Search Results (1,553)

Background: Chronic critical illness (CCI) following acute brain injury involves persistent immune dysfunction, yet its genetic determinants remain unclear. We investigated whether the rate of T-cell receptor excision circle (TREC) depletion—a proposed marker of adaptive homeostatic resilience—is associated with the burden of rare damaging genetic variants. Methods: Whole-exome sequencing (WES) was performed on a cohort of 84 patients (64 with traumatic brain injury, 20 with stroke). In a longitudinal sub-cohort (n = 27), patients were stratified into quartiles (Q1–Q4) based on the slope of their TREC trajectories. ‘Qualifying variants’ (QVs) were defined using strict rarity (gnomAD allele frequency ≤ 0.001) and pathogenicity criteria. Gene-level burden (collapsing) analysis and permutation-based statistical testing (10,000 iterations) were employed to evaluate genetic enrichment in the extreme quartiles. Results: While baseline TREC levels were strictly age dependent (p < 0.0001), the rate of change (TREC slope) was age independent. Rapid TREC decline (Q1) correlated with significantly higher final SOFA scores (p = 0.001) and neutrophil-to-lymphocyte ratios (p = 0.020). Rare variant burden analysis revealed that Q1 patients were significantly more likely to harbor QVs in immune-related genes compared to the Q4 recovery group (odds ratio = 8.25; permutation p = 0.016). Patients with rapid decline were enriched for QVs in putative core “housekeeping” pathways essential for T-cell maintenance and DNA repair (e.g., ERCC3, FANCM), whereas variants in recovering patients were restricted to peripheral effector or structural pathways. Conclusions: Our findings suggest, as a conceptual framework, that an individual’s ability to maintain T-cell homeostasis during critical illness is influenced by their underlying genetic buffering capacity. We propose a hypothetical “two-hit” framework where physiological stress unmasks pre-existing fragilities in core homeostatic pathways—potentially reflecting a state of functional haploinsufficiency under extreme proliferative demand—leading to accelerated immune exhaustion. These results position the TREC slope as a dynamic, age-independent biomarker of genomic resilience in the ICU. All findings are exploratory and hypothesis generating. Full article

Background/Objectives: Formalin-fixed paraffin-embedded tissue is widely used in pathology and molecular diagnostics, yet its variable quality can critically influence the accuracy of sequencing-based analyses. This study investigated pre-analytical and analytical factors that can affect exome sequencing performance in a Brazilian multicenter cohort of patients with breast cancer and prostate adenocarcinoma. Methods: Tumor samples were reviewed for diagnostic confirmation, and those with a minimum cellularity of 20% underwent DNA extraction, fluorometric quantification, fragmentation analysis, and exome sequencing. Pre-analytical parameters, including tumor content, DNA yield, and fragmentation profile, were recorded and correlated with sequencing results. Results: Only 36.7% of all analyzed samples (163/444) generated valid whole-exome sequencing data, corresponding to 55.6% of those that proceeded to sequencing (163/293). Although 94.5% of specimens met the minimum ≥20% cellularity threshold and 66.0% advanced to sequencing, a substantial proportion failed to yield usable exome data. Successful sequencing was associated with shorter storage durations (p < 0.001) and superior analytical parameters (higher autosomal coverage, longer read lengths, lower duplication rates, and higher target coverage at ≥500× and ≥100×; p < 0.001). Detailed fixation-related variables (e.g., formalin type, fixation time, ischemia time) were not consistently available across centers, representing a major limitation for causal interpretation of pre-analytical effects. Conclusions: Our study identified a high failure rate in sequencing archival tissue, highlighting the need to prioritize more recently collected specimens and refine standardized sample handling protocols to maintain DNA integrity. These improvements are essential for optimizing sequencing workflow performance and feasibility in real-world settings. Full article

Background: Diffuse Large B-cell Lymphoma (DLBCL) is a biologically heterogeneous subtype of non-Hodgkin’s lymphoma (NHL), accounting for 30–40% of cases worldwide. Despite the incorporation of rituximab into standard chemo-immunotherapy regimen, approximately one-third of patients present with relapsed or refractory disease, implicating the need for improved prognostic markers and therapeutic targets. Gene expression profiling successfully classified DLBCL into Germinal Center B-cell-like (GCB) and non-GCB subtypes, which differ in genetic alterations, response to therapy, and clinical outcome. While intrinsic tumor biology has been extensively studied, the contribution of the tumor microenvironment (TME) to disease progression and therapeutic resistance still remains incompletely understood. Methods: In this study, we investigated the mutational landscape of stromal-related genes in DLBCL and evaluated their impact on gene expression, downstream signaling pathways, and tumor progression. Results: A total of 176 DLBCL patients were screened, of which 113 were enrolled based on availability of complete clinical data. The cohort demonstrated male predominance (male:female ratio: 2.1:1), advanced disease stage in 72.6% of patients, and elevated serum lactate dehydrogenase levels in 57.5%. Based on immunohistochemistry, 43.4% cases were classified as GCB-DLBCL and 56.6% as non-GCB DLBCL. Although the International Prognostic Index (IPI) retained prognostic significance for event-free survival (EFS) and overall survival (OS), considerable heterogeneity was observed within similar risk groups. Whole-exome sequencing (WES) uncovered recurrent somatic mutations in key oncogenic and epigenetic regulators, including TNFAIP3, NFIB, NOTCH1, TSC2, EZH2, EP300, KMT2D, and B2M, with subtype-specific distribution. Pathway enrichment analysis implicated role of Notch, Wnt, mTOR, JAK-STAT, TGF-β, and antigen-presentation pathways. Comprehensive WES analysis identified multiple novel mutations in genes associated with the stromal/extracellular matrix with distinct patterns in GCB and non-GCB DLBCL, accompanied by concordant alterations in gene expression profiles, suggesting functional relevance within the TME. Functional validation through primary cell culture demonstrated significantly elevated Th2 (IL-4, IL-6, IL-10) and Th17 (IL-17) cytokines in co-cultures containing both neoplastic cells and stromal components, underscoring the role of TME in DLBCL progression. Conclusions: Taken together, this study provides novel insights into stromal mutational signatures and cytokine-mediated tumor–stroma interactions, offering potential prognostic biomarkers and therapeutic targets for the improved management of DLBCL. Full article

Background/Objectives: AA amyloidosis is a serious complication of chronic inflammation, which may arise in the setting of inborn errors of immunity (IEIs) due to recurrent or persistent infections. Common variable immunodeficiency (CVID) is the most frequent symptomatic IEI in adults, yet its association with secondary AA amyloidosis remains rarely reported. Case presentation: We describe a 37-year-old male with a history of recurrent pneumonia, chronic sinusitis, and osteomyelitis with sepsis since childhood. At age 33, he developed bilateral pneumonia after COVID-19, followed by repeated lower respiratory tract infections. At age 36, nephrotic syndrome (proteinuria 10.69 g/day, hypoalbuminemia) led to kidney and gastric mucosa biopsies, which confirmed AA amyloidosis. Immunological workup revealed panhypogammaglobulinemia (IgG 0.1 g/L, IgA 0.01 g/L, IgM 0.28 g/L), markedly reduced switched memory B cells, and an inverted CD4⁺/CD8⁺ ratio. Chest CT showed bronchiectasis, bronchiolitis, and mediastinal lymphadenopathy. Whole-exome sequencing excluded known monogenic IEIs, autoinflammatory, or hereditary amyloidosis genes; a heterozygous likely pathogenic variant in ODAD2 (associated with primary ciliary dyskinesia) was considered incidental. A diagnosis of CVID with secondary AA amyloidosis was established. Conclusions: This case illustrates that CVID may remain undiagnosed for decades and present with secondary AA amyloidosis as the first major complication. In any patient with nephrotic syndrome and a history of recurrent or unusual infections, an IEI should be actively excluded. Early recognition of CVID and appropriate immunoglobulin replacement therapy can prevent infectious exacerbations and potentially halt amyloid progression. Full article

Background/Objectives: How the histologically benign tier of lung preinvasive lesions—atypical adenomatous hyperplasia (AAH) and squamous dysplasia (SD)—relates genomically to its paired carcinoma is unclear. To identify early versus late events, we compared synchronous preinvasive and invasive lesions from the same patient. Methods: Whole-exome sequencing was performed on 33 FFPE samples from 11 patients (7 AAH–lung adenocarcinoma [LUAD] and 4 SD–squamous cell carcinoma [SqCC] pairs, with paired normal lung). FFPE artefacts were mitigated by paired-normal subtraction, panel-of-normals filtering, and orthogonal caller cross-validation. Cancer-panel variants were classified as cancer-only, shared, or preinvasive-only. Results: Only ∼10% of cancer-panel variants were shared between paired lesions (∼50% carcinoma-only, ∼40% preinvasive-only), indicating that benign AAH/SD do not broadly mirror the paired carcinoma. Within this small shared fraction, the early-driver pattern diverged between tracks: AAH–LUAD pairs tended to share EGFR alterations, whereas the four SD–SqCC pairs featured MET-pathway alterations without any shared EGFR events. TP53 and most other canonical drivers were carcinoma-confined (within-cohort contrast direction-consistent but non-significant); three patients lacked any canonical driver despite substantial mutational burden. Conclusions: In this pilot cohort, benign AAH and SD were genomically largely distinct from their paired carcinomas, sharing only a small set of key drivers whose identity diverged between glandular and squamous tracks. This suggests that benign-appearing AAH/SD differ from the more advanced AIS/MIA precursors not only histologically but also at the genomic level. These hypothesis-generating findings require confirmation in larger, multi-omic cohorts. Full article

Background: Dystonia is a heterogeneous hyperkinetic movement disorder characterized by sustained or intermittent muscle contractions causing abnormal movements and postures. Although numerous genes associated with dystonia have been identified, the genetic background remains unknown in many patients. Data on genotype–phenotype correlations in Polish populations remain limited. Objective: To analyze the clinical characteristics of patients with generalized dystonia and compare clinical features between individuals with and without genetically confirmed dystonia-causative variants in a Polish cohort. Methods: A retrospective analysis of patients diagnosed with generalized dystonia at a single neurological center was performed. Diagnosis was established according to MDS criteria. Genetic analysis included whole-exome sequencing, targeted NGS genetic panel, MLPA, Sanger sequencing and PCR_RFLP analysis. Clinical and demographic data were extracted from medical records. Clinical characteristics of individuals with and without causative variants were compared. Results: A total of 113 patients with generalized dystonia were included. Genetic variants were identified in 13 patients (11.5%). These included variants within the TOR1A, THAP1, SGCE, GCH1, NKX2-1, SLC2A1, KMT2B, PDHA1, MFN2, and GNAL genes. We found detailed clinical data of 46 patients included in the study. Our comparative analysis of patients with causative (n = 7) and without causative variants (n = 39) revealed no statistically significant differences in age of onset, initial symptom localization, treatment response, family history, or associated neurological features. Conclusions: In this cohort of Polish patients with generalized dystonia, we identified pathogenic variants in approximately 11.5% of cases. No significant clinical differences were observed between patients with genetically confirmed dystonia and those without identified variants. In this study, we report the first two Polish cases with DYT-GNAL variants. Further studies are required to reveal the clinical heterogeneity of dystonia and characterize dystonia subtypes. Full article

Objectives: Oculocutaneous albinism (OCA), a group of inherited disorders characterized by deficient melanin synthesis, leads to hypopigmentation of the skin, hair, and eyes. OCA type 2 (OCA2) is caused by mutations in OCA2. This study aimed to characterize the comprehensive clinical and genetic spectrum of OCA2, and to identify the key ocular determinants of visual acuity. Methods: We enrolled 90 probands clinically diagnosed with albinism. Whole-exome sequencing and comprehensive ophthalmic examinations were performed. Results: OCA2 was confirmed in 29 probands (32.2%). Visual impairment was distributed as mild/no impairment (30.8%), moderate (53.8%), and severe/blindness (15.4%). All patients exhibited nystagmus and photophobia. Ocular phenotype grading showed distinct distributions: iris translucency (n = 25) was 68% grade 3, 20% grade 2, 8% grade 1, and 4% grade 4; fundus hypopigmentation (n = 26) was 42.3% grade 1, 30.8% grade 2, and 26.9% grade 3; and foveal hypoplasia (n = 20) was 70% grade 4, 25% grade 3, and 5% grade 1. We identified 33 OCA2 variants (26 compound heterozygous and 3 homozygous), with missense variants accounting for 62.1% of alleles. Five variants were identified to be novel. The severity of foveal hypoplasia demonstrated a strong, statistically significant negative correlation with visual acuity (r = −0.71, p < 0.001). Conclusions: OCA2 accounts for 32.2% of albinism cases, with moderate visual impairment being the most common (53.8%). Graded phenotyping demonstrated moderate-to-severe iris translucency (88%), mild fundus hypopigmentation (42.3%), and severe (grade 4) foveal hypoplasia (70%). The severity of foveal hypoplasia emerged as an important determinant of visual acuity. Full article

Recurrent pericarditis (RP) remains challenging, especially in tuberculosis (TB)-endemic regions where empirical anti-TB therapy is often unnecessarily prolonged. We report a 35-year-old woman with three RP episodes over six months, presenting with pleuritic chest pain, elevated inflammatory markers, and moderate-to-large pericardial effusion. Extensive infectious (including TB), autoimmune, and malignancy workups were negative. Cardiac magnetic resonance revealed persistent pericardial late gadolinium enhancement despite clinical remission. Whole-exome sequencing identified a heterozygous MEFV c.442G>C (p.Glu148Gln) variant, suggesting an autoinflammatory predisposition. Although the patient finally achieved sustained symptom-free status for six months on a standardized low-dose colchicine regimen, still over 10% of patients have recurrent symptoms receiving colchicine in addition to conventional anti-inflammatory therapy with aspirin or ibuprofen. This case highlights the shifting paradigm from an infection-centered to an autoinflammatory framework for RP in TB-endemic countries, underscores the role of MEFV variants in idiopathic recurrent pericarditis, and illustrates the real-world gap between genetic insights and therapeutic accessibility to IL-1 inhibitors in resource-limited settings. Full article

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