Search Results (137)

Background/Objectives: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism caused by pathogenic variants in the ATP7B gene. Early diagnosis and appropriate treatment are essential for preventing irreversible complications. This study demonstrated the clinical utility of integrated high-throughput genomic analysis for molecular diagnosis and genetic counseling in a large Thai family affected by WD. Methods: A 32-year-old woman with clinical features suggestive of WD underwent clinical, biochemical, and molecular genetic evaluations, including sequencing of the entire ATP7B gene and SNP microarray. Fluorescent PCR followed by capillary electrophoresis was used for segregation analysis in available family members. SNP microarray analysis and whole-exome sequencing were performed on the proband’s husband to identify pathogenic variants in the ATP7B gene and other disease-associated genes for reproductive risk assessment. Results: The proband presented with hepatic dysfunction, Kayser–Fleischer rings, low serum ceruloplasmin, and a family history of fatal liver disease. She also developed progressive weakness, with nerve conduction findings consistent with axonal sensorimotor polyneuropathy predominantly affecting the lower limbs. Sequencing identified a novel homozygous 28-bp splice-junction deletion, c.4022-24_4025del, which disrupted the canonical splice acceptor site at the intron 19/exon 20 boundary and was classified as pathogenic variant. Segregation analysis confirmed carrier status in the proband’s father and identified heterozygous carrier or homozygous wild-type status among her living siblings. SNP microarray analysis revealed a 46.7 Mb copy-neutral long contiguous stretch of homozygosity (CN-LCSH) encompassing ATP7B, with CN-LCSH regions accounting for 2.046% of the total autosomal genome. These findings potentially reflected segmental uniparental isodisomy or identity by descent, while the overall homozygosity pattern did not support recent consanguinity. Combined genomic analyses of the proband’s husband revealed no pathogenic or likely pathogenic ATP7B variants. Based on the available testing, all offspring are expected to be heterozygous carriers, and the risk of an affected child is considered very low. Conclusions: This study highlights the value of integrated genomic analysis for molecular diagnosis, cascade testing, and reproductive risk counseling. Further functional studies should be conducted to validate their pathogenicity. Full article

Background and Aim: Germline testing (GT) is increasingly relevant in pancreatic ductal adenocarcinoma (PDAC) because of therapeutic and familial implications. We evaluated real-world GT uptake, the diagnostic yield of pathogenic/likely pathogenic germline variants (P/LP), and their clinical implications. Methods: We retrospectively evaluated 674 consecutive patients with PDAC. GT was performed using targeted single-gene testing or multigene panels. Survival analyses among patients receiving platinum-based chemotherapy according to P/LP germline variant status in HRR-associated genes were exploratory. Results: Overall, 28.9% of patients underwent GT, increasing to 45.9% in 2021–2025 (p < 0.001). Results were available for 194 patients; 28 (14.4%) harbored P/LP variants, most commonly BRCA2 (4.6%) and ATM (3.1%). P/LP variants were identified in 6.8% of patients who did not meet classical referral criteria. Among the 28 carriers, 12 (42.9%) harbored BRCA1/2 or PALB2, variants with established therapeutic relevance, while eight (28.6%) carried ATM, FANCA, or FANCM, variants with potential therapeutic relevance. Of these 20 patients, 11 (55.0%) received matched therapy, and treatment was modified because of the germline result in six (30.0%). In exploratory analyses, among platinum-treated patients, carriers of P/LP germline variants in HRR-associated genes had longer PFS than non-carriers (23.9 vs. 4.8 months; log-rank p = 0.017), although only six HRR-associated variant carriers were included in this platinum-treated survival analysis. Conclusions: GT remained underused despite increasing implementation. Early systematic GT may identify clinically relevant variants missed by selective referral strategies and inform treatment, genetic counseling, and cascade testing. Survival findings require prospective validation. 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

Background: Familial hypercholesterolaemia (FH) is a common monogenic cause of premature coronary artery disease (CAD), yet data from South-East Asia are sparse and the yield of family cascade screening has not previously been reported in Vietnam. Methods: In this prospective, single-centre cohort study (March 2023–September 2025), 500 consecutive patients with premature CAD (men < 55 years, women < 60 years) underwent targeted next-generation sequencing of LDLR, APOB and PCSK9, with Sanger confirmation of pathogenic or likely pathogenic (P/LP) variants. First-degree relatives of variant-positive index patients were offered structured counselling and cascade sequencing of the family-specific variant. Results: A P/LP variant was identified in 18 of 500 patients (3.6%; 95% CI 2.1–5.4%); 17 (94.4%) involved LDLR and one APOB. Nine distinct P/LP variants were observed, with several recurrent, consistent with possible founder effects. Two carriers were homozygous, including one with an APOB frameshift attributable to consanguinity. Variant carriers were younger (mean difference −5.6 years, 95% CI −9.2 to −2.0) with higher LDL-cholesterol (median 227.5 vs. 138 mg/dL) and more extensive coronary disease than non-carriers. Cascade screening was completed in 20 of 26 eligible families (77%); among 105 first-degree relatives tested, 46 (43.8%; 95% CI 34.7–53.4%) carried the family-specific variant, most of them young, asymptomatic offspring or siblings. Conclusions: Precise molecular diagnosis in a small number of index patients identified a much larger cohort of at-risk relatives who would otherwise have remained undiagnosed, providing the first Vietnamese evidence that hospital-anchored cascade screening is feasible and high-yielding in a resource-limited setting. Full article

Background/Objectives: Guideline-issuing organizations recommend that women with ovarian cancer undergo genetic testing to identify genetic variants related to hereditary breast and ovarian cancer. The National Cancer Institute proposed the Traceback framework to conduct genetic testing on previously untested women and their at-risk relatives. We implemented a pilot Traceback program in three large healthcare systems: Geisinger (GE), Kaiser Permanente Washington (KPWA), and Kaiser Permanente Mid-Atlantic States (KPMAS). We evaluated the performance, cost, and efficiency of the implementation. Methods: We developed three decision-analytic models representing implemented programs to evaluate performance and estimate direct implementation costs and efficiency from a healthcare system perspective using a bottom-up micro-costing approach based on real-world data. We generalize our findings by modeling hypothetical Traceback programs based on our implementation using national cost data and literature estimates. Results: The programs identified 450, 240, and 878 living ovarian cancer patients at GE, KPWA, and KPMAS, respectively. Of those, 224 (49.8%), 149 (62.1%), and 224 (25.5%) were previously untested, of which 18 (8.0%), 37 (24.8%), and 74 (33.0%) underwent genetic testing. The program costs were $41,564 (GE), $97,396 (KPWA), and $120,327 (KPMAS), with KPMAS showing the lowest cost per patient tested and cost per case detected ($1626, $17,190) versus ($2309, $41,564) (GE) and ($2632, $48,698) (KPWA). Conclusions: Traceback programs were feasible to implement and were associated with improved genetic testing uptake for ovarian cancer patients in this non-randomized pilot. Evaluable outcomes reflect proband testing; additional data and evaluations are needed for assessing cascade testing. Quantifying costs can inform decision-makers on resource allocation for similar programs. Full article

Background/Objectives: Beta-thalassemia (β-thal) is an inherited hemoglobin disorder caused by mutations in the HBB gene. Hb Malay (HBB:c.59A>G [NM_000518.5], p.Asn20Ser, CD19), a missense substitution (AAC→AGC; Asn→Ser) in exon 1 of the β-globin gene causing β⁺-thalassemia, has been mainly described in Southeast Asian populations but remains underreported in published Indonesian molecular epidemiology literature. This study aimed to identify the Hb Malay variant and investigate its familial segregation in a large Indonesian extended family. Methods: Cascade molecular screening was initiated following detection of the mutation in a proband referred for genetic testing. Sixteen individuals (one proband and 15 family members) consented to participate. Genomic DNA was extracted from peripheral blood and a 1.9-kb β-globin gene fragment was amplified by PCR. Mutation screening was performed using the Thalassemia GenoArray Kit HBGA-THAL-b31 (Hybribio) and confirmed by Sanger sequencing. A three-generation pedigree was constructed from molecular results and family interviews. Results: The Hb Malay mutation (HBB:c.59A>G) was identified in 13 of 16 individuals: 12 heterozygous carriers (A/G) and one homozygous individual (G/G, subject III-1, aged 15 years). Three individuals showed the normal genotype (A/A). Pedigree analysis demonstrated autosomal recessive inheritance across three generations. No α-globin deletions covered by the GenoArray panel were detected. Conclusions: To our knowledge, this is one of the few documented reports of cascade molecular screening for the Hb Malay (HBB:c.59A>G) variant in a large extended Indonesian family, confirmed by dual molecular methods. These findings illustrate the potential value of cascade molecular screening for early carrier identification in settings where hemoglobin fractionation testing is unavailable, and highlight the need for population-based epidemiological studies to guide thalassemia prevention policy in Indonesia. Full article

Background and Objectives: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic GLA gene variants, leading to progressive multi-organ damage including end-stage renal disease. Although dialysis patients represent a high-risk population for undiagnosed FD, data from Türkiye using genetic analysis as the primary screening method remain limited. This study aimed to determine FD prevalence among hemodialysis patients across multiple centers in Türkiye and to perform cascade family screening of confirmed cases. Materials and Methods: This multicenter cross-sectional study screened 1359 adult hemodialysis patients across 8 centers in Ankara, Türkiye, using complete GLA gene sequencing. Variants were classified per American College of Medical Genetics and Genomics criteria. Patients with pathogenic variants underwent confirmatory biochemical testing (α-galactosidase A activity and plasma lyso-Gb3). Cascade screening was performed for confirmed index cases. Results: Among 1359 patients (mean age 62.3 ± 14.3 years; 38.5% female), GLA variants were identified in 12 (0.88%): 8 benign/likely benign (including 7 p.D313Y pseudodeficiency alleles), 2 unclassified variants, 1 variant of uncertain significance, and 1 confirmed classic FD (prevalence: 0.07%; 95% CI: 0.002–0.41%). Cascade screening of the index patient identified 6 carriers among 10 relatives tested (60% yield). Three of 7 carriers (43%) were initiated on enzyme replacement therapy. Conclusions: Among 1359 hemodialysis patients, GLA gene sequencing identified 12 variants (0.88%), yet only one was confirmed as a disease-causing mutation responsible for end-stage renal disease (prevalence: 0.07%). The remaining variants comprised polymorphisms, likely benign pseudodeficiency alleles and variants of uncertain significance; most of which would not have been detected by enzyme-based screening alone, as enzyme activity was normal in these carriers. Cascade screening of the single confirmed index case yielded 6 carriers among 10 relatives tested (60%), including one hemizygous male with classic FD on hemodialysis, and three carriers were initiated on enzyme replacement therapy. These findings demonstrate that GLA gene analysis is a valuable instrument for screening in dialysis populations, as it captures the full variant spectrum while enabling rigorous distinction between the overall GLA variant carrier rate and the true disease prevalence defined by variants causing end-stage renal disease. Future screening studies should report prevalence based exclusively on confirmed disease-causing variants rather than total variant counts, which have inflated prevalence estimates in prior literature. Full article

Familial hypercholesterolemia (FH) and familial hypertriglyceridemia (FHTG) represent a spectrum of inherited conditions with profoundly different etiologies, risk profiles, and therapeutic implications. Despite decades of clinical experience, their formal diagnostic definitions remain rooted in frameworks developed before the genomic era (the Dutch Lipid Clinic Network (DLCN) score), leading to substantial gaps in diagnostic accuracy. This review traces the historical evolution of diagnostic criteria for FH and FHTG from early phenotypic observation to contemporary genomic and biomarker-driven models. It systematically evaluates the major limitations of current criteria, including the (DLCN) score, and integrates evidence from landmark Mendelian randomization (MR) studies to identify persistent gaps. A narrative synthesis of landmark clinical, epidemiological, and genetic studies was performed, encompassing the original discovery of the low-density lipoprotein cholesterol (LDL-C) receptor pathway, the development of international diagnostic criteria, and contemporary mendelian randomization (MR) evidence on the causal roles of LDL-C, lipoprotein (a) [Lp(a)], triglyceride-rich lipoprotein remnants, and apolipoprotein B (ApoB). Current diagnostic frameworks suffer from age-dependent confounding of LDL-C measurements, failure to account for Lp(a)-mediated phenocopies, inadequate discrimination between monogenic and polygenic etiologies, sex differences, ethnicity, and inapplicability to pediatric populations. MR data reveal that the causal architecture of cardiovascular risk in these disorders is particle-centric (ApoB) rather than LDL-C-centric, and that remnant cholesterol, not triglyceride per se, drives atherosclerotic cardiovascular disease risk in FHTG. We evidenced the evolution of treatment options and the morbidity and mortality rates for FH and FHTG from the 1970s until the 2020s. Future diagnostic paradigms should integrate lifetime Lp(a) measurement, polygenic risk scoring, ApoB quantification, and cascade genomic testing to replace phenotype-only approaches. This review concludes by proposing a four-step integrated diagnostic algorithm for FH and FHTG. Full article

Background: Cancer predisposition syndromes (CPS) are increasingly recognized in pediatric oncology. In many cases, malignancy in children represents one manifestation of a broader genetic syndrome, often accompanied by dysmorphic features or other distinctive clinical findings. Methods: Clinical documentation and genetic test reports of pediatric patients evaluated over a six-year period (2020–2025) at a genetic counseling unit in a tertiary university hospital in Varna, Bulgaria, were retrospectively reviewed. Referral patterns, clinical characteristics, and genetic findings in children assessed for suspected CPS were analyzed. Results: In total, 430 children underwent genetic testing during the study period; among them, 42 fulfilled the criteria for CPS and were subsequently included in the analysis. Patients were categorized into three groups: those with malignancy (21.4%), those with high-risk hematologic/immune features without malignancy (9.5%), and those referred based on phenotypic features alone (69.0%). Most referrals originated outside oncology services, primarily from general pediatric clinics and outpatient settings, highlighting the importance of non-oncologists in early CPS recognition. Multisystem phenotypic features were common, with 69.0% of patients exhibiting involvement of two or more clinical domains. Genetic testing, predominantly using multigene panels and exome sequencing, identified clinically relevant variants in established CPS genes, most frequently in autosomal dominant conditions within this diagnosis-confirmed cohort. The most common diagnostic categories included NF1 spectrum disorders and RASopathies. Conclusions: These findings emphasize that CPS identification often relies on recognition of non-oncologic features rather than malignancy alone. Genetic counseling plays a central role in diagnosis, risk assessment, and cascade testing. Strengthening awareness among general pediatricians and improving access to genetic services are critical for optimizing early detection and prevention strategies. Full article

Current urban logistics models often struggle to reconcile diurnal traffic dynamics with rigid spatial–temporal regulations. This decoupling causes “cascading infeasibility,” where traffic delays trigger structural regulatory violations and UAV energy depletion. This study formulates a time-dependent vehicle–UAV joint routing problem that strictly couples time-varying speeds with vehicle-restricted zones and no-fly zones. The mixed-integer program minimizes a composite cost by integrating speed curves, geometric detour models, and coupled energy functions. To solve large-scale instances, we propose a hybrid metaheuristic solver (IHGA-VNS-SL) combining genetic algorithms, variable neighborhood search, simulated annealing, and self-learning. Tested on calibrated Wuhan instances, IHGA-VNS-SL quantitatively outperforms baseline heuristics (GA and ALNS). It achieves a tight 2.31% optimality gap against exact solvers (CPLEX) and up to a 20% cost reduction over ALNS, alongside near-zero tardiness. Results demonstrate that this strict coupling effectively mitigates synchronization failures, confirming the framework’s robustness for megacity distribution. Full article

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is genetically heterogeneous, involving more than 11 genes. Since HCM genetic testing was covered by Japan’s national health insurance in 2022, variant detection and the need for family-based intervention have increased, although funding is limited to symptomatic patients only. In this study, we evaluated institutional genetic testing outcomes, factors associated with pathogenic variants, and follow-up of at-risk relatives. Methods: We retrospectively analyzed individuals with confirmed or suspected HCM who underwent genetic testing between October 2022 and June 2025. Data regarding molecular results, family history of cardiomyopathy or sudden cardiac death in first-, second-, and third-degree relatives, and cascade screening were collected. Statistical analysis was performed using R version 2025.09.2 + 418. Results: Among 33 probands (median age, 54 years; 51% male), 13 individuals (39%) had pathogenic or likely pathogenic variants (PV or LPV), while six (18%) harbored variants of uncertain significance (VUS), and 14 (43%) yielded negative results. The PV or LPV cohort was significantly younger at the time of testing (median, 34 vs. 59 years; p = 0.008) and had a family history of PV or LPV (77% vs. 20%; p = 0.005). Only three relatives from two PV or LPV probands underwent cascade genetic screening; two tested positive and initiated targeted cardiac surveillance. Conclusions: Despite achieving actionable results, the restricted uptake of cascade screening highlights the need for improved communication and systemic support to facilitate family-based testing and precision medicine. Full article

Pediatric gastrointestinal polyps are frequently associated with an underlying hereditary syndrome associated with multisystem manifestations and increased risk of early-onset cancer. Thus, the identification of polyps in a child should prompt evaluation with genetic testing to (1) characterize the syndrome to determine next clinical steps including surveillance recommendations, and (2) conduct cascade testing to identify affected family members. Given the considerations for pediatric genetic testing, including autonomy and psychosocial stressors associated with the early detection of a cancer risk syndrome, it is important to conduct targeted testing. Herein, we propose a stepwise approach to genetic testing in the pediatric patient with gastrointestinal polyps. Full article

Background: Channelopathies represent a heterogeneous group of rare inherited cardiac diseases associated with life-threatening arrhythmias. Our knowledge of their epidemiology in childhood is limited. The aim of this study is to evaluate the epidemiology of pediatric channelopathies on a Mediterranean island (Crete, Greece). Methods: Retrospective study of children < 18 years followed in the Regional Tertiary Pediatric Cardiology Unit during a 24-year period (2002–2025) and meeting the disease-specific diagnostic criteria. Results: A total of 43 children (32 families) were enrolled, corresponding to an average annual incidence of 1.43 (95% C.I.: 1.03–1.92) and a cumulative prevalence of 31.1 (95% C.I.: 22.1–42.5) cases per 100, 000 children, with significant regional incidence differences. Long QT syndrome (n = 38) was predominant; rare cases of Brugada syndrome (n = 3) and Catecholaminergic polymorphic tachycardia (n = 2) were recorded. The diagnosis was based on symptomatic presentation (n = 15, 35%), while asymptomatic patients (n = 28, 65%) were diagnosed during cascade family screening (n = 22, 51%) and preparticipation screening (n = 6, 14%). They represented the first diagnosis within affected families (index cases) in 21/43 (49%) of cases. Genetic testing was performed in 35/43 (81%) channelopathy cases and it was positive in 33/43 (77%) of them, specifically in 30 out of 38 (79%) LQT cases with a genotype of LQT2 in 15 (39%), LQT1 in 10 (26%), LQT3 in one (3%) and LQT5 in two (5%) cases. Conclusions: The incidence of pediatric channelopathies on the Mediterranean island of Crete seems comparable to that reported in the literature, with regional clusters of significantly increased incidence. Further study of the epidemiology of pediatric channelopathies is needed, to document any regional or ethnic differences and for the best design of large-scale screening programs. Full article

Background and Clinical Significance: Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant disorder caused by pathogenic variants in the SERPINA1 gene, resulting in reduced circulating alpha-1 antitrypsin (AAT) or production of dysfunctional protein. AAT is the principal inhibitor of neutrophil elastase, and its deficiency leads to unchecked proteolytic activity, progressive destruction of lung parenchyma, and increased susceptibility to infections. Severe deficiency, particularly in individuals homozygous for the Z allele (PI*ZZ), predisposes to early-onset panacinar emphysema, chronic airflow obstruction, and liver disease. Despite its clinical relevance, AATD remains markedly underdiagnosed and is frequently misclassified as smoking-related chronic obstructive pulmonary disease (COPD), delaying access to disease-modifying therapy, genetic counselling, and preventive strategies. Early recognition is therefore essential to improve outcomes. Case Presentation: We report the case of a 68-year-old ex-smoker with a long-standing diagnosis of “COPD” who presented with acute-on-chronic type 2 respiratory failure and community-acquired pneumonia. Spirometry revealed severe airflow obstruction, and high-resolution computed tomography demonstrated extensive basilar panlobular emphysema, raising suspicion for AATD. Serum AAT concentration was critically low at 26.8 mg·dL⁻¹, and isoelectric focusing confirmed a PI*ZZ phenotype. Next-generation sequencing identified homozygosity for the SERPINA1 c.1096G>A (Z) variant, with no additional pathogenic alleles. Cascade family screening revealed multiple heterozygous PI*MZ relatives. Before augmentation therapy could be initiated, the patient developed severe Legionella pneumophila pneumonia with secondary bacterial superinfection, progressing to refractory septic shock and death. Conclusions: This case illustrates how AATD can masquerade as smoking-related COPD for years, leading to missed opportunities for timely intervention. It underscores the importance of testing all adults with COPD or refractory asthma at least once, regardless of age or smoking history. Early diagnosis enables initiation of augmentation therapy, targeted vaccination, lifestyle modification, and genetic counselling, ultimately improving prognosis and reducing preventable morbidity and mortality. Full article

Background: RASopathies represent a clinically and genetically diverse group of syndromes resulting from germline mutations in genes regulating the RAS/mitogen-activated protein kinase (MAPK) signaling cascade. Methods: The aim of this study was to describe the clinical features and genetic variants identified in patients with genetically confirmed Noonan syndrome (NS) in a limited cohort from Romania. A total of 25 patients with positive genetic testing for NS-associated genes were included. Genetic testing was performed primarily using next-generation sequencing. Results: A total of twenty-six variants were identified in twenty-five patients, as one patient carried two pathogenic variants in the PTPN11 gene (c.188A>G and c.922A>G). Of these variants, twenty-four (92.31%) were classified as pathogenic and two (7.69%) as variants of uncertain significance (VUS). Pathogenic variants were found in different genes, including PTPN11, LZTR1, SOS1, and RAF1, with PTPN11 being the most frequently affected gene. Males predominated (17/25), with a male-to-female ratio of approximately 2:1. Two patients inherited the pathogenic variant from an affected parent. Cardiovascular involvement was present in 21 patients (84%), with pulmonary valve stenosis (PVS) being the most common finding (48%), followed by hypertrophic cardiomyopathy (16%). Additional cardiac anomalies included atrial septal defect, valvular regurgitation, dysplastic valves, coarctation of the aorta, and sinotubular junction narrowing. Short stature was observed in 64% of patients, and craniofacial dysmorphism was present in 96%. Cutaneous, ectodermal, dental, ophthalmologic, and auditory manifestations were variably observed. Conclusions: Although based on a limited cohort from Romania, this study provides insights into clinical features suggestive of NS. Our findings highlight the genetic heterogeneity of NS and emphasize the importance of comprehensive genetic testing for confirming diagnosis, guiding clinical management, and supporting family counseling. Full article