Search Results (1,792)

Background/Objectives: Amelogenesis imperfecta (AI) represents a heterogeneous group of inherited disorders affecting the quality and quantity of dental enamel, making clinical diagnosis challenging. This study aimed to identify genetic variants in Slovenian patients with non-syndromic AI and to evaluate enamel morphology using radiographic parameters. Methods: Whole exome sequencing (WES) was performed on 24 AI patients and their families. Panoramic radiographs (OPTs) were analyzed using Fiji ImageJ to assess crown dimensions, enamel angle (EA), dentine angle (DA), and enamel–dentine mineralization ratio (EDMR) in lower second molar buds, compared to matched controls (n = 24). Two observers independently assessed measurements, and non-parametric tests compared EA, DA, and EDMR in patients with and without disease-causing variants (DCVs). Statistical models, including bootstrap-validated random forest and logistic regression, assessed variable influences. Results: DCVs were identified in ENAM (40% of families), AMELX (15%), and MMP20 (10%), including four novel variants. AI patients showed significant enamel deviations with high reproducibility, particularly in hypomineralized and hypoplastic regions. DA and EDMR showed significant correlations with DCVs (p < 0.01). A bootstrap-validated random forest model yielded a 90% (84.0–98.0%) AUC-estimated predictive power. Conclusions: These findings highlight a novel and reproducible radiographic approach for detecting developmental enamel defects in AI and support its diagnostic potential. Full article

Background/Objectives: Lung cancer is a highly diverse disease, and reliable preclinical models that accurately reflect tumor characteristics are essential for studying lung cancer biology and testing new therapies. This study aimed to establish patient-derived tumor organoids (PDTOs) using small biopsy samples and surgical specimens to create a model system that preserves the genetic and histological features of the original tumors. Methods: PDTOs were generated from 163 lung cancer specimens, including 109 samples obtained using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) or bronchoscopy, 52 surgical specimens, and 2 pleural fluid samples. The organoid establishment rate beyond passage three was assessed, and histological subtypes and genetic profiles were analyzed using immunohistochemical staining and targeted exome sequencing. Results: The overall PDTO establishment rate was 34.4% (56/163), and 44.6% (25/56) of these organoids retained the histological and genetic features of the parental tumors. Genetic analysis identified key mutations, including KRAS G12C, EGFR L858R, MET exon 14 skipping mutation, and ROS1 fusion. PDTOs successfully formed tumors in mice while maintaining the genetic characteristics of the original tumors. Co-culture of PDTOs with cancer-associated fibroblasts (CAFs) resulted in increased resistance to paclitaxel. In the co-culture model of PDTOs with immune cells, dose-dependent growth inhibition of PDTOs was observed in response to immune checkpoint inhibitors. Conclusions: PDTOs established from small biopsy and surgical specimens serve as a valuable model for studying lung cancer biology, tumor microenvironment interactions, and drug response. This model has the potential to improve personalized treatment strategies. Full article

Background: HM is a rare, severe form of migraine with aura, characterised by motor weakness and strongly influenced by genetic factors affecting the brain. While pathogenic variants in CACNA1A, ATP1A2, and SCN1A genes have been implicated in familial HM, approximately 75% of cases lack known pathogenic variants in these genes, suggesting a more complex genetic basis. Methods: To advance our understanding of HM, we applied a variant prioritisation approach using whole-exome sequencing (WES) data from patients referred for HM diagnosis (n = 184) and utilised PathVar, a bioinformatics pipeline designed to identify pathogenic variants. Our analysis incorporated two strategies for association testing: (1) PathVar-identified single nucleotide variants (SNVs) and (2) PathVar SNVs combined with missense and rare variants. Principal component analysis (PCA) was performed to adjust for ancestral and other unknown differences between cases and controls. Results: Our results reveal a sequential reduction in the number of genes significantly associated with HM, from 20 in the first strategy to 11 in the second, which highlights the unique contribution of PathVar SNVs to the genetic architecture of HM. PathVar SNVs were more distinctive in the case cohort, suggesting a closer link to the functional changes underlying HM compared to controls. Notably, novel genes, such as SLC38A10, GCOM1, and NXPH2, which were previously not implicated in HM, are now associated with the disorder, advancing our understanding of its genetic basis. Conclusions: By prioritising PathVar SNVs, we identified a broader set of genes potentially contributing to HM. Given that HM is a rare condition, our findings, utilising a sample size of 184, represent a unique contribution to the field. This iterative analysis demonstrates that integrating diverse variant schemes provides a more comprehensive view of the genetic factors driving HM. Full article

Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more consecutive pregnancy losses before 20 weeks of gestation, encompassing both embryonic and fetal losses. Although previous studies have provided substantial insights into RPL, the causes in many cases remain unexplained. This lack of information has prompted continued investigation into various risk factors, including those identified through next-generation sequencing (NGS). In the present study, whole-exome sequencing (WES) was used to identify genes potentially associated with RPL and infertility, which may serve as novel biomarkers. Confirmation of the association between these genetic variants and RPL may help to develop functional biomarkers for early diagnosis. The findings revealed that the PCSK5 rs1110222 G > A polymorphism was significantly associated with a reduced risk of RPL. In contrast, the MUC2 rs10902088 C > T polymorphism was associated with an increased risk of RPL among women with more than four pregnancy losses. Notably, the A-T allele combination of PCSK5 rs1110222 G > A and MUC2 rs10902088 C > T showed a significant association with a decreased risk of RPL relative to the G-C combination. In conclusion, this study confirms that the PCSK5 rs1110222 G > A and MUC2 rs10902088 C > T polymorphisms are genetically associated with the prevalence of RPL in Korean women. Full article

Precision medicine is transforming hematologic cancer care by tailoring treatments to individual patient profiles and moving beyond the traditional “one-size-fits-all” model. This review outlines foundational technologies, disease-specific advances, and emerging directions in precision hematology. The field is enabled by molecular profiling techniques, including next-generation sequencing (NGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), as well as epigenomic and proteomic analyses. Complementary tools such as liquid biopsy and minimal residual disease (MRD) monitoring have improved diagnosis, risk stratification, and therapeutic decision making. We discuss major molecular targets and personalized strategies across hematologic malignancies: FLT3 and IDH1/2 in acute myeloid leukemia (AML); Philadelphia chromosome–positive and Ph-like subtypes in acute lymphoblastic leukemia (ALL); BCR-ABL1 in chronic myeloid leukemia (CML); TP53 and IGHV mutations in chronic lymphocytic leukemia (CLL); molecular subtypes and immune targets in diffuse large B-cell lymphoma (DLBCL) and other lymphomas; and B-cell maturation antigen (BCMA) in multiple myeloma. Despite significant progress, challenges remain, including high costs, disparities in access, a lack of standardization, and integration barriers in clinical practice. However, advances in single-cell sequencing, spatial transcriptomics, drug repurposing, immunotherapies, pan-cancer trials, precision prevention, and AI-guided algorithms offer promising avenues to refine treatment and improve outcomes. Overcoming these barriers will be critical for ensuring the equitable and widespread implementation of precision medicine in routine hematologic oncology care. Full article

Multiple chemical sensitivity (MCS) is a disease of unknown etiology with multiple symptoms. Triggered by exposure to environmental chemicals, it results in multiorgan effects. Studies on MCS use different approaches, ranging from searches for environmental triggers to susceptibility genes. Genetic research deals with genes for chemical detoxification, oxidative stress, inflammation, and neurodegeneration, as well as immune function and mast cell activation, with uneven results. The sensory hyperexcitability symptom has not been studied yet but has recently been linked to a member of the SLC gene superfamily. To explore its role in MCS disease, a complete-exome analysis was performed in a small number of subjects. Low-frequency genetic variants were analyzed for each individual, and their homozygous or heterozygous presence was determined in four groups of genes related either to the SLC superfamily members or to previous studies in MCS. We found homozygous rare variants in affected individuals only for the SLC gene superfamily, where each patient had at least one. Variants in heterozygosis and certain SNPs also point to SLC genes related to neurotransmitter synthesis, release, and clearance, as well as to the level of cellular excitability, as potentially underlying the differences. Full article

Peters anomaly (PA) is a rare congenital disorder within the anterior segment dysgenesis (ASD) spectrum, characterized by corneal opacity, iridocorneal adhesions, and potential systemic involvement. The genetic basis of PA and related syndromes are complex and incompletely understood. This study investigates novel genetic variants and their clinical impact in two unrelated individuals diagnosed with PA spectrum disorder. Whole-exome sequencing (WES), long-range PCR, and breakpoint analysis were applied to identify pathogenic variants. In the first patient, a heterozygous ~1.6 Mb deletion was detected, spanning the genes PEX2 and ZFHX4 (GRCh37 chr8:g.76760782_78342600del). The second patient carried a heterozygous FOXC1 variant (NM_001453.3:c.310A>G), classified as likely pathogenic. Both variants were confirmed by Sanger sequencing and considered de novo, as they were not present in the biological parents. Clinical evaluations revealed phenotypic variability, with the first patient displaying both ocular and systemic anomalies as in a Peters plus-like syndrome phenotype, while the second patient had isolated ocular manifestations as in a PA type 1 phenotype. These findings expand the genetic landscape of PA, underscoring the importance of comprehensive genomic analysis in subclassifying ASD disorders. Further studies are needed to elucidate the functional consequences of these variants and improve diagnostic and therapeutic strategies. Full article

The 26S proteasome is a large, ATP-dependent proteolytic complex responsible for degrading ubiquitinated proteins in eukaryotic cells. It plays a crucial role in maintaining cellular protein homeostasis by selectively eliminating misfolded, damaged, or regulatory proteins marked for degradation. In this study, whole-exome sequencing (WES) was performed on an individual presenting with developmental delay and mild intellectual disability, as well as on both of his unaffected parents. This analysis identified a de novo variant, c.959C>G (p.Pro320Arg), in the PSMC5 gene. As predicted, this gene shows a very likely autosomal dominant inheritance pattern. Notably, PSMC5 has not previously been associated with any phenotype in the OMIM database. This variant was recently submitted to the ClinVar database as a variant of uncertain significance (VUS) and remains absent in both gnomAD and dbSNP. Notably, it has been identified in six unrelated individuals presenting with clinical features comparable to those observed in the patient described in this study. Multiple in silico prediction tools classified the variant as pathogenic, and a PhyloP conservation score supports strong evolutionary conservation of the mutated nucleotide. Protein structure predictions using the AlphaFold3 algorithm revealed notable structural differences between the mutant and wild-type PSMC5 proteins. We hypothesize that the p.Pro320Arg substitution alters the structure and function of PSMC5 as a regulatory subunit of the 26S proteasome, potentially impairing the stability and activity of the entire complex. Although functional studies are imperative, this study contributes to a deeper understanding of PSMC5, expands the spectrum of associated neurodevelopmental phenotypes, and highlights its potential as a therapeutic target. Furthermore, this study resulted in the submission of the identified variant to the ClinVar database (SCV006083352), where it was classified as pathogenic. Full article

Background/Objectives: Neurodevelopmental disorders (NDDs) represent a clinically diverse group of conditions that affect brain development, often leading to varying degrees of functional impairment. Many NDDs, particularly syndromic forms, are caused by genetic mutations affecting critical cellular pathways. Ribosomopathies, a subgroup of NDDs, are linked to defects in ribosomal function, including those involving the synthesis of diphthamide, a post-translational modification of translation elongation factor 2 (eEF2). Loss-of-function (LoF) mutations in genes involved in diphthamide biosynthesis, such as DPH1, DPH2, and DPH5, result in developmental delay (DD), intellectual disability (ID), and multisystemic abnormalities. DPH5-related diphthamide deficiency syndrome has recently been reported as an ultrarare disorder linked to LoF mutations in DPH5, encoding a methyltransferase required for diphthamide synthesis. Methods: Clinical, neurological, and dysmorphological evaluations were performed by a multidisciplinary team. Brain MRI was acquired on a 3T scanner. Craniofacial abnormalities were assessed using the GestaltMatcher phenotyping tool. Whole exome sequencing (WES) was conducted on leukocyte-derived DNA with a trio-based approach. Bioinformatic analyses included variant annotation, filtering, and pathogenicity prediction using established databases and tools. Results: The affected subject carried a previously reported missense change, p.His260Arg, suggesting the occurrence of genotype–phenotype correlations and a hypomorphic behavior of the variant, likely explaining the overall milder phenotype compared to the previously reported patients with DPH5-related diphthamide deficiency syndrome. Conclusions: Overall, the co-occurrence of short stature, relative macrocephaly, congenital heart defects, variable DD/ID, minor skeletal and ectodermal features, and consistent craniofacial features suggests a differential diagnosis with Noonan syndrome and related phenotypes. Full article

Hearing impairments (HIs) are clinically and genetically very heterogeneous. Finding the causative mutations in patients is frequently a challenge. We investigated two brothers affected by a sensorineural, moderate non-syndromic HI. Exome sequencing revealed that they carried the heterozygous c.812C>T (p.Ser271Leu) variant in GATA3. This gene encodes a transcription factor involved in embryonic development, its mutations causing the autosomal dominant HDR (hypoparathyroidism, deafness, and renal disease) syndrome. The variant affects a conserved residue within the proximal zinc-finger motif of GATA3. Sanger sequencing confirmed the presence of the variant in the two brothers, but it showed that surprisingly it was not carried by any of the parents. Segregation studies on 20 fully informative microsatellite markers in the family confirmed that the variant arose de novo. A benign SNP in the mother, close to the position of the variant, allowed us to determine that this was inherited from the father. Gene reporter functional assays supported the pathogenicity of the variant. Clinical reassessment of the two brothers did not disclose any additional abnormality. We conclude that mosaicism for this de novo mutation in the father’s germ line explains the pattern of inheritance in this family and that p.Ser271Leu is causing this unexpected phenotype of non-syndromic HI. Full article

Mitochondrial dysfunction is a key driver of neurological disorders due to the brain’s high energy demands and reliance on mitochondrial homeostasis. Despite advances in genetic characterization, the heterogeneity of mitochondrial diseases complicates diagnosis and treatment. Mitochondrial dysfunction spans a broad clinical spectrum, from early-onset encephalopathies to adult neurodegeneration, with phenotypic and genetic variability necessitating integrated models of mitochondrial neuropathology. Mutations in nuclear or mitochondrial DNA disrupt energy production, induce oxidative stress, impair mitophagy and biogenesis, and lead to neuronal degeneration and apoptosis. This narrative review provides a structured synthesis of current knowledge by classifying mitochondrial-related neurological disorders according to disrupted biochemical pathways, in order to clarify links between genetic mutations, metabolic impairments, and clinical phenotypes. More specifically, a pathway-oriented framework was adopted that organizes disorders based on the primary mitochondrial processes affected: oxidative phosphorylation (OXPHOS), pyruvate metabolism, fatty acid β-oxidation, amino acid metabolism, phospholipid remodeling, multi-system interactions, and neurodegeneration with brain iron accumulation. Genetic, clinical and molecular data were analyzed to elucidate shared and distinct pathophysiological features. A comprehensive table synthesizes genetic causes, inheritance patterns, and neurological manifestations across disorders. This approach offers a conceptual framework that connects molecular findings to clinical practice, supporting more precise diagnostic strategies and the development of targeted therapies. Advances in whole-exome sequencing, pharmacogenomic profiling, mitochondrial gene editing, metabolic reprogramming, and replacement therapy—promise individualized therapeutic approaches, although hurdles including heteroplasmy, tissue specificity, and delivery challenges must be overcome. Ongoing molecular research is essential for translating these advances into improved patient care and quality of life. Full article

Background: Developmental delay and intellectual disability (DD/ID) are frequently accompanied by epilepsy, and growing evidence implicates variants in voltage-gated calcium channel genes in their pathogenesis. This study aimed to investigate the association of polymorphisms in CACNA1A, CACNA1C, and CACNA1H with DD/ID and epilepsy comorbidity in Korean children. Methods: We retrospectively analyzed 141 pediatric patients diagnosed with DD/ID who underwent whole-exome sequencing (WES) and were not found to have pathogenic monogenic variants. Nine single-nucleotide polymorphisms (SNPs) across CACNA1A, CACNA1C, and CACNA1H were selected based on functional annotation scores and prior literature. Genotype data were extracted from WES variant files, and allele and genotype frequencies were compared with control data from the gnomAD East Asian population and the Korean Reference Genome Database (KRGDB). Subgroup analyses were performed according to epilepsy comorbidity. Results: The CACNA1A rs16023 variant showed a significantly higher B allele frequency in DD/ID patients than in both control datasets and was also associated with epilepsy comorbidity. Genotype distribution analysis revealed that the BB genotype of rs16023 was more frequent in patients with epilepsy. Conclusions: The CACNA1A rs16023 variant may contribute to genetic susceptibility to DD/ID and epilepsy in Korean children, potentially through regulatory mechanisms. These findings support the relevance of calcium channel genes in neurodevelopmental disorders and highlight the importance of integrating functional annotation in variant prioritization. Full article

The global prevalence of hepatocellular carcinoma (HCC) is getting worse, leading to an urgent need for improved diagnostic and prognostic strategies. Liquid biopsy, which analyzes circulating tumor cells (CTCs), cell-free DNA (cfDNA), cell-free RNA (cfRNA), and extracellular vesicles (EVs), has emerged as a minimally invasive and promising alternative to traditional tissue biopsy. These biomarkers can be detected using sensitive molecular techniques such as digital PCR, quantitative PCR, methylation-specific assays, immunoaffinity-based CTC isolation, nanoparticle tracking analysis, ELISA, next-generation sequencing, whole-genome sequencing, and whole-exome sequencing. Despite several advantages, liquid biopsy still has challenges like sensitivity, cost-effectiveness, and clinical accessibility. Reports highlight the significance of multi-analyte liquid biopsy panels in enhancing diagnostic sensitivity and specificity. This approach offers a more comprehensive molecular profile of HCC, early detection, and tracking therapeutic treatment, particularly in those cases where single-analyte assays and imaging fail. The technological advancement in the isolation and analysis of CTC, cell-free nucleic acids, and EVs is increasing our understanding of extracting genetic information from HCC tumors and discovering mechanisms of therapeutic resistance. Furthermore, crucial information on tumor-specific transcriptomic and genomic changes can be obtained using cfRNA and cfDNA released into the peripheral blood by tumor cells. This review provides an overview of current liquid biopsy strategies in HCC and their use for early detection, prognosis, and monitoring the effectiveness of HCC therapy. Full article

Waardenburg syndrome (WS) is a rare genetic disorder that affects both hearing and pigmentation. The wide divergence of WS poses significant diagnostic and management challenges. This study investigated type 4 WS within an underrepresented Mongolian population. Whole-exome sequencing revealed that two unique heterozygous variants were identified in the SOX10 gene: c.393C>G (p.Asn131Lys) in a five-year-old female patient presenting with profound sensorineural hearing loss (SNHL), dystopia canthorum, and a white forelock; and c.535A>T (p.Lys179Ter) in a nine-year-old male patient presenting with profound SNHL, dystopia canthorum, and Hirschsprung’s disease. Temporal bone imaging revealed abnormalities in the inner ear structure in both patients. The genotypic and phenotypic characteristics were meticulously delineated, incorporating the deleterious effects of these variants, as evaluated by multiple predictive tools and the American College of Medical Genetics and Genomics (ACMG) criteria. In addition, structural characterizations were also presented using AlphaFold. The findings of this study contribute valuable genetic data to the limited literature on type 4 WS within this ethnic group and highlight the importance of genetic testing and multidisciplinary care for this rare disorder in settings with limited resources. Full article

The pathogenesis of diabetic neuropathy involves complex interactions between metabolic and genetic factors. This study aimed to identify novel genetic variants associated with neuropathy risk in type 2 diabetes through reanalysis of whole-exome sequencing data. We identified seven new SNPs with significant associations, including intronic variants in TTN, PLCB1, CCNI, and CDC34 and a 5′-upstream variant in BTG2. These variants are implicated in muscle elasticity, neurotransmission, endothelial regeneration, and apoptosis resistance, suggesting multifaceted genetic contributions to neuropathy development. These findings enhance our understanding of diabetic neuropathy and may support future advances in risk stratification and therapy development. Full article