Search Results (1,622)

Background/Objectives. Crohn’s disease (CD) is a chronic immune-mediated inflammatory disease that affects the gastrointestinal tract. The management of CD is complex, and treatment requires numerous therapies. One of the best gut-selective biologic drugs with proven efficacy in induction and maintenance therapy in patients with CD is vedolizumab (VDZ). Nevertheless, not all patients with CD respond to VDZ treatment, possibly due to their individual pharmacogenomic profiles. In this study, the association of variants in genes encoding molecules involved in biological pathways targeted by VDZ, ITGA4, ITGB7, and MADCAM1, with VDZ response was analyzed. In addition, Human Leukocyte Antigen (HLA) alleles were investigated. Methods. Whole exome sequencing was performed on 63 CD patients treated with VDZ as first-line biologic therapy. Genetic variants were associated with response to VDZ treatment, estimated as follows: (1) good clinical response (patients assigned to standard maintenance protocol after 14-week induction) or partial (patients assigned to optimized maintenance protocol after 14-week induction); (2) good biochemical response (CRP ≤ 10 mg/L at week 14) or poor (CRP > 10 mg/L at week 14). Results. Two MADCAM1 variants were associated with VDZ response, as defined by CRP values in week 14 of VDZ therapy. The genetic variant MADCAM1 rs758941486 was associated with poor CRP reduction in response to VDZ induction therapy, while MADCAM1 rs1555716175 was associated with optimal CRP reduction. Anti-drug antibody-related HLA-DRB1, DQB1, and DQA1 alleles were not associated with VDZ response. Conclusions. This is a pioneering pharmacogenomics study on the VDZ direct therapeutic targets in bio-naïve CD patients, which opens the door for future research. Full article

Neurodevelopmental disorders (NDDs) are a group of conditions that impair the development and function of the central nervous system. Recently, variants in the EZH1 gene have been associated with neurodevelopmental disorders. Here, using whole-exome sequencing coupled with confirmatory Sanger sequencing, we identified a homozygous nonsense variant in EZH1 in two affected siblings. Both parents were heterozygous carriers of the variant. The variant is predicted to result in a 44-amino acid C-terminal truncation within the catalytic SET domain, leading to loss of protein function. RT-qPCR analysis revealed significantly reduced EZH1 mRNA expression in patient-derived peripheral blood cells. The index patient (female) also exhibited elevated gamma-glutamyl transferase (GGT) levels and hypoalbuminemia, whereas the affected male presented with central precocious puberty. This study further expands the clinical, genetic, and molecular spectrum of EZH1-associated neurodevelopmental disorders by demonstrating that reduced EZH1 expression is consistent with a loss-of-function disease mechanism. Full article

Background: NTRK gene fusions are established oncogenic drivers in a diverse spectrum of mesenchymal neoplasms. Although classically described in pediatric entities, NTRK-rearranged sarcomas also occur in adults, where their clinicopathologic features, genomic context, and response to TRK inhibition are less well characterized. Methods: We retrospectively queried a national referral genomics database to identify sarcomas in patients >18 years harboring pathogenic NTRK1, NTRK2, or NTRK3 fusions. Gastrointestinal stromal tumors, duplicate specimens, and cases lacking digitized hematoxylin and eosin slides were excluded. Fusions were identified by whole-transcriptome sequencing, co-occurring genomic alterations by exome-based sequencing, and real-world survival and time on TRK inhibitor therapy were derived from linked insurance claims data; fusion-negative sarcomas and NTRK-rearranged non-sarcoma tumors from the same database served as comparison cohorts. Results: Among 13,040 profiled sarcomas, 19 adult tumors with pathogenic NTRK fusions were identified (median age, 43 years; range, 21–77), most of which were high grade (68%) and advanced stage (63% stage IV). Histology was heterogeneous, including spindle cell sarcoma (53%), pleomorphic sarcoma (21%), and tumors corresponding to defined entities such as NF1-associated malignant peripheral nerve sheath tumor and MDM2-amplified dedifferentiated liposarcoma (11% each). NTRK1 and NTRK3 fusions were equally frequent (9 cases each); fusion partners were diverse, with TPM3 (n = 5), EML4 (n = 2), and TFG (n = 2) recurrent and other partners non-recurrent. Additional genomic alterations were common and heterogeneous (72%), including high genome-wide loss of heterozygosity and infrequent but recurrent alterations involving the TERT promoter, NF1, and RB1. All evaluable tumors showed transcriptional activation of the NTRK fusion and increased MAPK pathway activity compared with fusion-negative sarcomas. Nine patients received TRK inhibitors; median time on larotrectinib was 12.5 months, similar to that observed in NTRK-rearranged non-sarcoma tumors, but treatment duration was variable. Conclusions: Adult sarcomas harboring NTRK fusions are rare, morphologically heterogeneous, and biologically diverse. NTRK fusion status alone may not fully capture oncogenic dependence and should be interpreted within the broader clinicopathologic and genomic context. Full article

Background and Objectives: Male factors account for approximately 30–50% of subfertile couples. Teratozoospermia is one of the major causes of male infertility; however, the genetic factors underlying many cases remain incompletely understood. This study aimed to identify potential genetic variants associated with teratozoospermia and to investigate the possible involvement of Caudal-Type Homeobox 4 (CDX4) in sperm morphogenesis. Materials and Methods: Whole-exome sequencing was performed in 44 individuals with teratozoospermia. A rare CDX4 variant (NM_005193.2, c.103G>T; NP_005184.1, Gly35Cys) was identified and confirmed by Sanger sequencing. Because CDX4 is located on the X chromosome, this variant was interpreted as hemizygous in the male patient. Sperm morphology, CDX4 localization, public GEO transcriptomic data (GSE6969), and CDX4 expression during murine spermiogenesis were analyzed. Results: The CDX4 p.Gly35Cys variant is located within the Caudal-like transactivation domain, a conserved region involved in transcriptional regulation. Spermatozoa from the patient carrying this variant exhibited severe morphological abnormalities, predominantly involving sperm-head defects, together with aberrant CDX4 localization along the midpiece and tail, in contrast to the neck- and annulus-enriched distribution observed in control spermatozoa. Reanalysis of the GEO dataset showed increased CDX4 transcript levels in teratozoospermic samples compared with normozoospermic controls. During murine spermiogenesis, CDX4 was detected in the nuclei of spermatogonia and spermatocytes and subsequently localized to the sperm head and neck/tail regions during sperm morphogenesis. Conclusions: CDX4 c.103G>T (p.Gly35Cys) is a rare hemizygous X-linked candidate variant associated with severe teratozoospermia in a single patient. Further cohort-based, segregation, and functional studies are required to clarify its role in sperm morphogenesis. Full article

Introduction/Aims: Myopathies with Tubular Aggregates (TAM) are rare, chronic neuromuscular disorders that may be inherited or acquired. The aim of this report is to present the diagnostic pathway and the challenges encountered in a family with three members affected by TAM caused by a rare ORAI1 variant. Case report: Two siblings (15 and 11 years old) developed severe rhabdomyolysis triggered by a viral respiratory infection. Histopathological analysis demonstrated numerous tubular aggregates with mild focal secondary inflammatory changes and no immunophenotypic evidence of autoimmune inflammatory myopathy. Whole-exome sequencing identified a likely pathogenic heterozygous missense variant, NM_032790.3(ORAI1):c.319G>A (p.Val107Met), in the ORAI1 gene, in both children and their asymptomatic mother. Conclusions: The identification of a rare ORAI1 variant in this family supports the association with TAM, broadens the spectrum of phenotypic presentation, and illustrates the phenotypic variability that may exist even among affected members of the same family. Careful interpretation of inflammatory changes in muscle biopsy, together with immunohistochemical and genetic findings, is essential to avoid misclassification of hereditary tubular aggregate myopathy as autoimmune inflammatory myopathy. Full article

Background/Objectives: Primary open-angle glaucoma (POAG) is a complex multifactorial optic neuropathy involving genetic, vascular, oxidative, inflammatory, and neurodegenerative mechanisms. Despite advances in genome-wide studies, the contribution of genetic variants remains incompletely characterized in underrepresented Latin American populations. This study aimed to characterize the genetic landscape of POAG in a Colombian cohort by identifying previously reported glaucoma-associated variants, rare candidate variants, and pharmacogenomic markers and integrating these findings into biologically relevant pathways. Methods: An exploratory descriptive study was conducted in 21 Colombian patients with confirmed POAG. Whole-exome sequencing (WES) was performed at an average sequencing depth of approximately 100×. Variants were quality-filtered, functionally annotated, and prioritized within 446 POAG-associated genes retrieved from DisGeNET. Previously reported glaucoma-associated variants and rare candidate variants were identified, while pharmacogenomic variants related to latanoprost and timolol response were evaluated using ClinPGx/PharmGKB. Identified genes were classified according to major biological pathways relevant to glaucoma pathophysiology. Results: Of the 446 POAG-associated genes, 381 were detected in the patients’ exomes. A total of 10,220 molecular variants were identified, of which 1,187 synonymous variants were excluded, leaving 9,033 variants for downstream analysis. Among these, 955 were non-synonymous SNVs, including 26 variants previously reported in association with glaucoma and 929 potentially novel coding variants. Previously reported variants included loci in SIX6, LOXL1, CYP1B1, NOS3, and SOD2. Two rare candidate variants (minor allele frequency <1%) were identified in FMNL2 and C3. Pharmacogenomic variants in PTGS1, ADRB1, and ABCC4 with potential implications for response to latanoprost or timolol were also detected. Functional integration highlighted pathways involving oxidative stress, extracellular matrix remodeling, vascular regulation, neurodegeneration, and inflammation. Conclusions: This exploratory analysis identifies known glaucoma-associated variants, rare candidate variants, and pharmacogenomic markers in Colombian patients with POAG. The findings support a multifactorial biological framework involving interconnected oxidative, structural, vascular, neurodegenerative, and inflammatory pathways. The FMNL2 and C3 variants represent candidates for further investigation, while the identified pharmacogenomic variants highlight the potential relevance of genomic profiling for personalized glaucoma management. Larger ancestry-informed case–control studies are required to validate these observations and determine their clinical significance. Full article

SLC25A4, solute carrier family 25 member 4, gene is a member of the mitochondrial carrier subfamily within the solute carrier protein family. Pathogenic variants in SLC25A4 are associated with a spectrum of mitochondrial disorders that exhibit variable inheritance patterns and clinical manifestations. Specifically, dominantly inherited variants are typically associated with progressive external ophthalmoplegia with mitochondrial DNA deletions, recessively inherited variants are linked to myopathy and cardiomyopathy, and de novo variants can result in early-onset fatal disease presentations. In this study, we aimed to identify and characterize the disease-causing mutation(s) in a nine-year-old female patient from a consanguineous Saudi family. The patient was asymptomatic until the age of 3 years, when she presented with cardiomyopathy and myopathy. Comprehensive genetic analysis inclusive of whole exome sequencing and segregation analysis using Sanger sequencing identified an SLC25A4 variant (NM_001151.4: exon 2: c.112-1G>C) as the most likely cause of the disease. To assess transcript-level effects, we performed RT-PCR on RNA extracted from the patient’s cultured lymphoblast cell lines (LCLs) and fibroblast cell lines (FCLs). RT-PCR analysis demonstrated that the variant causes aberrant splicing, resulting in a 6 bp in-frame deletion (p.Gln37_Val38del) in the ANT1 protein. Quantitative RT-PCR demonstrated reduced SLC25A4 transcript levels in both FCLs and LCLs. Quantitative PCR analysis of mitochondrial DNA demonstrated a trend toward increased mtDNA copy number in patient-derived FCLs compared with controls, suggesting a possible compensatory response to mitochondrial dysfunction. Furthermore, Seahorse assays revealed marked reductions in both oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in patient-derived FCLs compared with controls. These findings expand the molecular and functional spectrum of SLC25A4-associated disease and may inform clinical practice, including genetic interventions such as preimplantation genetic diagnosis, premarital genetic screening, targeted genetic counseling, and cascade testing of at-risk family members. Full article

Autism spectrum disorder (ASD) is genetically heterogeneous, involving rare and common variants that disrupt neurodevelopmental pathways. To explore this complexity, we performed whole-exome sequencing in children with ASD. Clinical phenotypes were systematically recorded, and severity was classified according to DSM-5 criteria. Variants were interpreted using ACMG guidelines, with recurrence analysis to identify genes shared across individuals and cohort enrichment testing against gnomAD. To examine genotype-phenotype relationships, we applied SKAT/SKAT-O across 16 phenotypes after covariate adjustment. Among 25 included individuals, pathogenic or likely pathogenic variants were found in 9, yielding a diagnostic yield of 36%. These involved genes linked to neurodevelopmental, epileptic, metabolic, and syndromic disorders. Recurrence analysis identified 586 genes present in at least two individuals, with PABPC1, GTF2I, PCLO, PKD1, and EP400 being the most frequent. SKAT/SKAT-O revealed the strongest burden associations for motor delay, aggressive behavior, mutism, anxiety, unresponsiveness to spoken voice, digestive disorder, and sleep disturbances, with limited overlap across phenotypes. Several recurrent genes also showed phenotype-specific associations. Overall, this integrative WES study provides clinically actionable diagnoses, highlights recurrent genes, and uncovers phenotype-specific signals, supporting convergent pathways with gene-level heterogeneity. Full article

Inherited retinal degeneration (IRD) comprises a genetically heterogeneous group of disorders in which the mechanisms linking genetic variation to molecular heterogeneity remain poorly understood. Here, we investigated the contribution of lipid and retinoid metabolism to the molecular etiology of IRD through an integrative analysis of proteomic and biochemical data. A cohort of 203 patients with inherited retinal degeneration was genetically characterized by whole-exome sequencing (WES), followed by targeted profiling of lipid-related proteins, including apolipoprotein A1 (ApoA1), apolipoprotein E (ApoE) and lipoprotein lipase (LPL), together with the quantitative assessment of systemic lipid parameters. Integrative analyses identified a coordinated lipid–retinoid–photoreceptor metabolic network linking systemic lipid metabolism with photoreceptor-associated processes. Although conventional lipid measures largely remained within clinical reference ranges, their distributions revealed substantial biological variability. Lipid-associated network architecture defined distinct patterns of molecular organization and exhibited pronounced sex-dependent differences, with female patients displaying denser and more interconnected networks than male patients. Furthermore, the integration of genetic and protein expression demonstrated that variant pathogenicity is associated with the coordinated remodeling of lipid-related molecular states. Our findings identify lipid and retinoid metabolism as integral components of the molecular architecture underlying disease heterogeneity in IRD and reveal a lipid–retinoid metabolic network linking genetic variation to coordinated molecular remodeling. These results provide new insight into the molecular mechanisms contributing to photoreceptor-associated degeneration. Full article

Background: Blue rubber bleb nevus syndrome (BRBNS) is a rare vascular disorder that primarily affects the skin and gastrointestinal tract, driven predominantly by somatic mosaic mutations, most commonly in TEK. Here, we report a case of a child with BRBNS and autism spectrum disorder (ASD). Case presentation: A 13-year-old boy diagnosed with ASD at 3 years presented with recurrent abdominal pain, blood in the stool, and severe anemia persisting for 6 months. At admission, his hemoglobin level was 5.6 g/dL. He had received a transfusion at age 6 for unexplained anemia. On examination, he appeared pale but stable, with bluish, compressible nodules on the right index finger and great toe, typical of BRBNS. Laboratory findings were consistent with chronic bleeding-induced iron deficiency. Endoscopic findings revealed multiple vascular lesions in the stomach, duodenum, ileum, and colon. Several colonic lesions were removed and pathologically confirmed as cavernous hemangiomas. Magnetic resonance enterography revealed additional small intestinal lesions. Whole-exome sequencing performed on buccal swab-derived DNA identified a heterozygous PDGFRA variant (c.2075G>T, p.Ser692Ile) classified as a variant of uncertain significance; no variants were identified in TEK, PIK3CA, or GNAQ. The patient underwent endoscopic resection of the larger lesions and received oral iron and a proton pump inhibitor. Hemoglobin stabilized at 11–12 g/dL, and no further transfusions were required. Conclusions: This case raises, but does not confirm, the possibility that genes other than TEK may contribute to BRBNS. The coexistence of ASD may be coincidental; a mechanistic link remains unproven. Careful endoscopic therapy and medical management controlled bleeding and anemia in this child. Full article

Introduction: Arrhythmogenic cardiomyopathy (ACM) is a myocardial disorder characterized by fibrofatty replacement of the myocardium and is associated with heart failure and sudden cardiac death. It can involve either ventricle, including left-dominant forms defined partly by genetic findings. Methods: We investigated a consanguineous family with four affected daughters presenting with ACM, epidermolytic palmoplantar keratoderma, and woolly hair. The two eldest siblings died suddenly during childhood. The remaining two affected siblings underwent genetic analysis using autozygosity mapping and whole-exome sequencing, followed by segregation analysis. Results: Autozygosity mapping identified a shared identity-by-descent (IBD) interval at the DSP locus on chromosome 6. Exome sequencing revealed a novel homozygous nonsense variant (c.4297C>T; p.Gln1433*; rs1554108283) in exon 23 of DSP. This variant introduces a premature termination codon within the region specific to transcript variant 1, sparing transcript variant 2. Both parents were heterozygous carriers. Cardiac imaging in the affected siblings demonstrated biventricular involvement, including left ventricular systolic dysfunction and right ventricular dilatation. Skin biopsy in one patient confirmed epidermolytic palmoplantar keratoderma. Conclusions: We describe a novel homozygous nonsense variant in the transcript 1-specific region of DSP causing Carvajal syndrome, characterized by severe biventricular ACM, epidermolytic palmoplantar keratoderma, and woolly hair, in a consanguineous Arabian family with four affected sisters. Full article

Arterial Tortuosity Syndrome (ATS) is a rare autosomal recessive connective tissue disorder caused by pathogenic variants in SLC2A10, which encodes the facilitative glucose transporter GLUT10. Although its vascular features are well recognized, the molecular consequences of many truncating variants remain poorly understood. We report a patient with ATS carrying a homozygous nonsense variant, c.485G > A (p.Trp162Ter), identified by whole-exome sequencing. Quantitative real-time PCR assessed SLC2A10 expression, and integrated bioinformatic analyses (structural modeling, druggability prediction, transmembrane topology, molecular docking, and molecular dynamics) explored its structural impact. The patient presented with severe systemic arterial tortuosity, congenital cardiovascular anomalies, hernias, connective tissue abnormalities, and neurovascular involvement involving cerebral tortuosity and distal intracranial narrowing. Structural modeling revealed extensive truncation of GLUT10 and loss of multiple α-helical domains, with transmembrane helices reduced from twelve to five. Docking of nine known ligands showed weaker binding to the mutant, and Compound 892 bound most strongly to the wild type (−7.469 kcal/mol). Across 300 ns simulations, the mutant complex proved markedly less stable. qRT-PCR showed no significant transcript differences among patient, carriers, and controls. Our findings broaden the neurovascular spectrum of SLC2A10-related ATS and demonstrate that p.(Trp162Ter) severely disrupts GLUT10 architecture, topology, and ligand binding. Full article

Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. In the U.S., HCC incidence is highest among Hispanic populations. With the exception of well-known PNPLA3 variants, the genetic risk factors underlying HCC in Hispanic individuals, particularly rare germline variants, are largely unexplored. Methods: We performed whole-exome sequencing in 719 Hispanic Americans, including 455 HCC cases and 264 controls. We analyzed rare to low frequency, putatively deleterious variants in 86 genes previously implicated in HCC susceptibility. Genetic associations were assessed at single-variant, gene, and cumulative multi-variant burden levels using Fisher’s exact tests and weighted burden tests. Results: We identified 29 rare deleterious variants across 16 genes enriched in HCC cases compared with controls. Single-variant tests identified statistically robust associations in pathways related to lipids metabolism, TM6SF2 R138W, immune regulation, HLA-DRB1 W38X, and Wnt signaling pathway, WNT9A R375H. Exploratory analyses showed that TM6SF2 R138W was further enriched among cases with alcohol and metabolic dysfunction-associated steatotic liver disease. Gene-based burden tests revealed five associated genes, including TM6SF2 and HLA-DRB1. A strong dose-effect relationship was observed, with HCC risk increasing ~4-fold per candidate variant carried (odds ratio, 3.84; 95% confidence interval, 2.40–6.53). Conclusions: Rare deleterious germline variants across lipid metabolism and immune pathways contribute to increased HCC risk in Hispanic individuals. These findings provide a genetic framework for understanding HCC disparities and support future mechanistic and epidemiologic studies in this high-risk population. Full article

Progressive Familial Intrahepatic Cholestasis (PFIC) is a rare liver disorder that, although typically present in childhood, can also occur in adulthood. Early diagnosis is crucial for appropriate clinical management, prognostic assessment, and therapeutic decision-making; however, it remains challenging due to phenotypic variability and the frequent identification of genetic variants of uncertain significance (VUS). Advances in next-generation sequencing (NGS) and whole-exome sequencing (WES) have improved the detection of disease-associated variants, revealing that the same genetic variants—often in a heterozygous state—may lead to adult-onset cholestatic disease, with milder or atypical presentations, while still conferring a significant risk of progressive liver injury and related complications. To assess the diagnostic yield and clinical utility of NGS panels and WES in adults with suspected PFIC or unexplained cholestatic liver disease, focusing on variant interpretation, emerging disease-associated genes, and clinical significance of VUS. A literature review was conducted to assess molecular diagnostics in adult cryptogenic cholestasis, with a focus on studies employing targeted NGS panels and WES. Selected studies were examined for diagnostic yield, variant classification, interpretive challenges, including VUS, and integration with clinical data. Data on patient demographics, sequencing techniques, and variant interpretation strategies were extracted to evaluate the current capabilities and limitations of genomic testing. From an initial search of 211 publications, 15 studies met the inclusion criteria, comprising five large adult cohorts and ten single-patient or trio-based reports. Across 72 patients, sequencing technologies identified 75 pathogenic or likely pathogenic variants, predominantly missense mutations, demonstrating high genetic heterogeneity. The most implicated genes included ABCB4, ABCB11, ATP8B1, TJP2, and USP53, with diagnostic yields ranging from 13.2% in large heterogeneous cohorts to substantially higher rates in carefully selected individual cases. VUS were identified in up to 67% of cases, highlighting the need for multidisciplinary interpretation integrating clinical, biochemical, and genetic data. Emerging evidence also implicated ciliopathy-associated genes such as DCDC2, NPHP3, PKHD1, TULP3, and TTC21B, expanding the genetic spectrum of adult cholestasis. Clinically, presentations ranged from mild biochemical abnormalities to progressive cholestasis, with pruritus being a common feature across studies. Comprehensive genetic testing significantly enhances diagnostic accuracy, informs prognosis, and guides individualized management in adults with cryptogenic cholestasis. Emerging evidence suggests that ciliopathy-associated genes may contribute to the genetic architecture of adult cholestatic disorders, further expanding the spectrum of disease-associated genes. However, the high prevalence of VUS remains a major challenge, highlighting the need for functional studies, longitudinal follow-up, and improved variant interpretation frameworks. As genomic technologies and analytical approaches continue to evolve, genetic testing is expected to play an increasingly central role in precision hepatology. Full article

Precision prevention and control of genetic diseases represent a major public health challenge. This paper provides a structured narrative review of advances in molecular diagnostic technologies across the preconception, preimplantation, and prenatal stages over the past five years. In the preconception phase, next-generation sequencing has become central to carrier screening, while long-read sequencing significantly enhances detection capabilities for complex variants. In the preimplantation phase, research has increasingly focused on non-invasive preimplantation genetic testing, leveraging maternal contamination quantification algorithms and deep learning models to address DNA contamination challenges. During the prenatal phase, stratified diagnostic strategies combining chromosomal microarray analysis and whole-exome sequencing have improved the diagnostic evaluation of fetal structural anomalies. Simultaneously, non-invasive prenatal testing is expanding to include microdeletion/duplication and monogenic disease screening, though positive screening results still require invasive diagnostic confirmation. Future trends lie in multi-technology integration, multi-omics data fusion, and artificial intelligence-assisted decision-making, aiming to enhance resolution while balancing health-economic considerations and ethical standards. Full article