-induced cardiovascular risk. Across the studies analyzed, the most extensively investigated genetic polymorphisms involve pathways related to oxidative stress regulation, xenobiotic metabolism and detoxification, hormone signaling, and lipid homeostasis. Variants in antioxidant defense genes, such as CAT, eNOS, and PON1, have been associated with increased hypertension risk and vascular dysfunction following exposure to bisphenols and PAHs. Polymorphisms in GSTP1, CYP2C19, CYP1A2, CYP2E1, ABCB1, and MTHFR may influence susceptibility to cardiometabolic alterations and congenital heart defects, whereas variants in ESR2, FTO, LEPR, and INSIG2 have been linked to obesity, dyslipidemia, and hypertension associated with PFAS, PBDEs, and bisphenols. A deeper understanding of gene–environment interactions is essential to advance preventive cardiology and mitigate the cardiovascular impact of environmental pollutants. Full article

Copy number variants (CNVs) are genomic rearrangements that carry a substantial risk for neurodevelopmental and neuropsychiatric disorders. Among these, recurrent deletions and duplications at the 16p11.2 locus are robustly associated with autism spectrum disorders, schizophrenia, epilepsy, and related conditions, yet also display marked variability in penetrance and phenotypic expression. Accumulating evidence indicates that 16p11.2 gene dosage influences multiple stages of brain development, from early progenitor dynamics and neuronal migration to synaptic formation, refinement, and plasticity. However, how disruptions across these processes are integrated over time, and how they relate to the observed variability and incomplete penetrance, remains poorly understood. In this review, we summarize the current evidence on the impact of 16p11.2 CNVs on brain development, focusing on cellular and circuit-level processes that shape neural connectivity. We discuss how gene dosage imbalance influences early developmental trajectories, synaptic formation and pruning, interneuron maturation, and activity-dependent plasticity, and consider how these processes interact across developmental stages. We suggest a conceptual framework wherein 16p11.2 CNVs do not impose fixed pathogenic outcomes, but rather they contribute towards developmental constraints that shape the timing and stability of neural circuit development. Consequently, these constraints increase vulnerability to neurodevelopmental and psychiatric outcomes in a context-dependent manner. Full article

Since January 2023, the Russian Federation has implemented expanded neonatal screening for 36 hereditary disorders, which has changed the diagnostic algorithm for hyperphenylalaninemia/phenylketonuria (HPA/PKU) by introducing tandem mass spectrometry (MS/MS) on the second day of life, followed by confirmatory biochemical and molecular testing in newborns at risk. We analyzed 1247 newborns aged 5–15 days with elevated phenylalanine levels (≥120 µmol/L) and a phenylalanine to tyrosine ratio of at least 1 detected during the first stage of screening using MS/MS. At the reference center, newborns underwent repeat biochemical testing and stepwise molecular analysis of HPA-associated genes. Two pathogenic variants in HPA-associated genes were identified in 538 newborns, including 534 newborns with biallelic pathogenic variants in PAH and 4 with BH4-deficient forms (PTS, QDPR). The incidence of molecularly confirmed HPA was 1:4518 newborns (95% CI: 1:4152–1:4925). The PAH variant spectrum was dominated by p.Arg408Trp (c.1222C>T) (33.4%). Genotype-based analysis indicated that 73 newborns (13.7%) were likely responsive to cofactor therapy, whereas 222 (41.6%) were potentially responsive. These findings define the molecular epidemiology of HPA in Russia and support early genetic stratification for diagnosis and treatment. Full article

Zinc deficiency is increasingly recognized as a risk factor for neurodegenerative diseases, yet the underlying molecular mechanisms remain incompletely understood. In this study, we investigated the impact of intracellular zinc depletion on oxidative stress and inflammasome activation in microglial (SIM-A9) and neuronal (SH-SY5Y) cell models, and evaluated the protective effects of polyphenolic compounds. Intracellular zinc chelation with the membrane-permeable chelator TPEN markedly increased reactive oxygen species (ROS) production, reduced cell viability, and upregulated the mRNA expression of NLRP3 inflammasome-related genes and pro-inflammatory cytokines. In contrast, extracellular zinc chelation had no effect, highlighting the critical role of intracellular zinc homeostasis in maintaining redox balance. Zinc supplementation significantly attenuated these responses. Among 32 polyphenols screened by DPPH radical scavenging assay, caffeic acid derivatives—chicoric acid (ChA), rosmarinic acid (RA), and caffeic acid phenethyl ester (CAPE)—exhibited the most potent antioxidant activity, surpassing that of edaravone. These compounds suppressed ROS production and differentially protected against zinc deficiency-induced cellular damage. ChA showed the strongest ROS inhibitory activity (IC50: 1.9 µM in SIM-A9), RA provided robust cytoprotection even at low concentrations, and CAPE most effectively suppressed inflammasome-related gene expression and inhibited aggregation of both Aβ1–42 and the highly neurotoxic pyroglutamate-modified variant pEAβ3–42. These findings demonstrate that intracellular zinc deficiency drives ROS-dependent upregulation of NLRP3 inflammasome-related genes, and suggest that caffeic acid derivative polyphenols may serve as complementary agents for mitigating neuroinflammatory and amyloidogenic processes relevant to Alzheimer’s disease. Full article

The Popeye domain-containing protein 1 (Popdc1), also known as Bves, plays a crucial role in maintaining skeletal muscle homeostasis, with its variants leading to limb–girdle muscular dystrophy type R25. Skeletal muscles of patients with the homozygous missense variant of Bves exhibit impaired membrane trafficking, while skeletal muscle fibers in bves^S191F homozygous mutant zebrafish are significantly reduced and disorganized. However, the mechanism by which the absence of bves induces skeletal muscle atrophy remains unclear. In this study, we discovered a novel mechanism whereby bves deficiency drives skeletal muscle atrophy by disrupting mitochondrial structure and function. Our findings indicate that bves knockout leads to a significant decrease in zebrafish’s ability to swim, atrophy of skeletal muscle tissue, loss of cell membrane localization signals, and abnormalities in mitochondrial structure and function. After an 8-week intervention of regular aerobic exercise, the symptoms of skeletal muscle atrophy in bves knockout zebrafish were significantly alleviated, and the expression levels of genes and proteins related to mitochondrial were effectively rescued. These findings establish a connection between bves deficiency-induced disruption of mitochondrial structure and function and the onset and progression of skeletal muscle tissue atrophy symptoms, thereby laying a molecular foundation for exercise rehabilitation strategies in atrophic myopathy. Full article

Transposable elements (TEs) are inserted into the genome and may change its properties; those occurring in or near regulatory regions may also alter gene expression. Given the challenges of detecting insertions in short-read sequencing, we analyzed structural variants in polar and brown bear genomes by a reciprocal alignment of one species’ sample genomes to a reference sequence of the other species, thus inferring TE insertion as the other genome’s “deletions”. With this approach, we detected short interspersed elements (SINEs) belonging to the CAN SINE family as dominant fixed TEs. We observed a non-random distribution of CAN SINE insertion positions near both protein- and RNA-coding genes, where TEs often overlap UTRs or occur in their vicinity. In contrast, SINEs avoid coding sequences, suggesting TE insertions that would disrupt such sequences are under purifying selection. We used black bear as an outgroup and determined that most of the CAN SINE insertions in the polar bear genome were derived, since they are not present in black or brown bear, while there is no dominant trend for CAN SINE insertions in brown bear relative to the outgroup. Many of the genes with UTRs affected by CAN SINEs are potentially relevant to the differences between the species (body shape, size, etc.) or to Arctic-adaptation phenotypes such as fur color, metabolism, and the immune system. This supports a model that CAN SINEs have contributed to regulatory evolution in bears and provides further evidence of such events across carnivore genomes in the animal kingdom. Full article

Prostate cancer (PrC) is one of the most common malignancies among men worldwide. However, the contribution of genetic variation in microRNA (miRNA) biogenesis pathway genes to PrC susceptibility remains poorly characterized in many ethnically diverse populations. We conducted a case–control study involving 532 PrC patients and 550 controls from the Volga-Ural region of Eurasia to evaluate the association of twenty-one single nucleotide polymorphisms (SNPs) with PrC risk using single-variant and polygenic approaches. Association analyses identified rs595055 in the AGO1 gene as significantly associated with PrC risk after correction for multiple testing. To evaluate the cumulative effect of genetic variation, weighted and unweighted polygenic risk scores (PRSs) were constructed. The weighted PRS was significantly associated with PrC risk (odds ratio per standard deviation increase = 1.63, 95% CI [1.43–1.85], P = 1.37 × 10⁻¹³), and demonstrated moderate discriminatory performance (AUC = 63.1%), outperforming the unweighted model. Individuals in the highest PRS quartile had approximately threefold higher odds of PrC than those in the lowest quartile. Combining the weighted PRS with prostate-specific antigen improved discrimination (AUC = 68.1%). These findings support the contribution of miRNA biogenesis pathway genes to PrC susceptibility and highlight the potential value of pathway-based polygenic risk stratification in understudied populations. Full article

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an adult-onset inflammatory disorder caused by acquired mutations in UBA1, the gene encoding the primary ubiquitin-activating enzyme. The recognition of VEXAS has transformed the current understanding of autoinflammatory disease by demonstrating that somatic alterations arising within hematopoietic stem cells can precipitate severe, multisystem inflammation in later life. While pathogenic UBA1 variants are essential to disease pathogenesis, many affected individuals also harbor additional somatic mutations associated with clonal hematopoiesis, most commonly involving DNMT3A and TET2. These concurrent mutations may contribute to clonal architecture; however, their independent impact on inflammatory phenotype and hematologic manifestations remains incompletely defined. Emerging evidence suggests that co-occurring clonal hematopoiesis mutations may be independently associated with poorer overall survival, though their causal role remains unestablished. This review examines the evolving genetic framework of VEXAS syndrome, emphasizing UBA1 as the obligate driver mutation while reviewing current evidence regarding non-Met41 UBA1 variants and co-occurring somatic mutations. Full article

Wilson–Turner syndrome (WTS) is an X-linked developmental disorder associated with variants in the LAS1L gene, which plays a role in ribosome biogenesis. We report a 6-year-and-5-month-old boy presenting with growth retardation, early developmental delay, and mild scoliosis. Exome sequencing analysis identified a novel hemizygous LAS1L frameshift variant, c.2082dup (p.Leu697ProfsTer59), inherited from his asymptomatic mother that was absent from population databases. Functional analysis in HEK-293T cells suggested reduced protein expression with a partial loss of function effect, while structural modeling indicated potential alteration of the C-terminal region. The patient lacked classical WTS features, including craniofacial dysmorphism, truncal obesity, hypogonadism, and neuromuscular involvement. This case expands the phenotypic spectrum of LAS1L-related disorders and highlights the consideration of LAS1L variants in children with unexplained growth failure, scoliosis, or developmental delay, even in the absence of classical WTS features. Full article

While ovarian cancer screening is not recommended in the general population, attention has shifted to screening women with elevated hereditary risks. Although germline BRCA 1/2 pathogenic variants account for 40% of inherited ovarian cancer risk and family history (FH) remains important, known germline variants alone do not fully explain familial ovarian cancer risk. Whole-exome sequencing (WES) was performed on blood samples taken from 231 individuals, including 39 patients with high-grade serous ovarian cancer (HGSOC) and 192 healthy controls (HCs) stratified by FH. We analyzed pathogenic or likely pathogenic (P/LP) germline variants in cancer-related genes and assessed their association with family cancer history. Additionally, we performed somatic variant comparisons using 1:4 propensity score matching and analyzed clonal hematopoiesis of indeterminate potential (CHIP)-related somatic variants. P/LP germline variants were detected in 56.4% of HGSOC patients, 49.4% of controls with FH, and 33.3% without. The HGSOC group and controls with FH exhibited similar P/LP germline mutation patterns in ovarian cancer-related genes. From CHIP analysis, somatic CHIP mutations were detected in 6.3% of the HGSOC group and 8.5% in HCs. Our findings demonstrate genomic overlap between ovarian cancer patients and FH-positive individuals. Therefore, germline variant screening could be considered to facilitate early diagnosis. Full article

Vitamin D is a fat-soluble secosteroid essential for skeletal development and calcium homeostasis, but it also exerts pleiotropic effects on numerous biological processes via its active metabolites. Vitamin D metabolites act as steroid hormones that regulate cell-cycle progression, proliferation, differentiation, apoptosis, immune responses, and multiple intracellular signaling pathways. Moreover, they modulate the expression of genes involved in carcinogenesis. As circulating vitamin D levels are influenced by diet, fortified foods, and supplementation, they represent a potentially modifiable factor. Whether vitamin D status affects cancer risk or disease progression in carriers of pathogenic BRCA1 variants remains unclear and continues to be actively investigated. Clarifying this relationship could have significant clinical implications for risk stratification and prevention in this high-risk population. This narrative review summarizes current evidence from epidemiological, clinical, and molecular studies examining the role of vitamin D in BRCA1 pathogenic variant carriers. It also highlights key limitations in the existing literature and identifies critical directions for future research, emphasizing the need for well-designed prospective studies in representative cohorts. Full article