Search Results (1,545)

Background: Hypermobile Ehlers–Danlos syndrome (hEDS), the most common EDS subtype, is characterized by chronic pain and joint laxity, yet no definitive causative genes or imaging-based diagnostic criteria have been established. This study investigated the genetic basis of hEDS using whole-exome sequencing (WES) and objectively evaluated ankle instability. Methods: We conducted an observational cohort study with a case–control comparison, including 22 patients and a three-generation Korean family (six individuals, four affected) diagnosed with hEDS by the 2017 criteria. WES was performed; ankle laxity was assessed by the anterior drawer test (ADT), stress ultrasonography, and stress radiography. Healthy young adults (n = 24, Beighton score < 5) from our previous study served as controls. Results: The hEDS cohort had a mean Beighton score of 8.5, with all participants reporting a family history of hypermobility and musculoskeletal complications. Family-based WES identified variants in CD44 (c.1516 + 1G > A), ITIH2 (c.783C > G), and ADAM21 (c.397C > T) in all affected individuals. In 22 unrelated patients, 114 variants in 103 candidate genes were identified; 17 patients harbored variants in genes from the same pathways as the family-derived causative genes. Compared with controls, the hEDS group showed significantly greater manual ADT grade, anterior talofibular ligament (ATFL) length at rest and under stress, dynamic ATFL change, anterior talar translation, and talar tilt. Conclusions: These findings provide molecular evidence that hEDS is a multifactorial disorder involving interconnected biological pathways, and confirm ankle instability as a clinically meaningful diagnostic feature. These complementary approaches may improve diagnostic accuracy and provide insights into the prognosis and therapeutic strategies for hEDS. Full article

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by progressive loss of motor neurons in the brain and spinal cord. While most cases are sporadic, around 10% are familial. Recent genetic studies show that many apparently isolated cases carry pathogenic mutations, highlighting the importance of penetrance, the probability that a causal mutation manifests clinically. This review focuses on mutation penetrance in ALS (C9orf72, SOD1, TARDBP, FUS genes), its variability across genes, age, and environmental or genetic modifiers, and its implications for genetic counseling. Identification of pathogenic mutations informs the monitoring of relatives and, in some cases, gives access to targeted therapies or clinical trials. Counseling of asymptomatic relatives must consider incomplete penetrance, which can lead to delayed or absent disease manifestation. ALS exists on a clinical and genetic continuum including related disorders, such as frontotemporal dementia, further influencing risk interpretation. Advances in panel, whole-exome and whole-genome sequencing refine our understanding of penetrance and enable precise diagnostics, and potential tailored therapies. Understanding penetrance is therefore essential to translate mutation discovery into informed clinical decisions and genetic counseling in ALS. Full article

Background/Objectives: As a global chromatin organizer, SATB1 is increasingly implicated in neurodevelopmental disorders (NDDs). This study aims to delineate the clinical and molecular characteristics of a novel de novo SATB1 variant in a patient presenting with epilepsy-dominant NDDs phenotypes. Methods: Triggered by the onset of seizures, trio-based whole-exome sequencing (Trio-WES) was performed to identify the genetic etiology. Subsequent sleep electroencephalogram (EEG) and magnetic resonance imaging (MRI) were then conducted to further characterize the patient’s clinical phenotypes. Pathogenicity was assessed through structural modeling and functional characterization. Nonsense-mediated mRNA decay (NMD) status, protein expression profiles, and subcellular localization were determined by reverse-transcription quantitative PCR (RT-qPCR), Western blotting, and immunofluorescence staining. The transcriptional regulatory impacts of the variant were quantified using dual-luciferase reporter system targeting known downstream regulatory elements. Clinical responses to antiepileptic intervention was also monitored. Results: We identified a novel de novo heterozygous pathogenic frameshift variant in SATB1 (NM_002971.5: c.1718_1719insCA; p.Val574Argfs*134) in a patient presenting with early-onset epilepsy, mild intellectual developmental disorder (IDD), speech delay, and dental anomalies. Functional assays demonstrated that the variant-derived transcript escaping NMD, yielding a truncated protein that forms irregular punctate aggregates within nuclei. Dual-luciferase assays revealed significantly increased transcriptional activity, indicating a loss of the protein’s innate transcriptional regulatory capacity. Clinically, treatment with sodium valproate (VPA) successfully stabilized seizures of the patient, markedly reducing both frequency and intensity. Conclusions: The study reports a novel SATB1 frameshift variant that exerts pathogenicity significant functional impairment by disrupting protein localization and transcriptional regulation. These findings expand the genetic spectrum of SATB1-related NDDs and underscore the efficacy of targeted antiepileptic management in genetic diseases. Full article

Background/Objectives: Very early onset inflammatory bowel disease (VEO-IBD), frequently associated with monogenic defects, is increasingly recognized worldwide but remains poorly characterized in Vietnam. This study aimed to characterize the clinical phenotypes and genetic spectrum of Vietnamese children with VEO-IBD. Methods: We conducted a retrospective cohort study at a tertiary pediatric referral center in Vietnam from July 2016 to January 2026. Clinical, laboratory, endoscopic, histopathological, genetic, and treatment data were systematically collected and analyzed. Monogenic variants were identified using next-generation sequencing and classified according to ACMG criteria. Results: Thirty-six children were included, with a median age at onset of 7.5 months, and 72.2% presenting before 24 months. Crohn’s disease predominated (72.2%). Disease burden was high, with growth impairment in 75.0% and anemia in 91.7%. Extraintestinal manifestations were frequent, particularly recurrent infections (72.2%), dermatitis (44.4%), and oral ulcers (44.4%). Perianal disease occurred in 58.3%, with early complications including perianal ulcer (44.4%), perianal abscess (30.6%) and fistulas (33.3%). Inflammatory markers were markedly elevated, and disease activity indices indicated moderate-to-severe disease at diagnosis. Genetic testing was performed in 91.7% of patients, identifying monogenic etiologies in 30.3%. Identified variants involved genes related to immune regulation (IL10RA/IL10RB, FOXP3, XIAP), autoinflammation (TNFAIP3), host defense (CYBB), and epithelial function (MYO5B). Conclusions: Monogenic etiologies account for a substantial proportion of VEO-IBD and are associated with distinct clinical phenotypes and therapeutic implications. Early integration of genomic testing with clinical phenotyping is essential to improve diagnostic precision and enable pathway-based treatment, supporting precision medicine in pediatric IBD. Full article

Background/Objectives: Gallbladder cancer (GBC) is an aggressive biliary tract malignancy with poor prognosis. Lymph node metastasis is a major determinant of adverse outcome in patients with GBC. Gene mutations play an essential role in tumorigenesis; however, it remains uncertain whether genetic mutations play a substantial role in lymph node metastasis in GBC. Methods: In this study, transcriptome and whole-exome sequencing (WES) were used to analyze gene mutations and expression in GBC tissues, focusing on lymph node metastasis. Bioinformatics tools identified differentially expressed genes (DEGs) and significantly mutated genes (SMGs), followed by pathway enrichment and survival analyses. Results: In total, 669 DEGs were identified between metastatic and non-metastatic GBC tissues. Through protein–protein interaction (PPI) network analysis of these DEGs, GPT and NR1I2 were identified as candidate genes associated with metabolic reprogramming in lymph node metastasis. Prognostic analysis revealed 22 DEGs associated with patient survival, and significant differences in overall survival, clinicopathological features (e.g., N-stage and positive lymph node count) were observed between cluster 1 and cluster 2. Mutation analysis identified 55 SMGs, primarily related to immune and inflammatory responses. By integrating DEGs and SMGs, PLCL2 was identified as a candidate gene potentially associated with both lymph node metastasis and prognosis. GSEA enrichment analysis suggested that PLCL2 was potentially linked to immunity, inflammation, and cellular processes, which may imply its possible involvement in GBC metastasis pending experimental validation. Conclusions: Based on integrative transcriptomic and exomic analyses, we identified PLCL2 as a candidate gene potentially associated with lymph node metastasis in GBC. These hypothesis-generating findings provide a preliminary basis for future mechanistic validation and biomarker exploration. Full article

Background/Objectives: Acute myeloid leukemia (AML) is a hematologic malignancy of substantial genetic heterogeneity that exhibits clonal growth and blocked differentiation of myeloid progenitor cells in the bone marrow (BM). Genetic alterations play a vital role in the progression, initiation, and recurrence of AML. The aim of this study was to identify the somatic mutational landscape, pathway perturbations, mutational signatures, and druggability of baseline (at diagnosis) and relapsed AML to determine possible treatment options. Methods: Between 2020 and 2026, 120 diagnostic BM or PB samples were prospectively collected from baseline (at diagnosis) AML patients at AIIMS, New Delhi. WES was conducted of 10 BM samples from five baseline (at diagnosis) and five relapsed patients with AML. Somatic variations were identified by GATK-Mutect2 and annotated by ANNOVAR. Driver genes and pathways were analyzed using Maftools, OncodriveCLUST, and clusterProfiler. Extraction of mutational signatures was performed with the help of SigProfilerExtractor, and evaluation of drug–gene interactions was carried out with the help of DGIdb. In addition, RT-PCR was performed to estimate the expression level of TET1. The recurrent TET1 variation was validated using Sanger sequencing and PCR amplification. Results: Missense mutations were the most common variant type in the cohort, and C > T transitions were the predominant nucleotide substitution pattern. There were recurrent mutations in core AML driver genes, including TET1, FLT3, and TP53, and relapsed samples demonstrated increased involvement and complexity of the signaling system. Pathway analysis revealed widespread dysregulation of carcinogenic networks, including RTK-RAS, WNT, TP53, and PI3K signaling. Mutational signature analysis identified COSMIC SBS5, SBS8, and SBS40, which are associated with mechanisms involving oxidative damage. A large number of actionable targets were identified through druggability screening, particularly involving epigenetic regulators and kinase-associated pathways. RT-PCR analysis also supported altered TET1 expression in AML samples. The TET1 A256V variant was detected and experimentally validated. Conclusions: This study highlights the somatic mutational landscape of baseline (at diagnosis) and relapsed AML and identifies recurrent driver genes, altered signaling pathways, mutational signatures, and actionable targets with possible therapeutic relevance. The integration of mutational and expression analyses further supports a potential role for TET1 in AML biology, although the functional significance of specific variants such as A256V remains uncertain. Full article

Background/Objectives: Titin (TTN; OMIM 188840) is the largest known human sarcomeric protein, and pathogenic variants in the TTN gene cause a broad spectrum of inherited myopathies and cardiomyopathies. The extent to which TTN variants may also involve the peripheral nervous system remains poorly defined. We aimed to describe two pediatric patients carrying heterozygous truncating TTN variants with neurophysiological evidence of peripheral nerve involvement, and to review the existing literature on this underrecognized association. Pathogenic variants in the TTN gene are associated with a wide spectrum of inherited myopathies and cardiomyopathies. To date, peripheral neur opathy has not been recognized as a defining feature of TTN-related disorders, and neurophysiological investigations in affected individuals typically demonstrate normal or myopathic findings without evidence of a primary neuropathic process. Here, we report two pediatric patients with heterozygous truncating TTN variants and neurophysiological evidence of bilateral axonal involvement of the deep peroneal nerve. Methods: This case report was structured and reported according to the CARE guidelines. Genetic testing was performed using whole-exome sequencing (Blueprint Genetics Whole Exome Family Test). Nerve conduction studies and needle electromyography were performed using the Galileo NT system. Variant classification followed current ACMG guidelines. Results: The first patient, a 10-year-old girl, presented with a symptomatic distal motor phenotype characterized by bilateral pes cavus, anterior compartment muscle atrophy, areflexia, and steppage gait with onset in early childhood. The second patient, an 8-year-old boy, had subclinical bilateral axonal neuropathy identified during neurophysiological evaluation prompted by intermittent lower limb pain; his father, carrying the same variant, showed concordant neurophysiological abnormalities. In both cases, nerve conduction studies demonstrated reduced compound muscle action potential amplitudes with preserved conduction velocities and distal latencies, consistent with axonal neuropathy. Whole-exome sequencing excluded other established genetic causes of inherited neuropathy in both probands. Conclusions: Although a causal relationship cannot be established, these observations raise the possibility that peripheral nerve involvement may represent an underrecognized feature of the titinopathy spectrum. Prospective studies in larger cohorts of TTN variant carriers are needed to clarify the prevalence and pathophysiological basis of neuropathy in this context. Full article

Background/Objectives: Bruck syndrome type 2 (BS2) is an ultra-rare autosomal recessive disorder within the osteogenesis imperfecta (OI) spectrum caused by biallelic pathogenic variants in PLOD2, which encodes lysyl hydroxylase 2 (LH2), an enzyme essential for bone-specific collagen cross-linking. Marked clinical heterogeneity complicates diagnosis, particularly in patients with atypical or incomplete presentations. We aimed to further delineate the clinical and molecular spectrum of PLOD2-associated disease. Methods: In this descriptive case series, we performed clinical, radiological, and molecular evaluations of four patients from three unrelated families, including two previously reported siblings. Molecular testing comprised targeted next-generation sequencing or whole-exome sequencing, followed by Sanger sequencing for variant confirmation and familial segregation analysis where feasible. Results: Four PLOD2 variants (NM_182943.3) were identified: homozygous c.1885A > G (p.Thr629Ala) in two siblings; c.8dup (p.(Cys4MetfsTer35)) and c.2222G > A (p.(Gly741Glu)) in one patient; and homozygous c.2027A > C (p.(Tyr676Ser)) in one infant. Three variants were previously unreported. Two missense variants remained classified as variants of uncertain significance, and the phase of the two heterozygous variants detected in one patient could not be established because a paternal sample was unavailable. Clinical severity was variable: age at first fracture ranged from 3 months to 4 years, and cumulative fracture burden ranged from 3 to multiple recurrent fractures. One 10-year-old patient had a severe OI-like phenotype without congenital contractures. Older patients showed additional axial and pelvic involvement, including craniovertebral junction abnormalities and acetabular protrusion. Conclusions: This case series broadens the range of clinical presentations observed in PLOD2-associated disease and indicates that severe bone fragility may occur in the absence of congenital contractures. These findings support inclusion of PLOD2 in the differential diagnosis of patients with unexplained bone fragility and progressive skeletal deformities. Additional well-characterized cases and functional studies are needed to refine genotype–phenotype correlations and clarify the clinical significance of newly identified variants. Full article

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), are increasingly recognized as conditions with a complex, multisystemic origin. ASD frequently co-occurs with other neurological conditions, such as epilepsy. We report a female patient, born to unrelated healthy parents, presenting with a complex clinical phenotype characterized by ASD level 1 with fluent speech, borderline intellectual functioning (BIF), coordination disorder, and epilepsy. Trio-based whole-exome sequencing (WES) revealed a de novo variant in the USP24 gene (c.3155G>T; p.Ser1052Ile), classified as likely pathogenic according to ACMG criteria (PS2, PM2, PP2, BP4). USP24 has previously been associated with Parkinson’s disease and has recently emerged as a candidate risk gene for ASD. In addition, WES detected two variants of uncertain significance (VUS), both inherited from the clinically unaffected father: c.388G>C (p.Gly130Arg) in NRXN2 and c.6395C>A (p.Ser2132Tyr) in LRP2. Although neither gene shows a fully penetrant causal relationship with the observed phenotype, both have been implicated in neurodevelopmental disorders. Array-CGH analysis did not reveal pathogenic copy number variants; however, the presence of additional genetic contributors not detectable by WES cannot be excluded. Overall, the de novo USP24 variant likely represents the primary genetic driver of the phenotype, while the potential contribution of the inherited NRXN2 and LRP2 variants remains plausible. This case underscores the complexity of the genetic architecture underlying NDDs and supports a model involving cumulative effects of multiple variants rather than a strictly multigenic interaction. Full article

Background: The etiological diagnosis of chronic thrombocytopenia in children remains challenging and is often established by exclusion. In this article, we present the case of a patient in whom we used whole-exome sequencing (WES) to help identify the underlying cause and determine the appropriate treatment. Methods: Whole-exome sequencing was performed to clarify the genetic background of the disease. Based on the results, transmission electron microscopy (TEM) was also carried out to confirm or exclude the pathogenic role of the identified NBEAL2 gene variant and to assess the presence of gray platelet syndrome. Results: In this patient, despite the presence of the NBEAL2 gene variant, neither gray platelet syndrome nor a pathogenic role of the variant could be confirmed. However, the genetic findings identified by WES led to numerous additional investigations, causing a considerable burden on both the patient and the family. Conclusions: Our case highlights that WES testing, which is emerging in pediatric hematology practice, offers not only diagnostic advantages but also pitfalls. Whole-exome sequencing has recently emerged as a new diagnostic tool and has been available nationwide in pediatric hematology-oncology care in Hungary for just over two years. While personalized treatment strategies for benign hematologic diseases increasingly rely on high-throughput genetic testing, the clinical application of WES requires a cautious, critical evaluation of results. Despite the method’s promise, the heterogeneity of the findings underscores the need to interpret WES results carefully and to place them in a clinical context in every case. Full article

Monogenic forms of Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) represent the two principal neurodegenerative disorders leading to early-onset dementia, primarily linked to mutations in key AD- and FTD-associated genes. The marked heterogeneity in age at onset and penetrance among carriers of pathogenic mutations suggests that monogenic variants act within a broader polygenic background. The combined impact of AD- and FTD-related genetic variation on disease incidence in monogenic forms remains largely unexplored. Herein, we investigate gene–gene interaction patterns in monogenic AD and FTD, with a focus on genetic variability in key AD (APP, PSEN1, PSEN2) and FTD (MAPT, GRN, C9orf72)-associated genes and their association with cumulative disease incidence. Within the GARDENIA Consortium, we studied 426 individuals from Italian pedigrees, including patients (n = 319) and presymptomatic (n = 107) carriers of causative variants in APP (n = 39), PSEN1 (n = 71), PSEN2 (n = 13), MAPT (n = 29), GRN (n = 188), and C9orf72 (n = 86). Age at symptoms onset, age at last follow-up and sex were recorded. Whole exome sequencing was performed, focusing on non-causative variants (n = 64) in the key AD (APP, PSEN1, PSEN2) and FTD genes (MAPT, GRN, C9orf72). Weighted genetic burden scores were derived using Fine–Gray competing risk models to estimate variant-specific effects on cumulative AD and FTD incidence, accounting for mutually exclusive outcomes and family clustering. Model fit was evaluated using Akaike Information Criterion. Higher AD-risk-weighted burden scores in AD-related genes were associated with a significantly increased cumulative incidence of AD, while higher FTD-risk-weighted scores in FTD-related genes showed a trend toward association with increased cumulative incidence of FTD. A significant interaction between burden scores was observed. AD and FTD burden scores showed a negative interaction for AD (~79% attenuation) but a modest synergistic effect for FTD (~6% increase). These findings could imply context-dependent pleiotropy rather than simple additive genetic effects. Our study suggests that even in carriers oh highly penetrant AD or FTD causative variants, genetic background could substantially modulate cumulative disease incidence. Integrating polygenic information with monogenic status may improve prognostic stratification and inform precision approaches in dementia research and clinical trials. Full article

Background/Objectives: The current study was designed to identify the underlying genetic causes of congenital stationary night blindness (CSNB) in the indigenous consanguineous families from the Southern Punjab region of Pakistan, a population where the inherited retinal disorders are relatively common. Methods: A detailed questionnaire and medical examination were done to check the presence of CSNB in the affected individuals of the enrolled families. Whole-exome sequencing (WES) was performed to identify the pathogenic variants, followed by segregation analyses to confirm the segregation of the identified variants with the disease phenotype in the available affected individuals of the families. Results: We identified two novel and three known pathogenic variants in SAG, GRK1, TRPM1, SLC24A1, and GPR179, having established roles in CSNB. Two novel variants, NM_001252020.1 (p.Gly1020Arg) and NM_001004334.3 (p.Trp508Ter), were identified, and their segregation was confirmed in two families, PKIURP102 and PKIURP564, respectively. NM_002929.3 (p.Arg19Ter) and NM_001301032.1 (p.Phe538CysfsTer23) were the reported variants identified in PKIURP17 and PKIURP528 families, respectively. NM_000541.5 (p.Glu306Ter) was identified in two independent families, PKIURP552 and PKIURP565. Conclusions: Identification of five pathogenic variants in five different genes shows the genetic heterogeneity of CSNB in Pakistani patients. Our findings also expand the mutational spectrum of CSNB in the Pakistani population and may help in the identification of mutational hotspots and may help in the genetic diagnosis of CSNB in consanguineous populations. Full article

Introduction: Recent advancements in genomic technologies have significantly improved the resolution of genetic variants driving rare genodermatoses, a heterogeneous group of inherited skin disorders caused by pathogenic variants affecting skin structure and function. However, many genodermatoses remain molecularly uncharacterized, particularly in Middle Eastern populations. Objectives: This study aimed to evaluate the diagnostic accuracy and inherent challenges of utilizing (WES) for genodermatoses within a Middle Eastern context. Methods: We performed WES on three unrelated Middle Eastern pediatric patients presenting with genodermatoses. Genetic variants were prioritized and adjudicated according to ClinVar and the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: WES identified pathogenic variants in three pediatric cases presenting with genodermatoses. Findings included a GJB2 missense variant (c.148G>T; p.Asp50Asn) associated with keratitis–ichthyosis–deafness (KID) syndrome. This represents one of the first documented cases in a Middle Eastern population. Two additional patients presenting with epidermolysis bullosa harbored truncating variants in COL7A1 (c.497dup; p.Val168Glyfs12) and EXPH5 (c.5786del; p.Pro1929Leufs8), respectively; the latter also carried a KRT5 missense variant (c.1607G>A; p.Ser536Asn). Conclusions: WES is a robust diagnostic adjunct for resolving ambiguity in rare genodermatoses, though its efficacy remains contingent on the availability of regional genomic references. Within pediatric dermatology, systematic exome sequencing serves as a powerful facilitator for transitioning from clinical suspicion to definitive molecular characterization. Collectively, these findings highlight the essential role of regionally representative genomic datasets in the accurate interpretation of novel variants and the advancement of precision dermatology. Full article

Background: Digestive tract cancers, like most other cancers, are usually categorized based on cell or tissue of origin. Molecular clustering based on the transcriptome often produces the same classification. Methods: We developed a new method, Newmanization, to reduce underlying tissue signals from transcriptomic analysis. To test our method, we downloaded data on 1635 samples of digestive tract cancers from The Cancer Genome Atlas. The available data includes transcriptomic data by RNA-Seq, as well as binary mutation allele frequency data by whole exome sequencing. We compared, using silhouette widths and visualization by dimension reduction plots, the effectiveness of Newmanized transcriptome and mutation data to separate digestive tract cancers. Results: The Newmanized transcriptome clusters have clearer separation and larger average silhouette widths. Feature analysis of each cluster for Newmanized transcriptomic data and mutation data revealed that clusters determined with Newmanized data contained more mRNAs present at higher frequencies than clusters defined by mutation data. Conclusions: This suggests that the Newmanized method holds great potential for advancing personalized transcriptomic medicine. Full article

Purpose: Obesity, characterized by abnormal fat accumulation with comorbidities, continues to increase dramatically, particularly in the pediatric population. Identifying the environmental and genetic causes underlying the development of obesity during early childhood is crucial for establishing preventive and protective treatments for this complex disease. We aimed to investigate genetic variants related to non-syndromic early-onset childhood obesity. Methods: Whole-exome sequencing was performed in three independent consanguineous families with obesity, including three index cases and two additional affected siblings. Non-synonymous variants with minor allele frequency < 0.01 in all normal populations were filtered using the Genomize-SEQ Platform. Variant confirmations and familial segregations were analyzed by Sanger sequencing. Results: WES revealed a shared ATXN3 gene variant and two known variants of the SH2B1 and ADIPOQ genes, which were reported to be associated with obesity. Additionally, five heterozygous novel gene variants of the ANKK1, NEGR1, OGDH, ABCB1, and GSK3B genes were identified, which are predicted to cause excessive fat accumulation and disruption of energy balance in individuals. Conclusions: We suggest that the cumulative effects of all obesity-associated detected variants lead to the early-onset obesity phenotype observed in individuals. Hence, periodic follow-up and treatment opportunities are recommended for index cases, alongside the adoption of a more active lifestyle and healthy nutrition practices. Full article