Search Results (10,039)

Alzheimer’s disease (AD) is a neurodegenerative disorder in which genetic susceptibility, aging, protein aggregation, and neuroglial dysfunction converge to drive progressive neuronal loss. Although animal models and conventional cell systems have provided fundamental insights into pathomechanisms, they only partially reproduce the human-specific and multifactorial nature of AD. Human induced pluripotent stem cell (hiPSC)-based models have emerged as a powerful platform to investigate disease-relevant processes within a patient-specific genetic background while enabling the generation of multiple neural cell types and multicellular systems. In this review, we present the evolution of hiPSC-based AD modeling, from reductionist paradigms based on exogenous amyloid-β exposure to CRISPR-engineered isogenic models addressing causal mutations and genetic risk variants associated with either familial or sporadic forms. We examine the contribution of three-dimensional brain organoids and neuroglial co-culture systems in recapitulating cell–cell interactions, neuroinflammatory responses, and tissue-level pathological processes. We focus on current challenges, including the limited representation of neuronal aging, variability among organoids, and the need for standardized protocols. Finally, we discuss the translational potential of hiPSC-derived systems for target identification, drug discovery, and regenerative medicine. Collectively, these advances position hiPSC-based platforms as essential complementary models for elucidating AD pathogenesis and accelerating the development of precision therapeutic strategies. Full article

Post-acute sequelae from SARS-CoV-2, or Long COVID, have evolved as SARS-CoV-2 has evolved into the Omicron subvariants, which have been the predominant and endemic circulating variants of SARS-CoV-2 since early 2022. Omicron is distinct from previous subvariants, with genetic mutations and biological characteristics that present and spread the virus differently, manifesting with upper rather than lower respiratory tract symptomology. Omicron COVID-19 expresses substantially decreased morbidity and mortality, but with higher transmissibility, resulting in Omicron’s endemicity. Unsurprisingly, Long COVID associated with Omicron recovery also presents differently, with dramatically reduced incidence and severity. These factors in turn have paralleled the closing of Long COVID care clinics, which has implications for Long COVID research. Full article

Kazakh populations occupy an important position within the genetic landscape of Central Asia and Inner Eurasia, yet compact ancestry-informative marker panels evaluated for Kazakh-related ancestry remain limited. We analyzed genome-wide single-nucleotide polymorphism data from 624 Kazakh individuals together with data from external reference populations. After harmonization, the discovery dataset comprised 1607 individuals from 41 population groups and 80,766 shared autosomal variants. Candidate ancestry-informative markers were ranked using allele-frequency differentiation and informativeness for assignment, followed by linkage disequilibrium filtering. The final panel comprised 385 markers. Because marker availability differed across external datasets, transferability assessment in two independent Kazakh cohorts (n = 224 and n = 132) was performed using the 341-marker subset shared across the internal dataset and both external cohorts. Principal component analysis showed that both external Kazakh cohorts overlapped substantially with the internal Kazakh cluster. In nearest-centroid analysis, 94.6% of internal Kazakh individuals and 92.0% and 91.7% of individuals from the two external Kazakh cohorts, respectively, were assigned as Kazakh-related. Among non-Kazakh reference individuals used in the discovery framework, 4.1% were assigned as Kazakh-related; this internal, selection-informed estimate was mainly driven by genetically close Central Asian and Inner Eurasian populations. These findings support the transferability of the shared marker subset across independent Kazakh datasets, while also showing limited discrimination between Kazakhs and several closely related neighboring populations. Full article

Population-specific genomic references remain limited for many Southeast Asian communities, particularly in Southern Thailand. We characterized the broad genetic affinity of 24 unrelated adults from Che He Subdistrict, Tak Bai District, Narathiwat Province, using whole-exome sequencing. Reads were processed against GRCh38, and population structure was assessed using reference-defined principal component analysis (PCA), ADMIXTURE, pairwise FST, EthSEQ, and KING-based relatedness analysis. A mean of 114.5 million reads per participant was retained (99.03%), with 99.98–99.99% mapping and a mean depth of 117.07× across the manufacturer-defined Agilent V8 targets. Joint genotyping identified 421,801 PASS variants. For expanded analysis, 24 Che He samples were compared with 3380 high-quality unrelated HGDP–1000 Genomes references. Group-specific missingness control retained 183,930 callable autosomal SNPs; reference-only minor-allele-frequency filtering and LD pruning retained 43,353 SNPs for projection. Che He clustered within the East Asian reference space, with its centroid closest to Cambodian across higher-dimensional summaries. Unpruned Weir–Cockerham FST was also lowest versus Cambodian (0.00256), followed by Dai (0.00892), KHV (0.00956), CDX (0.01149), and Lahu (0.01202). These results indicate relative genetic proximity within the available reference panel and should not be interpreted as definitive ancestry or ethnicity assignment. Full article

Hypertrophic cardiomyopathy (HCM), the most common cardiac disease in cats, is associated with genetic variants, including MYBPC3, which encodes cardiac myosin-binding protein C (cMyBP-C), a key sarcomeric protein involved in myocardial contractility. Although circulating cMyBP-C has emerged as a biomarker of myocardial injury in humans, its clinical relevance in feline HCM remains unclear. This study characterized plasma cMyBP-C and N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations across different stages of feline HCM, evaluated their diagnostic performance, and assessed their associations with echocardiographic parameters. A cross-sectional study included 65 cats: 25 healthy cats, 25 with subclinical HCM, and 15 with clinical HCM (chronic and treated). Plasma NT-proBNP was significantly higher in clinical HCM than in healthy cats (p = 0.0117), whereas plasma cMyBP-C was lower in clinical HCM than in subclinical HCM (p = 0.0462) and healthy cats (p = 0.001). At a cut-off of <1.270 ng/mL, plasma cMyBP-C showed 76.19% sensitivity and 65.38% specificity for distinguishing HCM. NT-proBNP alone showed higher overall diagnostic accuracy (76.67%) than the combined use of cMyBP-C and NT-proBNP. Neither plasma NT-proBNP nor cMyBP-C correlated significantly with echocardiographic parameters. Reduced circulating cMyBP-C concentrations in cats with chronic, treated HCM suggest a biomarker pattern distinct from that reported in acute myocardial injury and warrant further investigation. Full article

Background/Objectives: toxicity related to treatment with the anti-cancer drugs fluoropyrimidines (FP) is mainly driven by a deficiency in the dihydropyrimidine-dehydrogenase (DPD) enzyme activity. Standardized pharmacogenomic markers in the DPYD gene allow pre-emptive prediction and therapy adjustment in patients testing positive, but the rarity of these markers lowers screening sensitivity, leaving a significant part of at-risk individuals undetected. This study aimed to explore the diagnostic performance of genetic screening tests modelled to include unclassified rare DPYD variants and the common SNPs rs1801160 and rs2297595. Methods: this is a retrospective genotype-phenotype association study including 687 Italian subjects who underwent DPD-phenotyping by the 5-fluorouracil degradation assay (5-FUDR) and DPYD genotyping by full exon sequencing. According to their DPD-phenotype, subjects were grouped into a DPD deficiency group (DD, N = 94; >30% reduction in 5-FUDR) and a normal DPD activity group (NDA, N = 593). The phenotype was used as the reference standard to assess genotype-based functional prediction, and discordant genotype-phenotype cases were scored as false negatives or false positives. The phenotype (DD or NDA) prediction power of a genetic, binary (presence/absence) screening test including standardized pharmacogenomic markers (Test 1) was compared to binary tests including missense, nonsense, frameshift or splice-site rare variants (Test 2) or the co-occurrence of rs1801160 and rs2297595 (Test 3). Statistical significance was set at p < 0.05, correcting for multiple testing when appropriate. Results: positivity for all binary tests was significantly associated with the DPD deficiency phenotype (Test1: OR = 6; Test 2: OR = 4.85; Test3: OR = 4.9). Notably, overlap among subjects testing positive in the different tests was minimal. Combining all tests, a 3-fold increase in screening sensitivity was achieved compared to the reference Test 1 (from 12.77% to 35.11%), with a slight decrease in specificity from 97.64% to 91.74%. Conclusions: the proposed approach can refine the genetic predictivity of the DPD-deficiency phenotype in pre-emptive screening, capturing a significantly larger pool of biochemically at-risk patients. Full article

Congenital fibrinogen disorders (CFDs) comprise quantitative deficiencies—afibrinogenemia and hypofibrinogenemia—and qualitative defects—dysfibrinogenemia and hypodysfibrinogenemia. This review is confined to the quantitative disorders, and the term quantitative CFDs is used throughout in preference to the wider umbrella term; qualitative defects are considered only insofar as they must be distinguished at the bench. Afibrinogenemia results from biallelic loss-of-function variants in FGA, FGB, or FGG, and is defined by fibrinogen activity below the analytical limit of detection with undetectable antigen; hypofibrinogenemia results from monoallelic variants and is defined by a proportionate reduction in activity and antigen. Several authoritative reviews of this field have appeared recently. The contribution intended here differs in emphasis. Rather than restate the stepwise diagnostic approach, we set out what actually goes wrong at the bench: the analytical variability among fibrinogen methods, the behavior of the Clauss assay near its limit of detection, and overestimation by prothrombin time-derived fibrinogen. We also address interference from anticoagulants and sample factors, the requirement for laboratory-specific reference intervals, the interpretation of discordant results, and the molecular workflow, including copy-number analysis and the handling of variants of uncertain significance. We also address a question that the descriptive literature largely leaves open: why patients carrying identical variants, sometimes within a single family, differ so markedly in phenotype. We propose a four-layer framework—cis-acting effects at the fibrinogen locus, hepatocyte proteostasis and endoplasmic reticulum quality control, trans-acting genetic modifiers, and acquired factors—and review the evidence supporting each. Population genomic data are reconsidered: current estimates derived from gnomAD suggest that predicted-deleterious fibrinogen genotypes are considerably more frequent than clinically ascertained disease, a discrepancy that reflects incomplete penetrance and the limits of in silico prediction rather than a hidden burden of undiagnosed severe disease. Management recommendations are presented with the strength of the supporting evidence made explicit. Fibrinogen concentrate is a first-line replacement. Widely accepted targets are a peak > 1.5 g/L before major surgery, and >1.0 g/L before minor procedures; >1.0 g/L postoperatively until hemostasis, and >0.5 g/L until wound healing; and a trough ≥ 1.0 g/L in pregnancy, rising to ≥1.5 g/L peripartum. All data are derived from expert consensus, registry data, and small interventional series rather than randomized trials, and are presented here as starting points for individualized care. Paradoxical thrombosis, its uncertain mechanism, and the possibility that replacement precipitates it are treated as an unresolved problem rather than a footnote. Full article

Background/Objectives: Vitamin D regulates both the adaptive and the innate immune system, while having anti-inflammatory, immunomodulatory and anti-fibrotic properties. In clinical studies, 25(OH)D₃ deficiency was associated with systemic inflammation, but it is unclear whether these associations are causal. In this study, we aimed to investigate the impact of Vitamin D receptor (VDR) polymorphisms (SNPs)—as surrogates for functional relationships—on 25(OH)D₃ status and systemic inflammation in decompensated liver cirrhosis. Methods: Patients with compensated and decompensated cirrhosis with or without ACLF were enrolled prospectively from a monocentric cohort study (N = 355). Pyrosequencing was performed for genotyping SNPs (rs7968585, rs731236 (TaqI), rs7975232 (ApaI), rs2239179 and rs2228570 (FokI)). VDR-SNPs were analysed for their association with 25(OH)D₃ concentrations and markers of systemic inflammation. Results: Severe 25(OH)D₃ deficiency was frequent in decompensated cirrhosis. 25(OH)D₃ supplementation was associated with significantly higher circulating 25(OH)D₃ in compensated and decompensated liver cirrhosis, whereas in ACLF, 25(OH)D₃ levels did not differ significantly between supplemented and unsupplemented patients. An inverse correlation of 25(OH)D₃ and IL-6 levels was identified (R = −0.2286, 95% CI −0.328 to −0.124, p < 0.0001). In exploratory analyses among the analyzed VDR-SNPs, the GG-variant of rs2239179 was associated with lower 25(OH)D₃ levels (β = 0.705, 95% CI 0.498-0.998, p = 0.049). Moreover, the functionally important VDR-SNP rs2228570 TC-variant showed a nominal independent association with higher IL-6 levels (ß = 1.685, 95% CI 1.102–2.576, p = 0.016) after adjustment. Conclusions: These exploratory findings suggest that VDR genetics may partially contribute to 25(OH)D₃ status and systemic inflammation in liver cirrhosis and ACLF and warrant further replication in independent cohorts. Full article

X-linked adrenoleukodystrophy (X-ALD) is the most common leukodystrophy and peroxisomal disorder. It was added to newborn screening (NBS) programs following its first implementation in New York in 2013. Since then, X-ALD screening has expanded rapidly, although important differences exist among programs. This systematic review aimed to evaluate the global implementation of NBS for X-ALD, including screening methodologies, screening performance, prevalence estimates, genetic findings, and clinical follow-up outcomes. A systematic search of PubMed and EMBASE identified 13 publications describing NBS programs conducted between 2013 and June 2026. All programs used C26:0-lysophosphatidylcholine (C26:0-LPC) as the primary biomarker, although substantial heterogeneity was observed in analytical methodologies, cut-off values, screening algorithms, and follow-up strategies. Positive predictive values ranged from 9.1% to 100%, while screening detection rates varied from 1:3118 to 1:51,081, reflecting differences in study design, screening population, sample size, and screening approaches. Variants of uncertain significance (VUS) accounted for 52.6% of individuals detected with classified ABCD1 variant findings, representing a major challenge for genetic counseling and clinical management. Most identified newborns were asymptomatic at diagnosis, supporting the role of NBS in enabling early surveillance for adrenal insufficiency and cerebral disease before irreversible manifestations occur. In addition, differences between universal and sex-specific screening strategies highlight ongoing clinical and ethical debates regarding the scope of X-ALD NBS. Overall, current evidence supports the feasibility of NBS for X-ALD and its ability to enable presymptomatic ascertainment and early clinical surveillance; however, greater harmonization of screening protocols, improved variant interpretation, and long-term outcome studies are needed to optimize program performance and clinical benefit. Full article

Background: Leigh encephalopathy is one of the most common phenotypes of mitochondrial diseases. It is characterized by progressive psychomotor regression, accompanied by elevated lactate/pyruvate ratios in blood and cerebrospinal fluid (CSF) and lactate on MRS, and symmetric lesions in the bilateral basal ganglia on brain MRI. A clinical diagnosis is made based on these findings and is confirmed by demonstrating mitochondrial dysfunction through genetic or enzymatic testing. However, some patients who present with clinical features of Leigh encephalopathy actually develop secondary mitochondrial dysfunction due to inborn errors of metabolism, thereby exhibiting a Leigh syndrome phenotype. Case Presentation: The patient was born at term without perinatal complications. Poor feeding was noted from two months of age, and microcephaly and hypotonia were identified at the 4-month health checkup. At 5 months, the patient was admitted for further evaluation. CSF analysis revealed an elevated lactate-to-pyruvate ratio of 21. Brain MRI demonstrated symmetrical T2-weighted hyperintensities in the bilateral basal ganglia, and MR spectroscopy detected a lactate peak in the same region. Based on clinical findings, CSF results, and MRI features, Leigh encephalopathy was suspected. At 9 months, mitochondrial DNA sequencing of skeletal muscle showed no significant mutations, and skeletal muscle biopsy revealed no findings suggestive of neuromuscular disease. At 7 years of age, two weeks after contracting COVID-19, the patient was admitted to the hospital with acute metabolic decompensation characterized by acidosis and complicated by a small intraventricular hemorrhage. Tandem mass spectrometry performed during the episode suggested homocystinuria due to MTHFR deficiency. Subsequent trio-based genetic testing revealed compound heterozygous variants in MTHFR. Measurement of MTHFR enzyme activity revealed a profound reduction, confirming the diagnosis of homocystinuria due to MTHFR deficiency. After initiation of specific metabolic therapy, including betaine, both urinary and plasma homocysteine levels decreased, and clinical symptoms improved. Conclusions: Homocystinuria due to MTHFR deficiency may cause secondary mitochondrial dysfunction, leading to a Leigh syndrome phenotype. When Leigh encephalopathy is suspected, metabolic screening should be performed to avoid missing potentially treatable diseases. Full article

Background: Catechol-O-methyltransferase (COMT) metabolizes catecholamines and polyphenols unique to the Mediterranean-DASH Diet Intervention for Neurodegenerative Delay (MIND). The COMT Val158Met variant modified the effect of MIND on change in perceptual speed after 3 years in a randomized controlled trial. We aimed to evaluate and extend these findings to dementia incidence in a community-based prospective cohort. Methods: We included 745 older adults (mean age 80.0 years) from the Rush Memory and Aging Project. MIND adherence was estimated using a validated food-frequency questionnaire (0–15 points). Repeated cognitive assessments and dementia diagnoses were based on standardized clinical neurological examinations and criteria. Linear regression, linear mixed-effects, and Cox proportional hazards models examined associations of COMT Val158Met and its interactions with MIND with baseline cognition, cognitive decline, and incident dementia. Associations with neuropathology and COMT protein were also explored. Results: Significant COMT × MIND interactions were observed for Alzheimer’s (p = 0.003) and all-cause (p = 0.004) dementia and for COMT × MIND × time interactions with declines in global cognition (p = 0.008), episodic memory (p = 0.009), and visuospatial ability (p = 0.01). Cognitive benefits associated with MIND adherence were greater among Met/Met carriers (lower COMT activity). The hazard ratio (95% CI) per MIND point for Alzheimer’s dementia was 0.82 (0.69–0.98) for Met/Met, 1.00 (0.87–1.15) for Met/Val, and 1.05 (0.84–1.33) for Val/Val. Greater MIND adherence was associated with lower plasma COMT (p = 0.01), while each additional Val allele was associated with higher brain COMT (p < 0.0001). Conclusions: Individuals with genetically reduced COMT activity may be especially responsive to cognitive benefits of the MIND diet. Further study is needed to determine whether these effects differ across cognitive domains. Full article

Gut microbial dysbiosis is common in inflammatory bowel disease (IBD), but whether specific taxa are causal, and through which host genes, remains unclear. We integrated two-sample Mendelian randomization (MR), replication, cis-eQTL colocalization, and single-cell mapping to identify microbial taxa with genetically predicted associations and candidate host mediators. Instruments for 211 taxa from MiBioGen (p < 1×10⁻⁵, r² < 0.001) were used in two-sample MR (inverse-variance weighted IVW primary; sensitivity: Egger, weighted median, MR-PRESSO) against IBD, Crohn’s disease (CD), and ulcerative colitis (UC) in the International IBD Genetics Consortium (IIBDGC), with false discovery rate (FDR) correction. Replication was conducted in FinnGen R12; gene prioritization was performed via cis-SMR/coloc.abf using GTEx v8/CAGE eQTLs, and localization in 11,175 colonic cells. MR identified 15 significant associations (FDR < 0.05) across eight features; applying a pre-specified heterogeneity-based rule, 13 across seven independent features were retained as primary associations (strongest NB1n → CD, OR 1.32) and two were downgraded to suggestive; at the independent-signal level, three of 11 associations were replicated and seven were direction-concordant in FinnGen. Colocalization supported shared variants at SENP7 (blood, CD PP.H4 = 0.86, IBD = 0.70) and ZBTB11-AS1 (colon, IBD = 0.76, CD = 0.74); single-cell analysis mapped SENP7 to T/NK, and ZBTB11-AS1/VIPR1 to epithelial/goblet. Replicated MR and colocalization prioritized SENP7 (whole-blood eQTL; minor T/NK-cell detection) and ZBTB11-AS1 (colon epithelium) as candidate effectors, though the latter lacks functional characterization. Full article

Background and Objectives: This study aimed to determine the diagnostic yield of familial hypercholesterolemia (FH) genotyping and to describe the clinical phenotype and pharmacogenomic (PGx) implementation readiness of adults referred for clinically suspected FH at a Lithuanian tertiary cardiology center. The study was designed as a descriptive retrospective analysis of existing clinical and genetic test results generated using heterogeneous historical sequencing platforms. Materials and Methods: This single-center descriptive cohort included 48 adults with clinically suspected FH evaluated between February 2022 and June 2023. Patients were classified according to Dutch Lipid Clinic Network criteria before genetic testing. Historical targeted next-generation sequencing (NGS) and whole-exome sequencing (WES) results were reviewed. Genetic findings were interpreted using a three-tier reporting framework: diagnostic FH-associated findings, pharmacogenomic findings relevant to future implementation, and VUS, common polymorphisms, or other non-diagnostic findings. Because harmonized PGx star-allele/diplotype calling was not available across historical platforms, PGx findings were not analysed as a mutually exclusive patient-level category. Results: Pathogenic FH-associated variants were identified in 13 of 48 patients (27.1%), including eight LDLR and five APOB variant carriers. In the remaining 35 patients (72.9%), no pathogenic or likely pathogenic FH-associated variant was identified within the analytical scope of the historical test used. This non-diagnostic category could include VUS, common polymorphisms, exploratory findings, or no reportable variant. Patients carrying pathogenic LDLR variants had higher total cholesterol and LDL-C concentrations than patients without detected pathogenic variants. PGx-related findings were considered observations relevant to reporting and future implementation; they were not evaluated as predictors of statin response, statin intolerance, or LDL-C reduction. Conclusions: In this Lithuanian real-world cohort, pathogenic LDLR or APOB variants were identified in 27.1% of patients referred for suspected FH. Retrospective analyses of heterogeneous historical genetic results can inform diagnostic reporting and implementation planning but cannot establish PGx associations with statin efficacy or intolerance without harmonized diplotype calling and prospectively collected treatment outcomes. Full article

Classical liquid chromatography–tandem mass spectrometry (LC-MS/MS) remains a cornerstone of proteomics, but deep profiling of complex biofluids is constrained by the extreme dynamic range of protein abundance and low sample throughput. Emerging high-multiplex platforms address these limitations through distinct high-throughput configurations, including antibody-based proximity assays, modified aptamers, nanoparticle-assisted mass spectrometry, and digital single-molecule immunoassays. Despite their discovery potential, these technologies operate within alternative bottom-up or affinity-based frameworks, meaning that they are not interchangeable. Quantitative measurements of nominally identical proteins frequently show poor to moderate cross-platform agreement, reflecting fundamental differences in chemistry, epitope accessibility, matrix susceptibility, genetic variants, and peptide-level protein inference. Crucially, because these platforms generally yield aggregate quantitative readouts, they typically average across the proteoform spectrum, limiting their ability to differentiate whether an abundance shift is driven by specific splice variants, localized post-translational modifications, or a uniform increase in the protein’s overall concentration. This review provides a balanced, decision-oriented comparison of the Olink Proximity Extension Assay, SomaLogic SomaScan, Seer Proteograph and Quanterix Simoa, delineating their operational utility alongside their respective technical limitations. We propose a practical framework to guide platform selection based on the specific biological question, cohort size, and required structural resolution, while evaluating strategies to enhance cross-platform reproducibility via standardized reference matrices, structure-informed interpretation, and multi-tiered validation workflows. Full article

Background/Objectives: Noonan syndrome (NS) is characterized by marked phenotypic variability. Although the classical phenotype includes short stature, craniofacial dysmorphism, skeletal abnormalities, and congenital heart defects, some patients present with subtle or atypical manifestations, making clinical recognition challenging. Methods: This retrospective case series included six pediatric patients with molecularly confirmed NS managed at the Department of Endocrinology and Metabolic Diseases, Polish Mother’s Memorial Hospital-Research Institute, Lodz, Poland. Medical records were reviewed for auxological data, phenotypic features, endocrine and skeletal assessment, cardiovascular findings, associated conditions, and multidisciplinary management. The aim of this study was to characterize the phenotypic diversity of NS in pediatric endocrine practice, with particular emphasis on growth patterns, endocrine and skeletal manifestations, and atypical clinical presentations. Results: The six patients demonstrated markedly heterogeneous clinical presentations. One boy exhibited the classical phenotype with severe short stature and pulmonary valve stenosis, whereas a girl with typical NS features maintained relatively preserved growth around the 3rd percentile. Another patient presented with progressive resorption of permanent incisor roots and a coexisting pathogenic NBN variant. A boy with LZTR1-associated NS and Klinefelter syndrome (47,XXY) demonstrated a blended phenotype and height between the 25th and 50th percentiles. Two girls lacked characteristic NS dysmorphism and presented predominantly with growth impairment, accompanied by markedly low bone mass in one case and a prolonged diagnostic pathway in the other. GH deficiency was not identified in the evaluated patients, and rhGH therapy was initiated in three patients. Conclusions: NS encompasses a broad clinical spectrum, ranging from classical phenotypes to atypical presentations dominated by growth, skeletal, or dental abnormalities. Neither the absence of characteristic dysmorphism nor relatively preserved growth excludes the diagnosis, while coexisting genetic conditions may further modify the phenotype. Awareness of this heterogeneity is essential for appropriate recognition and individualized multidisciplinary care. In selected children with otherwise unexplained growth or atypical clinical findings, consideration of NS and genetic evaluation may help establish a unifying diagnosis and potentially shorten the diagnostic pathway. Full article