Search Results (695)

Objective: To investigate the clinical characteristics, inheritance patterns, and genotype–phenotype correlations of DHX37 variants in 46,XY disorders of sex development (DSD). Methods: We retrospectively reviewed 108 patients with 46,XY karyotype who underwent DSD evaluation and trio-based whole-exome sequencing (trio-WES) at our center between January 2021 and December 2025. Six probands with DHX37 variants and no concurrent pathogenic or likely pathogenic variants in other known DSD-associated genes were analyzed in detail. Clinical presentations, endocrine profiles, imaging findings, and pedigree data were collected. Variant segregation was confirmed by Sanger sequencing; variants were assessed using in silico prediction, conservation analysis, and structural modeling, and were classified according to ACMG/AMP guidelines. Results: The six probands exhibited marked phenotypic heterogeneity, with manifestations ranging from complete gonadal dysgenesis to mild testicular underdevelopment with gynecomastia. Six heterozygous DHX37 missense variants were identified across distinct functional domains: one in RecA1 [c.1000C>T (p.Arg334Trp)], four in RecA2 [c.1379T>C (p.Val460Ala), c.1432G>A (p.Gly478Arg), c.1730A>G (p.Asp577Gly), and c.1954G>A (p.Val652Ile)], and one in the linker region proximal to the HA2 domain [c.2180C>T (p.Thr727Met)]. Of these, p.Arg334Trp is an established pathogenic variant; p.Gly478Arg has been reported previously, albeit in the same patient included in the present study; and the remaining four were novel. According to ACMG/AMP guidelines, p.Arg334Trp was classified as pathogenic, and the remaining five as variants of uncertain significance. Conclusions: This study provides additional case evidence supporting the pathogenicity of p.Arg334Trp and expands the DHX37 variant spectrum. Computational and structural analyses suggest that p.Gly478Arg may underlie the testicular regression syndrome phenotype of the corresponding proband and that the four novel variants may be involved in testicular development. However, these genotype–phenotype correlations remain speculative; larger cohorts and in vitro functional assays are warranted to confirm these associations. Full article

Introduction: Adult-onset Alexander disease (AOAD) is a rare astrocytopathy linked to the glial fibrillary acidic protein (GFAP) gene, which is known for its clinical heterogeneity and common misdiagnosis. In adults, it may present with bulbar dysfunction, pyramidal signs, ataxia, dysautonomia, cognitive decline, or parkinsonism, which often mimics atypical parkinsonian syndromes like multiple system atrophy (MSA). The purpose of this case series was to define practical clinical, radiological, and genetic cues for suspecting AOAD in adults with atypical parkinsonism, autonomic dysfunction, or paroxysmal focal symptoms, particularly when genetic findings are inconclusive. Case Presentation: Four patients, aged 40 to 59 years, had progressive and varied neurological symptoms, like gait disturbance, lower limb weakness, dysarthria, dysphagia, autonomic dysfunction, parkinsonism, cognitive decline, and paroxysmal focal deficits. Initial diagnoses were parkinsonian syndrome, stroke, transient ischemic attack (TIA), and MSA. Diagnostic Assessment and Intervention: Brain magnetic resonance imaging (MRI) in all patients showed characteristic lower brainstem abnormalities, particularly atrophy of the medulla oblongata and upper cervical spinal cord, consistent with the “tadpole sign.” GFAP sequencing identified one likely pathogenic variant (p.Arg70Trp) and three variants of uncertain significance: p.Glu122_Arg124del, p.Met415Ile, and p.Glu195Val. Management was mainly symptomatic; one patient showed significant motor improvement after repetitive transcranial magnetic stimulation (rTMS). Conclusions: AOAD should be considered in adults with parkinsonism-plus syndromes or unexplained combinations of bulbar symptoms, pyramidal signs, autonomic dysfunction, and cognitive decline. Recognizing the tadpole sign on MRI may improve diagnostic accuracy, particularly when genetic results are inconclusive. Full article

Background: Congenital ichthyoses are a clinically and genetically heterogeneous group of Mendelian disorders of cornification. According to the 2025 classification, non-syndromic epidermal differentiation disorders (nEDDs) are categorized based on the biological function of the causative gene products. Variants in TGM1 cause a transglutaminase-related nEDD (TGM1-nEDD), typically corresponding to the traditional phenotype of lamellar ichthyosis (LI), whereas biallelic variants in CYP4F22 cause a lipid-metabolism-related nEDD (CYP4F22-nEDD), formerly classified as ARCI type 5. The latter form is characterized by impaired acylceramide synthesis and epidermal barrier dysfunction. Although CYP4F22-nEDD usually follows a persistent course, considerable phenotypic variability has been reported, including milder forms and self-improving collodion ichthyosis. Methods and Results: We report two unrelated Italian neonates with congenital ichthyosis, investigated by targeted next-generation sequencing (NGS). Patient 1 presented with a phenotype consistent with LI and carried compound heterozygous TGM1 variants: the known pathogenic c.1147G>A p.(Val383Met) variant, and the novel c.860C>T p.(Thr287Ile) variant, classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria. Patient 2 presented as a collodion baby and carried two heterozygous CYP4F22 variants: the known pathogenic nonsense variant c.1084C>T p.(Arg362Ter), and the previously unreported in-frame deletion c.543_545del p.(Ile181del), currently classified as a variant of uncertain significance (VUS). Because parental segregation analysis was unavailable, the allelic phase of the CYP4F22 variants could not be established, and molecular confirmation of autosomal recessive inheritance was not possible. Both patients showed marked clinical improvement during follow-up with topical emollient therapy alone. In Patient 2, the clinical course was consistent with a self-improving collodion ichthyosis phenotype. A structured literature review was performed to contextualize the clinical and molecular findings. Conclusions: These cases illustrate the clinical and genetic heterogeneity of nEDDs, and confirm the value of NGS in the management of neonates with congenital ichthyosis. The principal novelty of this report lies in the identification of previously unreported TGM1 and CYP4F22 sequence variants. While functional validation is lacking, integration of clinical and genetic findings with literature evidence may assist interpretation of rare variants and support genetic counselling. Full article

Background and Clinical Significance: Cantú syndrome (OMIM #239850) is a rare autosomal dominant disorder caused by gain-of-function variants in ABCC9 or KCNJ8, which encode subunits of the ATP-sensitive potassium (K_ATP) channel. Its characteristic features—generalized hypertrichosis, coarse facial appearance, skeletal abnormalities, and cardiovascular involvement—may be overlooked when other major comorbidities dominate the clinical picture. Case Presentation: A 29-year-old Taiwanese woman, born prematurely and complicated by neonatal hydrocephalus with subdural hemorrhage requiring ventriculoperitoneal shunt placement, had been followed since infancy under a working diagnosis of cerebral palsy with left hemiparesis and borderline-to-mild intellectual disability. Over the ensuing years, additional features gradually emerged, including generalized hypertrichosis with thick scalp and body hair, coarse facial features, bilateral hallux valgus, mild thoracic scoliosis, polycystic ovaries, mild aortic regurgitation, recurrent hemoptysis associated with abnormal pulmonary vasculature, and iron-deficiency anemia. Earlier genetic investigations—including chromosome analysis (46,XX), array comparative genomic hybridization (array-CGH; 2013), and a trio-based next-generation sequencing study performed under a national rare disease research initiative (2019)—were unrevealing. Whole-genome sequencing performed in December 2025 identified a heterozygous ABCC9 variant (NM_020297.4:c.4174A>G, p.(Ile1392Val)), initially classified as a variant of uncertain significance. Parental Sanger sequencing confirmed the variant to be de novo, and reclassification according to ACMG/AMP criteria supported a likely pathogenic interpretation. Re-evaluation of the patient’s phenotype demonstrated findings consistent with Cantú syndrome. Conclusions: This case illustrates how Cantú syndrome may remain unrecognized for years when a prominent neurological comorbidity—perinatally acquired hydrocephalus and presumed cerebral palsy—dominates the clinical narrative. We report a previously undescribed de novo ABCC9 missense variant (c.4174A>G, p.(Ile1392Val)), thereby expanding the mutational spectrum associated with Cantú syndrome. This case also highlights the practical value of resequencing and periodic reanalysis using updated next-generation sequencing platforms in patients with long-standing undiagnosed disease, even after prior negative genetic testing. Full article

Heart failure with preserved ejection fraction (HFpEF) is an increasingly common form of heart failure (HF) that is best understood as a systemic, multiorgan syndrome rather than a disease of left-ventricular filling alone. This review has three specific aims: first, to synthesize genetic and molecular pathways that are most relevant to non-ischemic HFpEF; second, to distinguish HFpEF-enriched mechanisms from evidence extrapolated from ischemic cardiomyopathy or HFrEF; and third, to consider translational implications for populations with high consanguinity, including the Kingdom of Saudi Arabia. The available evidence indicates that chronic inflammatory signaling involving CCL2, CCL5, TLR3, PTGS2/COX-2, IL-6/JAK/STAT3, NF-kB, and NLRP3 acts upstream of endothelial dysfunction, nitric-oxide/cGMP/PKG impairment, mitochondrial reactive oxygen species generation, and fibroblast activation. Extracellular-matrix regulators including ASPN, COL1A1, and MMP2 then amplify collagen deposition and myocardial stiffness, whereas mitochondrial genes and proteins such as ATP5C1 contribute to impaired oxidative phosphorylation, reduced ATP reserve, defective fatty-acid oxidation, and blunted mitophagy. Protein-quality-control pathways involving HSP90AA1, CCT2/CCT5, PSMA3, and stress-responsive STAT3 further link metabolic stress to proteotoxic injury. Epigenetic mechanisms, including DNA methylation and microRNAs such as miR-155, miR-1297, and miR-4649-3p, add a regulatory layer that may improve risk stratification but remains insufficiently validated for routine clinical use. In high-consanguinity settings, recessive cardiomyopathy variants can cluster in families and contribute to earlier NIHF presentations; however, population-level HFpEF-specific variant frequencies remain limited, and findings from HFrEF or dilated cardiomyopathy should be interpreted as candidate pathway evidence rather than definitive HFpEF markers. Translationally, SGLT2 inhibitors, mineralocorticoid-receptor antagonism, biomarker panels, and structured genetic evaluation provide the most clinically actionable bridge from molecular mechanisms to precision HFpEF care. Full article

Obesity and metabolic dysregulation are closely associated with chronic low-grade inflammation, in which interleukin-6 (IL-6) plays a key regulatory role. Genetic variation in the IL-6 gene may influence inflammatory responses and metabolic homeostasis. To identify single-nucleotide variants (SNVs) in the IL-6 gene in a cohort of Colombian high-performance athletes and to evaluate their potential functional and structural consequences using bioinformatic prediction and protein-modeling approaches. A descriptive observational study was conducted in a cohort of 23 high-performance Colombian athletes from Valle del Cauca representing cycling, karate, and weightlifting disciplines. Genomic Deoxyribonucleic Acid (DNA) extracted from peripheral blood samples was analyzed using Next-Generation Sequencing (NGS). Identified variants were evaluated using several in silico prediction tools, including Basic Local Alignment Search Tool (BLAST version 2.16.0), Expert Protein Analysis System (ExPASy version 4.0), Open Reading Frame Finder (ORFfinder version 0.4.3), and population databases such as Genome Aggregation Database (gnomAD version 4.0). Structural modeling was used to explore the potential impact of amino-acid substitutions on IL-6 protein stability. Eight single-nucleotide variants were identified in the IL-6 gene. Among them, the rs1524107 variant generated a missense substitution predicted to modify the amino-acid sequence of the IL-6 protein. Structural modeling suggested a potential alteration in protein stability associated with this variant. The rs1524107 variant may influence IL-6 protein structure according to computational predictions. These findings provide preliminary hypothesis-generating evidence regarding the potential role of IL-6 genetic variation in inflammatory regulation; however, functional validation and larger cohort studies are required to determine their biological significance. Full article

Major Depressive Disorder (MDD) has a multifactorial etiology and pathogenesis that significantly impacts an individual’s quality of life. One of the possible correlations for its onset is the activation of inflammatory responses resulting in neurodegeneration and, consequently, the emergence of depressive symptoms. Interleukin-1β is a regulatory cytokine of the immune and nervous systems that acts on several processes, including mood regulation. This systematic review analyzed the IL1B (C-511T) (rs16944) variant’s CC and CT genotype frequencies and their associations with MDD in different populations while also verifying the TT genotype’s influence on response to antidepressant therapy. This review involved searching five databases, and articles were selected according to the PECOS inclusion criteria, resulting in eight articles. The findings highlight distinct clinical outcomes: the CC genotype was more frequently associated with greater MDD symptom severity, whereas the TT genotype was predominantly associated with antidepressant treatment response; thus, these associations should not be considered equivalent in terms of susceptibility to disease onset. However, despite these findings, other studies have found no significant association between this genetic variant and MDD. Therefore, further studies across different populations are needed to better understand the role of this polymorphism in the etiology of this disorder. Full article

Chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma, and interstitial lung diseases (ILDs), represent a major global health burden. Their significant clinical and biological heterogeneity complicates diagnosis and limits the efficacy of traditional, one-size-fits-all management approaches. The advent of high-throughput genomic and multi-omic technologies has initiated a paradigm shift from syndromic classification to molecular-based endotyping. A narrative review of the literature was performed, synthesising foundational and recent research in the genomics, epigenomics, and multi-omics of chronic respiratory diseases. Key studies were selected based on their relevance to genetic architecture, biomarker development, and translational applications in precision medicine. We discuss the complex genetic architecture of pulmonary conditions, highlighting the contribution of both rare, high-penetrance variants, such as SERPINA1, CFTR, and BMPR2, and polygenic risk from many common variants, such as HHIP, FAM13A, and IL33. We provide detailed analyses of polygenic risk scores (PRSs) for COPD and asthma, including their construction, validation across ancestries, and predictive performance. We detail how integrative multi-omic approaches, including transcriptomics, proteomics, and metabolomics, are successfully defining molecular endotypes, such as Type 2-high asthma, which, in turn, inform the use of targeted biologic therapies. Finally, we review the development of molecular diagnostics, including metagenomic sequencing of infections and liquid biopsies for lung cancer and the development of prognostic biomarkers. The genomic revolution is transforming pulmonary medicine through the discovery of novel disease pathways, precise molecular classification, and the recognition of new therapeutic targets. Despite major challenges in functional interpretation, data integration, and clinical–translational equity, these technologies hold the key to a new era of personalised respiratory health and precision medicine. Full article

Background: Mutations in the FBXO7 gene (PARK15) cause an autosomal recessive, early-onset neurodegenerative disorder typically presenting as Parkinsonian-Pyramidal Syndrome (PPS). Despite its recognition, the high phenotypic variability often delays diagnosis. Here, we report a novel Italian family and synthesize data from all published cases to date, offering an updated clinical and molecular overview of the disease. Methods: We performed clinical and molecular characterization of a newly identified family. Furthermore, we conducted a systematic literature review (from 2008 to 2026) to aggregate clinical, genetic, and geographic data of all reported PARK15 cases. Results: Two siblings presented with a complex phenotype including early-onset parkinsonism, cognitive decline, psychiatric symptoms, and aphasia-type speech disorders. Genetic analyses identified two novel likely pathogenic variants: a missense substitution in the UBL domain (p.Ile74Met) and a frameshift indel (p.Val233GlufsTer8). The literature review (incorporating clinical data from Europe, Asia, and South America) confirms a high prevalence of postural instability (87.5%), bradykinesia (83.3%), and pyramidal signs (~60%). We observed a distinct distribution of variants: missense mutations cluster in the N-terminal UBL and F-box domains, while truncating variants are more common in the C-terminal region. Discussion: Our findings expand the FBXO7 mutational landscape and underscore the “atypical” clinical markers, such as pyramidal signs and cognitive decline, that distinguish PARK15 from other recessive forms of parkinsonism like PARK2 and PARK6. The dual role of FBXO7 in mitochondrial quality control and proteasomal assembly suggests a broad disruption of cellular homeostasis. These observations refine genotype–phenotype correlations and may guide variant interpretation in routine diagnostic settings. Full article

Background: High body mass index (BMI) is a causal risk factor for endometrial cancer, but the tumor molecular mechanisms affected by adiposity remain poorly understood. Here, we characterize the tumor multi-omic landscape of endometrial cancers that have developed on a background of lifelong germline genetic liability to elevated BMI. Methods: We built a polygenic score (PGS) for BMI in women using data on independent, genome-wide significant variants associated with adult BMI in 434,794 women. We performed germline (blood) genotype quality control and imputation on data from 354 endometrial cancer cases from The Cancer Genome Atlas (TCGA). We assigned each case in this TCGA cohort their genetically predicted BMI based on the BMI PGS. Multivariable generalized linear models adjusted for age, stage, microsatellite status and genetic principal components were used to test for associations between the BMI germline PGS and endometrial cancer tumor genome-wide genomic, transcriptomic, proteomic, epigenomic and immune traits in TCGA. Results: High BMI germline PGS was associated with (i) upregulated tumor gene expression in IL6-JAK-STAT3 signaling (FDR = 4.2 × 10⁻⁷) and in other immune/inflammatory pathways; (ii) increased estimated intra-tumor activated mast cell infiltration (FDR = 0.008); and (iii) increased single base substitution (SBS) mutational signature 1 (FDR = 0.03), implicating age-related mutagenesis. In contrast, BMI at diagnosis associated with elevated progesterone receptor expression and alterations in estrogen and androgen signaling. Conclusions: Thus, we integrated germline, somatic and clinical data to identify associations between genetically predicted lifelong liability to higher BMI and endometrial cancer tumor molecular features. These associations inform our understanding of how high BMI may influence the development of this cancer, shaping endometrial tumor biology differentially over the long term. Full article

Backgrounds/Objectives: Allele frequencies of genetic variants associated with complex diseases can contribute to varying degrees to predisposition depending on the population’s genetic profile. The aim of this study was to analyze the genetic diversity of 15 relevant SNVs that could modulate bone and cartilage metabolism in underrepresented structured populations. Methods: In a sample of 130 Mestizos and 304 natives from 8 native Mexican populations, SNVs related to multifactorial diseases were genotyped using a SNaPShot Multiplex kit and analyzed via capillary electrophoresis using an ABI PrismTM 3130 Genetic Analyzer (Applied Biosystems, Waltham, MA, USA.), and genetic profiles for 15 SNVs were obtained using GeneMapper software v. 3.2. Allele frequencies were calculated by locus and population using Power Stats and Arlequin v.3.1 software, for which the EM algorithm was used to compare reference populations obtained from the dbSNV database of the International HapMap project. Population structure, paired comparisons, and genetic differentiation between native, admixed, and reference populations (p value) were estimated through Fst tests using the STRUCTURE v.2.3.2 and Arlequin v.3.1 software. Results: Haplotype frequency combinations grouped as profiles showed higher predominance in the allelic combination A/A/G for rs9340799 (ESR1), rs700518 (CYP19A1), and rs1800795 (IL6) genes, respectively. Conclusions: Allelic profiles could be useful as medical tools for preventing and managing individuals or populations. Mexican populations showed high genetic variability among allelic risk profiles for estrogen control and response, as well as high frequencies of variant combinations associated with an increased inflammatory response, potentially resulting in high osteoclastogenesis. This analysis advances our understanding of the complexity of bone and cartilage metabolism in highly stratified populations. Full article

Oncolytic virotherapy offers a promising avenue for solid tumor treatment, yet single-agent approaches are frequently limited by insufficient tumor lysis and inadequate immune activation. Here we report that combined therapy with two recombinant variants of the oncolytic vaccinia virus, armed with either herpes simplex virus thymidine kinase (VV-HSVtk) or the interleukin 15 receptor subunit alpha (VV-mIL15Rα), leads to enhanced cytotoxicity and immune stimulation in a murine mammary adenocarcinoma model (4T1). In vitro, VV-HSVtk exhibited dose-dependent cytotoxicity markedly potentiated by ganciclovir (GCV) through HSVtk-mediated phosphorylation into a cytotoxic nucleoside analog, and co-culture of VV-infected tumor cells with donor-derived NK cells further increased oncolytic efficiency. In vivo, combined treatment with VV-HSVtk, VV-mIL15Rα, and GCV resulted in significant tumor regression and extended survival relative to monotherapy controls in 4T1 syngeneic mice. Histological examination revealed increased lymphocytic infiltration at tumor sites and absence of hepatic or splenic toxicity. Together, these data indicate that integrating direct viral cytotoxicity, HSVtk/GCV-mediated suicide gene therapy, and IL-15-pathway-targeted immunomodulation within an oncolytic vaccinia platform can improve antitumor efficacy in a stringent breast cancer model. Full article

Endothelial dysfunction is an early event in the development of cardiovascular diseases and is characterized by impaired barrier function, inflammatory activation of endothelial cells (ECs), and alterations in lipid metabolism. In addition to typical (mononuclear) endothelial cells (TECs), multinucleated variant endothelial cells (MVECs) are present within the vascular wall; however, their functional role remains poorly understood. The aim of the present study was to investigate the molecular and functional characteristics of MVECs and their potential contribution to the development of endothelial dysfunction. Primary human umbilical vein endothelial cells (HUVECs) were used, and multinucleated cells were generated by polyethylene glycol-induced fusion. Cells were incubated under control conditions or exposed to low-density lipoproteins (LDL; 100 µg/mL, 24 h). A comprehensive analysis was performed, including transcriptomic and proteomic (secretome) profiling using gene set enrichment analysis (GSEA), as well as functional assays assessing transendothelial LDL transport, intracellular cholesterol accumulation, macrophage migration, and the expression and secretion of pro-inflammatory cytokines (IL-6, IL-8). MVECs exhibited pronounced differences compared to TECs. GSEA revealed reduced enrichment of pathways related to canonical nuclear factor kappa B (NF-κB) signaling and negative regulation of NF-κB transcription factor activity, actin cytoskeleton organization, focal adhesion assembly, basement membrane organization, and vesicle-mediated transport in MVECs relative to TECs, indicating impaired cytoskeletal integrity, altered cell–matrix interactions, dysregulated inflammatory signaling, and reduced vesicular trafficking activity. Functionally, MVECs demonstrated an increased capacity for cholesterol accumulation and enhanced transendothelial migration of macrophages. Notably, transendothelial LDL transport across the MVEC monolayer was not increased, suggesting a predominance of intracellular lipid accumulation. MVECs also exhibited a pronounced pro-inflammatory phenotype, characterized by elevated expression and secretion of IL-6 and IL-8. Taken together, these findings indicate that MVECs represent a functionally altered endothelial phenotype with impaired barrier function, dysregulated lipid metabolism, and enhanced inflammatory activity. Local accumulation of MVECs within the vascular wall may contribute to the formation of pro-atherogenic regions and play a role in the initiation and progression of endothelial dysfunction. Full article

Background/Objectives: IL23R encodes a pivotal component of the IL-23/Th17 signaling axis and represents a validated genetic susceptibility locus for inflammatory bowel disease (IBD), psoriasis, and ankylosing spondylitis. Despite extensive GWAS data, the functional consequences of the full spectrum of IL23R missense single-nucleotide variants (SNVs) have not been systematically characterized. This study aimed to identify high-risk missense SNVs through a multi-tool in silico pipeline. Methods: A total of 723 missense SNVs from NCBI dbSNP were verified against transcript NM_144701.3/Q5VWK5-1 (629 aa) using Ensembl VEP (GRCh38). Sequential filtering was performed using applied SIFT, PolyPhen-2, PROVEAN, E-SNPs&GO, MutPred2, and ConSurf (grade ≥ 7); AlphaMissense and FATHMM-MKL were used as independent annotation layers. Protein stability was assessed with MuPro and DynaMut2 (AlphaFold2 AF-Q5VWK5-F1-v6; pLDDT = 68.19); structural characterization was performed with Project HOPE, and interaction networks were constructed using STRING and GeneMANIA. Results: Sequential filtering identified 37 high-risk missense variants. MuPro predicted destabilizing effects for 36/37 variants, with concordant DynaMut2 results for 35/37. Project HOPE identified disulfide bond disruption in 11 variants, charge-altering substitutions in 8, and glycine/proline backbone conformational changes in 11. STRING analysis identified IL12RB1 (0.999), IL23A (0.999), JAK2 (0.995), IL12B (0.986), and STAT3 (0.980) as the leading IL23R interactors. The protective variant R381Q was appropriately characterized as neutral by PROVEAN (−1.16) and AlphaMissense (likely_benign), supporting the specificity of the pipeline. Conclusions: Comprehensive in silico analysis identified 37 high-risk IL23R missense candidates with convergent computational evidence of predicted deleteriousness, predominantly involving cysteine bridge disruption, charge alteration, and glycine/proline backbone conformational changes. These variants are presented as prioritized candidates for future functional validation and may inform subsequent investigations of IBD susceptibility and IL-23 pathway pharmacogenomics. Full article

Background: Pycnodysostosis is a rare autosomal recessive skeletal disorder caused by biallelic pathogenic variants in CTSK, which encodes cathepsin K, a lysosomal cysteine protease required for osteoclast-mediated degradation of bone matrix. Case Report: We describe a girl with short stature, skeletal deformities, osteosclerosis, craniofacial features, clavicular dysplasia, and radiological evidence of fractures. Clinical exome sequencing identified two heterozygous CTSK variants, c.85T > C (p.Trp29Arg) and c.679A>T (p.Ile227Phe), both currently classified as variants of uncertain significance. Segregation analysis showed that the variants were inherited in trans. Computational modeling and in silico prediction tools supported a possible deleterious effect on cathepsin K structure or function. Serum cathepsin K was higher in the patient than in two age-matched controls; this result is reported as an exploratory observation only. Increased serum cathepsin K may reflect altered expression, secretion, clearance, or accumulation of dysfunctional protein, but cannot be interpreted as proof of compensatory upregulation. Conclusions: The patient’s clinical and radiographic features, the biallelic trans configuration of the CTSK variants, their rarity in population databases, and computational predictions support p.Trp29Arg and p.Ile227Phe as strong candidate disease-associated variants. Functional studies are required to confirm their effect on cathepsin K expression, maturation, and enzymatic activity. Full article