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PubMed2026

Gene-environment interaction between perinatal oxytocin exposure and Pten mutation shapes epigenetic reprogramming of oxytocin signaling and behavior in mice.

Synthetic oxytocin (Pitocin) is the most commonly used pharmacologic agent for induction and augmentation of labor. Beyond its uterotonic effects, oxytocin plays a critical role in neurodevelopment and social behavior. Dysregulated oxytocin signaling has been implicated in autism spectrum disorder (ASD), raising concern that perinatal exposure to exogenous oxytocin may have lasting neurodevelopmental consequences. This study aimed to determine whether offspring harboring a genetic predisposition for ASD are differentially impacted by perinatal oxytocin exposures, with a focus on long-term oxytocin signaling and autism-like behavior. Pregnant mice carrying offspring with heterozygous mutations in phosphatase and tensin homolog deleted on chromosome ten (Pten), a well-established monogenic risk factor for ASD, received continuous oxytocin versus phosphate-buffered saline (PBS) control via micro-osmotic pumps during late gestation. Wild-type (WT) offspring exposed to each treatment served as a secondary control. Adult offspring were assessed for oxytocin receptor (Oxtr) methylation in the frontal cortex and hippocampus, oxytocin expression in the hypothalamus, serum oxytocin levels, and were subject to a battery of social and anxiety-related behavior tests. Perinatal oxytocin exposure produced genotype-dependent effects in offspring. Epigenetic analyses revealed bidirectional remodeling of Oxtr methylation in the frontal cortex and hippocampus, with increased exon 1 methylation in WT mice and decreased methylation in Pten-mutant mice, resulting in significant genotype-treatment interactions. Hypothalamic oxytocin expression increased following treatment regardless of genotype, though baseline levels were higher in Pten-mutant mice. Neither oxytocin treatment nor genotype impacted long-term serum oxytocin levels. Behavioral outcomes were modest but context-specific: repetitive behaviors and cognition performance were unchanged, but oxytocin-treated Pten-mutant mice exhibited increased anxiety-like behavior alongside improved social memory. In contrast, oxytocin-treated WT mice showed reduced social novelty preference. Exploratory analyses suggested potential sex-dependent trends. Our findings support a model in which genetic susceptibility shapes the epigenetic encoding of early-life hormonal signals, thereby recalibrating oxytocin system function and downstream behavioral outcomes. Together, these data highlight the context-dependent effects of perinatal oxytocin exposure and argue against uniformly beneficial or detrimental effects, emphasizing the importance of gene-environment interactions in neurodevelopmental trajectories.

Animals↗

PubMed2026

Rethinking schizophrenia: insights from genomics and implications for research.

Recent genomic research, considered in the wider context of knowledge from outside genomics, provides significant conceptual insights into the aetiology and pathogenesis of schizophrenia. The evidence indicates that genetic risk is expressed across the lifespan, from foetal development through to adulthood, and involves multiple neuronal types and brain regions. Schizophrenia appears to be primarily a neuronal disorder, with synaptic dysfunction playing a central role in pathogenesis both during development and in mature adult brain function, alongside earlier non-synaptic neurodevelopmental mechanisms. Importantly, non-familial genetic and environmental factors substantially influence neurodevelopmental impairment, and this is often reflected in cognitive performance falling below familial expectations. Cognitive deficits and structural brain abnormalities are weakly correlated with familial genetic risk and are better understood as markers of neurodevelopmental vulnerability rather than causal mediators. Genomic findings also position schizophrenia within a neurodevelopmental continuum, spanning childhood-onset disorders to adult-onset psychiatric conditions, and suggest heterogeneity within schizophrenia, with some cases exhibiting stronger neurodevelopmental involvement. These findings challenge notions that schizophrenia can be ascribed to, or understood by studying, dysfunction in particular neuronal types, brain regions or circuits, or to defects at a particular stage of neurodevelopment. While schizophrenia appears to be predominantly a neuronal disorder, pathophysiology appears to be manifest widely across time and space, and in different neuronal types across the adult and foetal brain. Moreover, despite schizophrenia's high heritability, there is mounting evidence that non-familial genetic and environmental factors play important roles in the neurodevelopmental processes that impact on schizophrenia risk. Finally, variation in the impact of the neurodevelopmental factors appears to be key to understanding some of the heterogeneity within schizophrenia and the relationship between schizophrenia and other conditions. These observations have profound implications for future research, particularly in clarifying pathogenic mechanisms and refining diagnostic frameworks.

Humans↗

PubMed2026

Long-read proteogenomic atlas of human neuronal differentiation reveals isoform diversity informing neurodevelopmental risk mechanisms.

RNA splicing shapes neuronal identity and disease risk, yet current maps lack the developmental resolution and depth to resolve this complexity. Here, we integrate deep long-read RNA sequencing and proteomics in induced pluripotent stem cell-derived cortical neurons to generate a high-resolution proteogenomic atlas of human neuron development. We identify 182,371 mRNA isoforms (over half previously unknown) and provide direct peptide evidence for the translation of hundreds of novel protein-coding sequences. Population genetics demonstrates that variants affecting novel exons and splice sites are under negative selection, underscoring the potential significance of these isoforms. During neuronal maturation, we observe that autism risk genes undergo dynamic isoform switching, including microexon inclusion and intron retention, that remodel key protein domains and regulatory regions. Furthermore, we uncover widespread, long-range coordination between alternative transcript processing events, including transcription start sites, exon splicing, and polyadenylation. Finally, our atlas enables variant reinterpretation in autism, highlighting the value of an isoform-centric view for interpreting pathogenic variation in neurodevelopment.

Humans↗

PubMed2026

Pregnancy diet based on ancestral patterns increases growth in subcortical fetal brain regions.

Evidence on the biological basis for maternal nutrition effects on fetal and newborn neurodevelopment remains limited. This randomized controlled trial in Ecuador tested a maternal dietary pattern-derived from empirical studies of nutrition in human evolution and adapted locally-on offspring growth and brain development. Pregnant women (n = 215) in their first trimester were randomized to: 1) control (n = 104); or 2) Mikhuna ("nourish" in Kichwa) intervention (n = 111). The intervention, from 12 wk gestation to birth, consisted of a weekly food delivery (8 eggs, 500 g fish, and a variety of sustainably sourced fruits and vegetables) and a behavior change communication strategy encouraging diet diversity and limiting highly processed foods. Longitudinal data collection occurred at 12 wk, 21 wk, 35 wk gestation, and 2 wk postpartum, and included ultrasound imaging of fetal bone and brain parameters, maternal dietary intakes, anthropometry, socioeconomic and demographic variables, and other biomarkers. At close of intervention, a significantly higher percentage of women met the minimum dietary diversity threshold in Mikhuna (74.5%) vs. control groups (55.8%) (P = 0.004). Generalized linear regression models showed significant differences in Mikhuna compared to control for: corpus callosum length 0.19 cm (95% CI [0.02, 0.35]), gangliothalamic ovoid height 0.15 cm (95% CI [0.03 to 0.26]), and femur length -0.10 cm (95% CI [-0.19, -0.02]) from 21 wk to 35 wk; and corpus callosum Z 0.56 (95% CI [0.03, 1.09]) and femur length Z -0.21 (95% CI [-0.42, 0.00]) at 35 wk. The Mikhuna intervention increased the growth of subcortical fetal brain structures, which have established roles in motor control, cognition, and signal transmission.

Female↗

PubMed2026

Tailless terminates the neural stem cell temporal cascade in both the optic lobe and central brain.

Temporal patterning is an evolutionarily conserved mechanism to produce neuronal and glial diversity from common cells of origin during neurodevelopment. This process is controlled by a series of temporal transcription factors that are transiently expressed and drive the sequential production of specific progeny subtypes. Intermediate neural progenitors (INPs) and optic lobe neural stem cells (OL NSCs) share striking similarities in temporal factor expression despite divergent cells of origin. Tailless (Tll) is a terminal temporal factor in the visual system in OL NSCs. Its expression coincides with the termination of neurogenesis and onset of gliogenesis. Here, we report that Tll also acts as a terminal factor in Drosophila INPs, demonstrating functional conservation. Tll expression is activated by the preceding temporal factor Scarecrow, and represses odd-paired and hamlet. tll also plays a partial role in promoting gliogenesis in gliogenic NSCs. We performed genome-wide binding analysis of Tll in the OL NSCs and INPs by Targeted DamID, revealing both conserved and divergent targets, reflecting differences in regulatory outcomes. We show that temporal patterning mechanisms are conserved between different brain regions, whilst facilitating lineage-specific outputs.

Animals↗

PubMed2026

Shielding the First 24 Postnatal Months of Life: A Proposal for a Prospective Cohort Study of Early-Life Electromagnetic Exposure and Autism Risk.

BACKGROUND: Autism Spectrum Disorder (ASD) involves Mirror Neuron System (MNS) dysfunction, driving core social and imitative impairments. Systemic physiological alterations such as autonomic dysregulation, mitochondrial dysfunction and neuroinflammation are known to impair synchronization and plasticity of neuronal clusters. A less-evident environmental cofactor, coinciding with rising ASD prevalence, is the considerable world-wide increase in electromagnetic radiation (EMR) overall exposure among children. Experimental evidence shows how low-intensity EMR influences cellular processes, via voltage-gated calcium channels (VGCCs), oxidative stress, and mitochondrial metabolism. The Resonant Convergence framework, allow to predict how chronic EMR exposure during the first 24 postnatal months of life can act as a factor in ASD pathogenesis. The best candidate mechanism is chronic Ion Cyclotron Resonance (ICR) detuning the Ca2+-calmodulin pathway, thus disrupting MNS synchronization. METHODS AND ANALYSIS: A prospective observational pilot cohort study (24-month follow-up) proposes to enroll 1000 full-term newborns into two arms: an EMR-reduced cohort (n = 500, rest and sleep-phase Faraday shielding) and a standard exposure cohort (n = 500). Exposure is quantified via radiofrequency (RF)/extremely low frequency(ELF) measurements, proximity analysis, device inventories and wearable dosimetry. The primary endpoint is a continuous neurodevelopmental trajectory score (joint attention, language, electroencephalogram (EEG) mu-rhythm); binary ASD diagnosis (Autism Diagnostic Observation Schedule, Second Edition (ADOS-2), Autism Diagnostic Interview-Revised (ADI-R)) is a secondary, exploratory endpoint. Moreover, an optional genomic screening will evaluate gene-environment interactions within extremely low-frequency electromagnetic field (ELF-EMF) vulnerable pathways, including ASD-associated genes upregulated by RF via bromodomain and extraterminal protein (BET)-mediated epigenetic mechanisms. Analyses will employ risk ratios, Fisher's exact tests and logistic regression adjusted for confounders; mixed-effects and Bayesian modeling will evaluate longitudinal outcomes and exposure reduction effects. Given a 2-3% baseline prevalence, approximately 20-30 ASD cases are expected. The study is therefore powered for exploratory signal detection rather than definitive causal inference, providing the critical baseline data required to justify and design future confirmatory trials. Sex-stratified modeling will address the 4:1 male-to-female prevalence ratio. ETHICS AND DISSEMINATION: Ethics committee approval is not yet sought; full protocol review and approval will be obtained prior to the study initiation, in strict accordance with the Declaration of Helsinki. Written parental informed consent will be mandatory for all participants prior to enrollment. Study findings and methodological milestones will be disseminated through peer-reviewed international scientific publications. This protocol provides a structured methodological framework for the first prospective investigation of sleep-phase EMR reduction as a potential modulator of ASD incidence during early neurodevelopment. Results will inform adequately powered confirmatory trials in electromagnetic neurodevelopmental epidemiology.

autism spectrum disorder↗

PubMed2026

Polygenic risk score for neurodevelopmental disorders and cognitive impairment at long-term follow-up of first-episode psychosis.

BACKGROUND: One of the most outstanding contributions to the understanding of the etiopathogenesis of schizophrenia spectrum disorders (SSD) was the neurodevelopmental hypothesis. SSD and neurodevelopmental disorders (NDD) share pathogenetic mechanisms and overlapping clinical and cognitive impairment features. METHODS: We investigated whether polygenic risk scores (PRSs) for NDD are associated with cognitive performance in patients with first-episode psychosis (FEP). The sample comprised 127 patients with FEP who were followed up for a mean of 20.9 years. Cognitive examination was performed using the MoCA test at follow-up. Pearson coefficient correlations and multiple regression analyses were performed to examine the contribution of the three PRSs for rare neurodevelopmental conditions (PRSNDD), attention-deficit hyperactivity disorder (PRSADHD) and autism spectrum disorder (PRSASD) to cognitive impairment after allowing for the effect of covariates. Furthermore, we examined the interconnections between the PRS for NDD and cognitive impairment using network analysis (NA), including core premorbid variables. RESULTS: PRSNDD showed significant associations with impairment on visuospatial/executive, attention, and language MoCA subtests, after allowing for the influence of covariates. PRSNDD and PRSADHD, but not PRSASD, were significantly associated with worse performance on the total MoCA score. Moreover, in the network analysis, the relationships between PRSs for NDD and cognitive impairment were highly interconnected with premorbid variables and PRSs for schizophrenia and educational attainment. CONCLUSIONS: These results provide evidence for a possible direct genetic effect on cognitive performance for the PRS of common genetic variations related to neurodevelopment and attention deficit hyperactivity disorder in patients with FEP.

Cognitive impairment↗

PubMed2025

Gestational vitamin D concentration and child cognitive development: a longitudinal cohort study in the Environmental influences on Child Health Outcomes Program.

BACKGROUND: Low vitamin D concentrations are common-especially among those with darker pigmented skin-and are frequently observed during pregnancy. Given its important role in brain development, inadequate gestational vitamin D may impair child cognitive development. OBJECTIVES: We aimed to evaluate associations of gestational vitamin D concentrations with childhood cognitive scores, explore whether this relationship differs by self-reported race, and examine sensitive exposure windows within pregnancy. METHODS: This prospective cohort study included 912 mother-child dyads (37.3% Black, 52.3% White) from the Environmental influences on Child Health Outcomes program. 25-hydroxyvitamin D [25(OH)D] concentrations were measured in prenatal or cord blood collected between 4 and 42 wk gestation (median: 23 wk). Children's cognition was assessed at ages 7-12 y using the NIH Toolbox Cognition Battery. Relationships of 25(OH)D and cognitive scores were examined using mixed-effects linear models adjusted for confounders. Potential sensitive periods were explored by estimating population 25(OH)D patterns across gestation for varying levels of the cognitive outcomes. RESULTS: Mean gestational 25(OH)D was 23.8 ng/mL (SD: 10.0 ng/mL). Each 10-ng/mL increase was associated with greater overall (β: 1.11; 95% CI: 0.08, 2.14) and fluid cognition scores (β: 1.21; 95% CI: 0.07, 2.34), but not crystallized cognition. Although these associations were not significantly modified by self-reported race, associations appeared stronger in children of Black mothers (β: 2.99; 95% CI: 0.82, 5.16) than those in non-Black mothers (β: 0.43; 95% CI: -0.93, 1.78) for fluid cognition. Early pregnancy may be a critical exposure period, evidenced by the greatest divergence in the pattern of 25(OH)D during this period between the mothers of children in the 90th and those in the 10th percentiles of cognitive outcomes. CONCLUSIONS: Gestational 25(OH)D concentrations were positively associated with cognitive scores, especially in children of Black mothers. Given higher deficiency risk among Black women, vitamin D repletion before or in early pregnancy may be an important strategy for reducing racial disparities in child neurodevelopment.

Humans↗

PubMed2026

Bi-allelic loss-of-function variants in JKAMP cause a neurodevelopmental syndrome associated with dysregulation of GPR37 trafficking.

The endoplasmic reticulum (ER) serves as a key hub for protein homeostasis, maintaining a strict quality-control system that ensures only properly folded proteins reach their destinations, while misfolded proteins are degraded via ER-associated degradation (ERAD) or selective ER-phagy. JKAMP, which encodes an ER-resident transmembrane protein involved in ERAD, has not previously been associated with human disease. Here, we report bi-allelic loss-of-function variants in JKAMP in 14 affected individuals from 10 unrelated families presenting with a neurodevelopmental syndrome characterized by intellectual disability, developmental delay, seizures, hypotonia, microcephaly, and dysmorphic features. An in vivo zebrafish model lacking jkamp recapitulated key aspects of the human disorder, including developmental abnormalities and impaired myelin production, further corroborating its pathogenic role. Mechanistic studies identified GPR37, a brain-enriched orphan G protein-coupled receptor (GPCR) and known JKAMP interactor, as a critical downstream effector. GPR37 plays essential roles in dopaminergic signaling, inflammatory pain regulation, neuroprotection, and myelination. Loss of JKAMP resulted in defective folding and degradation of GPR37, leading to its accumulation within the ER and impaired trafficking to the plasma membrane, likely due to impaired ER quality control. These findings establish JKAMP as a previously unrecognized contributor to human neurodevelopment and uncover a pathogenic mechanism linking ER protein quality control to GPCR regulation and neurological disease.

Humans↗

PubMed2026

A recurrent CCDC82 frameshift variant associated with syndromic neurodevelopmental disorder in a consanguineous Pakistani family.

BACKGROUND: Intellectual disabilities (IDs) are part of neurodevelopmental disorders (NDDs) and are genetically heterogeneous conditions characterized by impairments in cognition, learning, and adaptive functioning. Despite advances in gene discovery, many individuals, particularly those from understudied populations, remain without a molecular diagnosis. Recent reports implicate CCDC82 (HGNC: 26282) as an autosomal recessive ID gene, although the phenotypic spectrum and biological context remain incompletely defined. METHODS: Exome sequencing (ES) was performed in a consanguineous Pakistani family (PKMR06A) with four affected individuals presenting with moderate to severe ID. Variant segregation was confirmed by Sanger sequencing. In silico analyses, including pathogenicity prediction, protein structural modeling, and domain intolerance assessment, were used to evaluate the functional consequences of the identified variant. Spatiotemporal gene expression patterns were examined using bulk and single-cell human brain transcriptomic datasets. RESULTS: Clinically, affected individuals of family PKMR06A presented with early childhood global developmental delay, speech delay, hypotonia, gait abnormalities, spasticity, and mild facial dysmorphism. Genetic screening revealed a recurrent rare homozygous frameshift variant in CCDC82 (NM_024725.4): c.373del; p.(Asp125Ilefs*6), segregating with disease in all available affected individuals of the family. The identified c.373del variant was absent from the gnomAD database and was classified as pathogenic (PVS1, PM2, and PP1) based on ACMG/AMP criteria. The c.373del variant is predicted to introduce a premature termination codon, p.(Asp125Ilefs*6), leading to deletion of essential coiled-coil domains from the encoded protein, supporting a loss-of-function mechanism. In silico, transcriptomic analyses demonstrated preferential CCDC82 expression during prenatal human brain development, providing developmental context for the neurodevelopmental phenotype associated with the identified truncating variant. CONCLUSIONS: This study expands the mutational landscape of CCDC82 and provides additional clinical and molecular evidence supporting its role in autosomal recessive NDD. The findings reinforce the importance of CCDC82 in human neurodevelopment and highlight the value of genomic investigation in underrepresented populations.

Autosomal recessive↗

PubMed2025

Deleterious, protein-altering variants in GSPT2 are putatively associated with an X-linked neurodevelopmental disorder with intellectual disability, language impairment, autism, and epilepsy.

PURPOSE: Approximately 6% of individuals with neurodevelopmental disorders are predicted to be X-linked, and the GSPT2 gene, located at Xp11.22, has not yet been associated with any Mendelian disease. METHODS: To establish genotype-phenotype associations between GSPT2 and neurodevelopmental disorders, clinical investigations were performed in unrelated individuals, genomic and functional studies were conducted on the participants' blood and heterologous cell system. RESULTS: We described 6 individuals from 6 unrelated families carrying hemizygous variants in GSPT2 with intellectual disability, delayed speech and language development, autism spectrum disorder, epilepsy, or abnormal fetal neurodevelopment. Structural molecular modeling revealed significant deleterious effects of the identified variants. GSPT2 is preferentially enriched in the brain and cerebellum compared with other tissues. GSPT2-deficient H4 neuroglioma cells slow down the proliferation and downregulate the expression of cell-cycle-related genes. Transcriptomics revealed that GABAergic and calcium-signaling-related genes were significantly downregulated in GSPT2-deficient cells. Consistent with the transcriptomic data, RT-PCR analysis verified the marked downregulation of critical genes (CACNA1B, etc) in GSPT2-knockout cells and further confirmed these findings with proteomic profiling. CONCLUSION: Our data suggest a putative GSPT2-related X-linked neurodevelopmental disorders through dysregulation of cell-cycle progression and calcium/GABAergic signaling pathways.

Humans↗

PubMed2025

Prenatal pyrethroid exposure, placental gene network modules, and neonatal neurobehavior.

Prenatal pesticide exposure may adversely affect child neurodevelopment which may partly arise from impairing the placenta's vital role in fetal development. In a cohort of pregnant farmworkers from Thailand (N = 248), we examined the links between urinary metabolites of pyrethroid pesticides during pregnancy, placental gene expression networks derived from transcriptome sequencing, and newborn neurobehavior assessed using the NICU Network Neurobehavioral Scales (NNNS) at 5 weeks of age. Focusing on the 21 gene network modules in the placenta identified by Weighted Gene Co-expression Network Analysis, our analysis revealed significant associations between metabolites and nine distinct modules, and between thirteen modules and NNNS, with eight modules showing overlap. Notably, stress was negatively associated with the interferon alpha response and Myc target modules, and the interferon alpha response module was correlated positively with attention, and negatively with arousal, and quality of movement. The analysis also highlighted the early and late trimesters as critical periods for the exposures influence on placental function, with pyrethroid metabolites measured early in pregnancy significantly negatively associated with the protein secretion module, and those measured later in pregnancy negatively associated with modules related to oxidative phosphorylation (OXPHOS) and DNA repair. Additionally, the cumulative sum of 3-phenoxybenzoic acid across pregnancy was significantly negatively associated with the OXPHOS module. These findings suggest that prenatal exposure to pyrethroids may influence neonatal neurobehavior through specific placental mechanisms that impact gene expression of metabolic pathways, and these effects may be pregnancy period specific. These results offer valuable insights for future risk assessment and intervention strategies.

Prenatal Exposure Delayed Effects↗

PubMed2025

Impact of the maternal microbiome on neonatal immune development.

Historically, multigenerational health and disease transmission have primarily focused on genetic inheritance. However, the discovery that beneficial microorganisms known as commensal microbiota outnumber human genes tenfold has reshaped this perspective, highlighting their critical role in maintaining homeostasis and protecting against pathogens. Unlike the human genome, commensal microbiota is not genetically inherited but is acquired anew with each generation. with initial gut colonization playing a pivotal role in shaping an infant's immune system, neurodevelopment, and long-term health, all heavily influenced by maternal factors. In this review, we examine emerging research on maternal microbial influences on the fetus beginning in utero. We provide an updated overview of the current insights into the impact of the vaginal microbiome during parturition on offspring immunity and discuss the potential long-term health implications for infants born via cesarean section. We explore the advantages and limitations of techniques designed to mitigate these effects, such as vaginal seeding and emphasize that the development of the neonatal immune system is a dynamic process influenced by maternal factors beyond birth, including the transfer of microbiota through breast milk and skin contact. Finally, we present gaps in current research and propose future research directions to deepen our understanding of the impacts of the maternal microbiome on her child. Together, these insights demonstrate how maternal influence on offspring health and immunity extends beyond genetic factors, encompassing the transmission of microbiota, which, in turn, has profound long-term implications for health and disease resilience, offering a novel perspective on intergenerational health dynamics.

Humans↗

PubMed2026

Epigenome-wide placental methylation landscapes in relation to antenatal depressive symptoms.

Antenatal depressive symptoms (ADS) are common during pregnancy and are linked to adverse maternal and offspring neurodevelopmental outcomes. The placenta plays a central role in maternal-fetal communication and may function as an epigenetic sensor of maternal psychological stress. However, placental epigenetic signatures associated with ADS remain poorly understood. This study investigated epigenome-wide placental DNA methylation patterns associated with ADS in an Indian cohort. Placental samples were collected at delivery from women recruited in early pregnancy into the STRiDE cohort. Depressive symptoms were assessed at 24-28 weeks' gestation using the Patient Health Questionnaire-9 (PHQ-9). Participants were classified as controls (PHQ-9 ≤ 4; n = 53) or ADS (PHQ-9 > 4; n = 54). Genome-wide DNA methylation profiling was performed using the Illumina Infinium MethylationEPIC array. Epigenome-wide association analysis identified no CpG sites that remained statistically significant after Benjamini-Hochberg FDR correction. Top nominal CpGs showed medium-to-large effect sizes for ADS. Exploratory analyses of the top nominally associated CpGs annotated to genes including TAP2, LRCH1, SLITRK2, RASSF1 and IL3 implicated in immune regulation, cellular signalling and neurodevelopment. Gene enrichment analysis suggested the involvement of biological processes and pathways related to synaptic organization, ion transport, Hippo signalling, and thyroid hormone regulation. In conclusion, the study findings provide preliminary evidence of DNA methylation signatures linked to potential candidate genes and biological pathways that may be relevant to ADS, supporting the need for validation in larger independent cohorts and functional experimental studies.

Asian Indians↗

PubMed2026

Generation of a hiPSC from a patient with an ITSN1-associated neurodevelopmental disorder spectrum carrying biallelic c.2893_2894insA (p.Tyr965Ter) genetic variant.

De novo truncating variants in ITSN1 are implicated in neurodevelopment disorders spectrum, however, biallelic variants in ITSN1 have not been previously identified. Here we present a hiPSC line generated from a patient dermal fibroblast carrying biallelic variant, c.2893_2894insA (p.Tyr965Ter). The hiPSC line expresses core stemness markers, mycoplasma free with normal karyotype and demonstrate trilineage differentiation capacity. The hiPSC line provides a valuable in-vitro model system to investigate its role in early brain development and neurodevelopmental disorders.

Humans↗

PubMed2026

Individualized antisense oligonucleotides for SCN2A-related developmental epileptic encephalopathy.

SCN2A variants are among the most common genetic causes of developmental and epileptic encephalopathies (DEEs), which can present with uncontrolled seizures at birth and account for 1-2% of all epileptic encephalopathies. A substantial fraction of causal variants are gain-of-function or mixed-function variants associated with increased channel open probability or greater sodium current flux. Here two parallel n = 1 clinical studies were conducted in two patients (9-year-old and 14-year-old boys) with SCN2A-related DEE. Individualized allele-selective antisense oligonucleotides (ASOs) were designed to target heterozygous intronic single-nucleotide polymorphisms (SNPs) for decreased expression of mutant SCN2A transcript while preserving the wild-type copy. Primary endpoints included quantitative change from baseline in seizure frequency and neurodevelopment, including motor scores. Efficacy measures were also individualized to each patient's phenotype, including refractory seizures, developmental delay, autism spectrum disorder, choreoathetosis and gastrointestinal dysfunction. Patients experienced a reduction in seizure frequency (26% and 90% in the two patients, respectively), decreased use of concomitant medications and improvement in neurodevelopmental skills. Both ASOs were well tolerated, with no ASO-related serious adverse events. Continued long-term follow-up of these preliminary positive safety and efficacy findings is needed to confirm the disease-modifying potential of these ASOs. Haplotype phasing in a separate cohort of infants with SCN2A-related disorder (SCN2A-RD), diagnosed by rapid whole-genome sequencing, identified 16% of patients with compatible SNPs. These data provide a pathway from n = 1 to n of more patients with SCN2A-RD and other monogenic disorders. ClinicalTrials.gov registration: NCT06314490 .

Adolescent↗

PubMed2026

Sex-specific biological aging clocks across organs and omics.

Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches.

Journal Article↗

PubMed2026

Prenatal cell-free DNA methylome detects association with autism and maternal obesity.

Early identification of autism spectrum disorder (ASD) remains a critical challenge, particularly in utero when non-genetic factors such as maternal obesity (MO) are implicated. Here, we report results of whole-genome bisulfite sequencing of cell-free DNA (cfDNA) from third-trimester maternal plasma in a high-likelihood ASD pregnancy cohort associated with child (3 y) ASD diagnosis and/or MO. Differentially methylated regions (DMRs) between ASD and control cfDNA are strongly enriched for synaptic functions and genes previously implicated in ASD. These cfDNA ASD DMRs recapitulate those observed in ASD placenta and postmortem cortex and significantly overlap with MO DMRs. Our findings establish cfDNA methylation derived from maternal blood as a minimally invasive window into fetal brain ASD etiology, providing a framework for future mechanistic and early intervention studies. Future studies could investigate additional prenatal environmental exposures interacting with genetics during neurodevelopment.

Journal Article↗