Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Neurodevelopmental conditions”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed2026

Prenatal BPA exposure perturbs RNA-binding protein-mediated splicing regulation and synaptogenesis in the developing cerebellum in a sex-dependent manner.

BACKGROUND: Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social communication deficits, exhibiting a male bias in prevalence. Emerging evidence suggests that prenatal exposure to bisphenol A (BPA) may perturb neurodevelopmental trajectories relevant to ASD. While the cerebellum is increasingly recognized as a brain region implicated in ASD pathophysiology, the impact of gestational BPA exposure on its post-transcriptional alternative splicing machinery remains fundamentally undefined. METHODS: Here, we investigated sex-dependent effects of prenatal BPA exposure on the alternative splicing landscape of the neonatal rat cerebellum. We utilized RNA-seq to profile differential alternative splicing (DAS) events. Ingenuity Pathway Analysis (IPA) was used to predict biological functions and canonical pathways, and to construct the interactome network of DAS genes. To explore candidate upstream regulatory mechanisms, we performed in silico molecular docking and used high-resolution melting (HRM) qRT-PCR to validate selected splicing events. Furthermore, we assessed in vitro cellular phenotypes in primary cerebellar neurons by measuring MTS-based viability and Syn1/Psd95 puncta colocalization. RESULTS: Prenatal BPA exposure was associated with widespread DAS in genes enriched for ASD-relevant pathways in the neonatal rat cerebellum. To our knowledge, this study is the first to report molecular docking analyses predicting favorable interactions between BPA and several candidate RNA-binding proteins (RBPs), including CPEB1, RALYL, HNRNPDL, and ACO1. Our findings support a model in which BPA may perturb RBP-associated splicing regulation, including altered splicing of chromatin regulators such as Ccar1 in males. These molecular and cellular findings were accompanied by sex-stratified differences in neuronal viability and synaptic puncta measurements. BPA exposure was associated with an increased MTS viability signal in male primary cerebellar neurons, together with significant reductions in Psd95 and Syn1 puncta density, whereas female neurons showed significantly increased synaptic puncta colocalization together with reduced viability. CONCLUSIONS: In this study, we propose that prenatal BPA may be relevant to ASD-related neurodevelopmental pathways through sex-dependent changes in RBP-associated alternative splicing, including altered splicing of Ccar1 in males, together with distinct cellular outcomes. Together, these findings identify the developing cerebellum as a sensitive target of prenatal BPA exposure and highlight alternative splicing as a candidate pathway relevant to ASD biology.

Animals↗
PubMed2025

Cell-type-specific DNA methylation dynamics in the prenatal and postnatal human cortex.

The human cortex undergoes extensive epigenetic remodeling during development, although the precise temporal and cell-type-specific dynamics of DNA methylation remain incompletely understood. In this study, we profiled genome-wide DNA methylation across human cortex tissue from donors aged 6 post-conception weeks to 108 years of age. We observed widespread, developmentally regulated changes in DNA methylation, with pronounced shifts occurring during early- and mid-gestation that were distinct from age-associated modifications in the postnatal cortex. Using fluorescence-activated nuclei sorting, we optimized a protocol for the isolation of SATB2-positive neuronal nuclei, enabling the identification of cell-type-specific DNA methylation trajectories in the developing cortex. Developmentally dynamic DNA methylation sites were significantly enriched near genes implicated in autism and schizophrenia, supporting a role for epigenetic dysregulation in neurodevelopmental conditions. Our findings underscore the prenatal period as a critical window of epigenomic plasticity in the brain with important implications for understanding the genetic basis of neurodevelopmental phenotypes.

Humans↗
PubMed2026

Stratifying the risk of transition to adult-onset psychiatric disorders in adolescents with anxiety.

BACKGROUND: Escalating mental health service demands have created a need to better identify young people most likely to require continued support from mental health services at the transition between childhood and adulthood. Anxiety is the most common adolescent mental health condition, yet its clinical significance and prognosis are not well understood. We aimed to examine the risk of young adult-onset psychiatric disorders in individuals with an adolescent anxiety disorder, and identify stratifiers of risk of subsequent psychiatric disorders in this group. METHODS: Individuals from the Norwegian Mother, Father, and Child Cohort Study (MoBa) with linked health records and aged 18 or over as of the 31st December 2023 were included. Those diagnosed with any ICD-10 anxiety disorder when aged 10-17 years were defined as having an adolescent anxiety disorder (n=2107, controls n=47,582). Polygenic scores (PGS) for psychiatric and neurodevelopmental conditions were calculated using LDpred2. Anxiety, comorbidities, and parental psychiatric history were defined through linked ICD-10 diagnoses. Sex was defined through linked records. Individuals were defined as having a young adult-onset psychiatric disorder if they first received any new psychiatric diagnosis aged 18-24. RESULTS: Adolescent anxiety diagnosis was associated with increased risk of all adult-onset psychiatric disorders (HR= 2.33-8.65). Post-traumatic stress disorder PGS, parental history of severe mental illness, and female sex were associated with increased risk of transition to a young adult-onset psychiatric disorder in people with an adolescent anxiety disorder. CONCLUSIONS: Adolescent anxiety greatly increases the risk of a psychiatric disorder during the transition to adult life. Clinicians should consider female sex and parental psychiatric history when prioritising young people with anxiety for adult mental health service support. Future research needs to further consider whether polygenic scores would aid risk stratification in clinical practice.

Norwegian Mother Father and Child Cohort Study↗
PubMed2026

Untargeted metabolomics and proteomics reveals cocoa-mediated mitigation of valproic acid-induced dysregulation in a zebrafish model of autism: pilot study.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by behavioral impairments and limited therapeutic options. Emerging evidence suggests that plant-derived polyphenols may offer neuroprotective benefits. OBJECTIVES: This pilot study aimed to investigate the therapeutic potential of polyphenol-rich cocoa extract in a valproic acid (VPA)-induced zebrafish model of ASD. METHODS: Zebrafish were exposed to 3 μM VPA, cocoa powder providing 2.5 μM (-)-epicatechin, a combination of both, or left untreated. Behavioral phenotyping was conducted using DanioVision and gut morphology was assessed. Untargeted metabolomic and proteomic profiling was performed followed by univariate and multivariate analyses. RESULTS: VPA exposure induced ASD-like behavioral hyperactivity, and severe gastrointestinal abnormalities. Cocoa co-treatment ameliorated both behavioral performance and gut architecture. Metabolomic profiling revealed VPA-associated disruptions in neurotransmission, methylation, mitochondrial function and redox homeostasis. Proteomic profiling showed elevated levels of trafficking protein particle complex subunit 11, proteasomal ubiquitin receptor, betaine-homocysteine S-methyltransferase 1 (BHMT-1), and desmoplakin-A, consistent with genotoxic stress and impaired protein trafficking. Cocoa co-treatment normalized BHMT-1 and desmoplakin-A expression and mitigated broader metabolic dysregulation. CONCLUSION: Collectively, these results suggest that polyphenol-rich cocoa may represent a promising multi-targeted nutraceutical approach for mitigating ASD-related neurodevelopmental and metabolic disturbances.

Animals↗
PubMed2026

Shared genetic architecture between ADHD and intelligence varies across ADHD subtypes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition frequently accompanied by cognitive difficulties. Although previous genetic studies have demonstrated substantial overlap between ADHD and intelligence, most have treated ADHD as a single phenotype. However, whether this shared genetic architecture differs across ADHD subtypes remains unclear. METHODS: We conducted a genome-wide cross-trait analysis integrating large-scale genome-wide association study (GWAS) datasets of overall ADHD, its subtypes-childhood ADHD, persistent ADHD, and late-diagnosed ADHD-and intelligence (total N > 300,000). Genome-wide genetic correlations, polygenic overlap, local genetic correlations, and variant-level associations between ADHD phenotypes and intelligence were evaluated to characterize their shared genetic architecture. Shared variants were identified through cross-trait enrichment analyses and subsequently mapped to genes for functional annotation and gene-set enrichment. Bidirectional associations were evaluated using two-sample Mendelian randomization with sensitivity analyses. Additional GWAS datasets were used to validate the robustness of shared loci by assessing the consistency of effect directions. RESULTS: All ADHD phenotypes showed significant negative genetic correlations with intelligence (rg ranging from -0.3442 to -0.4205). Despite these modest genome-wide correlations, cross-trait analyses revealed substantial genetic overlap, including polygenic overlap, local genetic correlations, and variant-level associations. We identified 184 loci jointly associated with ADHD traits and intelligence, including 64 novel loci, whereas no shared loci were detected for persistent ADHD under the current analysis. Functional annotation revealed biologically distinct enrichment patterns across subtypes: childhood ADHD loci were linked to early neurodevelopmental processes, while late-diagnosed ADHD loci were enriched in synapse-related and neuronal signaling pathways. Mendelian randomization analyses suggested bidirectional associations, with stronger evidence supporting a directional association from intelligence to ADHD risk. Furthermore, these shared loci showed largely consistent effect directions across additional GWAS datasets, providing support for the robustness of the findings. CONCLUSIONS: The shared genetic architecture between ADHD and intelligence varies across ADHD subtypes, highlighting distinct biological pathways underlying cognitive heterogeneity in ADHD. These findings suggest that the relationship between ADHD liability and general cognitive ability is not uniform across ADHD subtypes and may inform future research on risk stratification and early identification in child and adolescent psychiatry.

Humans↗
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↗
PubMed2026

Deciphering the Role of LNX2 as a Potential Contributor to Neurodevelopmental Disorders.

BACKGROUND/OBJECTIVES: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition characterized by a complex and multifactorial genetic architecture. In this study, we report a male patient, born to non-consanguineous healthy parents, presenting with ADHD and oppositional defiant disorder (ODD). METHODS: Trio-based whole-exome sequencing (WES) was performed in the proband and both parents. Variant classification was performed according to American College of Medical Genetics and Genomics (ACMG) guidelines, and the potential pathogenicity of the identified variant was further assessed through multiple in silico prediction algorithms and protein structural analyses. RESULTS: WES identified a homozygous variant in the LNX2 gene (NM_153371.4: c.1165G>A, p.Ala389Thr), classified as a variant of uncertain significance (VUS) and supported by multiple in silico predictions. LNX2 is expressed during brain development and encodes an E3 ubiquitin ligase involved in neuronal differentiation and synaptic function. The identified variant is located within the PDZ2 domain, a functionally relevant region involved in protein-protein interactions. Although the variant is reported in population databases (gnomAD ID: rs148429804), it has not been associated with any clinical phenotype, and its presence in the homozygous state has been reported only once, remaining extremely rare and lacking clinical annotation. Structural modelling predicted localized rearrangement of the hydrogen-bonding network within the PDZ2 domain without major conformational changes. Integrative transcriptomic, and single-cell analyses further supported the biological relevance of LNX2 in neurodevelopment, highlighting its preferential association with neuronal projection-cell networks, synaptic vesicle trafficking pathways, and neuron-specific regulatory programs. CONCLUSION: Although the identified LNX2 variant cannot be considered causative for the patient's phenotype and a definitive disease-gene relationship cannot be established based on a single individual, the complementary genetic, structural, and transcriptomic findings support the biological plausibility of LNX2 as a candidate gene for neurodevelopmental disorders. Additional independent patients and functional studies will be required to clarify its contribution to human disease.

Child↗
PubMed2026

[Tics and Tourette Syndrome].

Tics disorders and Tourette syndrome (TS) are neurodevelopmental conditions characterized by motor and/or vocal tics with onset in childhood. Their clinical presentation is heterogeneous and fluctuating over time, with exacerbations related to emotional, environmental, and medical factors. Diagnosis is clinical and based on medical history and neurological examination, following DSM-5-TR criteria, with ancillary testing rarely required. The prevalence of TS is estimated at 0.7%, while transient tic disorders affect up to 10% of children. The natural history is generally favorable, with symptom improvement during adolescence, although a subset of patients continues to experience tics into adulthood. Most individuals with TS present psychiatric comorbidities, particularly attention-deficit/hyperactivity disorder and obsessive-compulsive disorder, which significantly impact quality of life and should be prioritized in management decisions. Treatment is recommended only when tics cause functional impairment and follows a stepwise approach including psychoeducation, behavioral interventions, and individualized pharmacological therapy. Comprehensive behavioral intervention for tics is considered first-line treatment when available. Alpha-2 adrenergic agonists and dopamine antagonists are the most commonly used pharmacological options. Neuromodulation therapies are reserved for severe, refractory cases. These recommendations from the Ibero-American Academy of Pediatric Neurology summarize current evidence and provide a practical, updated framework for the diagnosis and management of tic disorders and Tourette syndrome in pediatric patients.

Humans↗
PubMed2026

Neurocorrelates of nocturnal enuresis in pre-adolescent children.

INTRODUCTION: Nocturnal enuresis (NE) is a common neurodevelopmental condition, yet its underlying neural mechanisms remain unclear. This study leverages the large-scale Adolescent Brain Cognitive Development (ABCD) dataset to identify structural and functional brain correlates associated with active symptoms and the resolution of bedwetting. METHODS: Using cross-sectional data from 3472 participants aged 9-10 years, children were categorized into three groups: active nocturnal enuresis (ANE, n = 225), history of nocturnal enuresis (HNE, n = 1171), and healthy control groups (CG, n = 2076). Multimodal neuroimaging protocol evaluated macrostructural properties via structural MRI (sMRI), microstructural white matter integrity via diffusion MRI (dMRI), and functional connectivity via resting-state fMRI (fMRI). Group differences were evaluated using linear models within an ANCOVA framework, adjusting for intracranial volume and handedness with False Discovery Rate (FDR) correction. RESULTS: Compared to controls, the ANE group exhibited a significant volume deficit in the right caudate, decreased sulcal depth in the left insula, and lower internal correlation within the Cingulo-Opercular Network (CON). Conversely, the dry HNE group demonstrated significant structural adaptations, including bilaterally larger putamen volumes and increased right caudate volume compared to the ANE group. The HNE group also showed increased microstructural density (decreased mean diffusivity) in the bilateral hippocampus and an increased cortical surface area in the left insula. Both NE groups demonstrated persistently reduced functional coupling within the CON. CONCLUSIONS: Nocturnal enuresis appears to be associated with a potential complex central signaling deficits. Reduced internal correlation within the CON across both active and former bedwetters indicates a potential for impairment in processing internal homeostatic bladder signals during sleep.

Humans↗
PubMed2026

Clinical Utility of Trio Exome Sequencing in Rwandan Children With Autism Spectrum Disorder.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental condition with substantial genetic and phenotypic heterogeneity. However, populations of African ancestry remain underrepresented in genomic studies, limiting understanding of ASD genetic architecture. This study aimed to characterize rare, clinically relevant genetic variants in a Rwandan pediatric ASD cohort using trio-based whole-exome sequencing (WES). METHODS: Trio-based WES was performed in 31 Rwandan pediatric patients with ASD (aged 2-18 years) and their parents. Variants were analyzed using a trio-based workflow and classified according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: Eleven candidate variants were identified in 9 of 31 patients, including four likely pathogenic variants and seven variants of uncertain significance. This resulted in a diagnostic yield of 12.9% (4/31), expanded to 29.0% when phenotypically concordant variants of uncertain significance were considered. Most likely pathogenic variants were identified in individuals with syndromic ASD who presented with intellectual disability, epilepsy, and global developmental delay. Likely pathogenic findings included two single nucleotide variants in GABRB3, SYNGAP1, and two copy-number variants involving the GNAS locus and chromosome 1p35.3-p35.2. CONCLUSIONS: The diagnostic yield observed in this cohort is consistent with previous trio-based WES studies of ASD. The findings support the clinical utility of WES for the genetic evaluation of ASD and underscore the need for expanded genomic studies in African populations.

Humans↗
PubMed2026

CRISPR-Enabled functional genomics in hPSCs-derived neural models for autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a genetically heterogeneous neurodevelopmental condition in which hundreds of individually rare risk variants converge on a small number of shared biological pathways, including synaptic scaffolding, chromatin remodeling, excitation-inhibition balance, and cellular energy metabolism. Translating this genetic heterogeneity into mechanistic insight requires experimental systems capable of interrogating individual gene functions in human-relevant neural contexts at scale. CRISPR-enabled functional genomics in human pluripotent stem cell (hPSC)-derived neural models, spanning neural progenitors, cortical and inhibitory neurons, astrocytes, microglia, and brain organoids, provides precisely this capability. By integrating pooled perturbation screens with multimodal readouts including single-cell and spatial transcriptomics, chromatin accessibility profiling, proximity labeling proteomics, multi-electrode array electrophysiology, and metabolic flux analysis, these platforms enable systematic, causal mapping of ASD gene function at system resolution. Early applications have already revealed convergent mechanisms: BAF complex disruption expands the ventral progenitor pool and biases its fate toward oligodendrocyte and interneuron lineages; ADNP loss impairs microglial synaptic pruning through altered endocytic trafficking; and mTOR pathway dysregulation in PTEN- and TSC2-perturbed models links genetic risk directly to metabolic and mitochondrial dysfunction. Computational frameworks including MIMOSCA and SCEPTRE enable causal network reconstruction and pseudotime inference from these datasets, moving the field from gene lists toward pathway-level models of ASD pathobiology. Translational applications leverage isogenic iPSC panels and variant-level base and prime editing to stratify ASD variants by functional impact, informing gene therapy design for haploinsufficient targets such as CHD8 and SCN2A via AAV or antisense oligonucleotide delivery. Remaining challenges, including model developmental immaturity, batch variability, and the difficulty of modeling polygenic risk, are addressed by a roadmap integrating spatial perturbomics, AI-driven causal inference, and population-scale standardized biobanks. This review synthesizes the current state of CRISPR-based functional genomics in human stem cell neural models as a coherent experimental framework for converting ASD genetic associations into mechanistic understanding and therapeutic opportunity.

Humans↗
PubMed2026

Animal-assisted therapy in pediatric urodynamics.

INTRODUCTION/BACKGROUND: Urodynamics (UDS) is associated with high levels of patient anxiety/discomfort. Children are often unable to complete UDS, with anesthesia needed to place catheters. Animal-assisted therapy (AAT) has been used in a variety of settings, but it has not been studied for UDS before. OBJECTIVE: To determine if AAT can increase success of completing UDS testing without anesthesia in children who were previously unable to perform UDS, along with decreasing distress levels. STUDY DESIGN: We performed a pilot case series of 7 patients (2 female, 5 male) aged 4-16 (mean 9.7) years who previously were unable to complete UDS awake, with AAT prior to and during the UDS procedure. A visual analog scale (VAS) was used to measure patient stress levels before and after AAT. RESULTS: We were able to successfully complete UDS testing with AAT in 6 of the 7 patients (85.7%) without the need for anesthesia. VAS scores decreased from before to after AAT (5.4-3.6, p = 0.020) but with discrepancy when compared to UDS success. DISCUSSION: Our study was the first to describe AAT during UDS. Our preliminary data found AAT to be feasible in UDS. Subjective distress may not correlate with procedural success. AAT in UDS may be more beneficial in certain populations, such as anxious children who previously were unable to tolerate UDS, and not in others such as severe neurodevelopmental conditions. Our study was limited by the small sample size, a single provider, single center, single therapy dog, inclusion of a specific population of patients, and no control group due to this being a pilot study. CONCLUSION: AAT for certain children undergoing UDS testing could help improve the ability to complete the testing without anesthesia. Further studies are needed to fully demonstrate its usefulness in UDS.

Humans↗
PubMed2026

Individual differences in brain dynamics across a social cognition network induced by cortico-cerebellar tDCS in adults with autism spectrum disorder (ASD).

Autism spectrum disorder (ASD) is a neurodevelopmental condition with core diagnostic domains of social communication impairments, restricted interests and repetitive behaviors. Idiosyncratic brain organization is a potential hallmark of ASD. Previous transcranial direct current stimulation (tDCS) studies often targeted dorsolateral prefrontal cortex, with changes oin brain dynamics averaged across the cohort. We utilized a magnetoencephalographic (MEG) array to characterize individual differences in brain dynamics induced by cortico-cerebellar tDCS across nodes of a social cognition network. A randomized, sham-controlled, double-blind, within-subject clinical trial was conducted in a cohort of 24 young adults with ASD or high autistic traits. Two separate sessions of computerized social learning activities were combined with verum/sham tDCS, with anodal electrode over right temporoparietal junction (TPJ) and cathode on right deltoid. Following stimulation, theta- and alpha-band activity were evaluated within nodes of a social cognition network: bilateral TPJ, fusiform, medial prefrontal cortex and Crus I/II of cerebellum. Idiosyncratic participant-specific up- and down-regulation of theta- and alpha-band activity occurred across the network. Activity in right Crus I/II, a region inundated by the stimulation current, strongly correlated with the change of activity summed across all cerebral cortical nodes in theta- but not alpha-band. Intrinsic theta-band activity is believed to mediate input/output relationships in cerebellar cortex and to drive synaptic plasticity. These results suggest that theta-band stimulation of cerebellar cortex might be an effective therapy for individuals on the autism spectrum who present with cerebellar hyperactivity.

Humans↗
PubMed2026

Guidance (challenges and priorities) in the assessment of children with low vision: ERN-EYE clinical consensus statement.

Across Europe, children living with low vision often face inconsistent approaches to the assessment of their visual function, leading to delays in diagnosis and unequal access to care. To address this gap, a multidisciplinary group of experts from 8 European countries developed a clinical consensus statement (CCS), using a modified Delphi process. This CCS provides guidance on evaluation of primary visual functions in children with low vision, regardless of etiologies. Assessing visual function can be challenging and cannot be limited to testing visual acuity. It requires a comprehensive approach that takes into account the child's developmental age and necessary adjustments for vision loss. This consensus statement presents different validated tools to evaluate visual acuity, contrast sensitivity, visual field, and color vision. It provides practical guidance for their use across developmental stages, including infancy and in children with syndromic or neurodevelopmental conditions, and highlights the critical role of caregivers in ensuring reliable assessments. The recommendations emphasize the need for age-appropriate testing strategies, tailored adaptations for low vision and additional impairment, and the importance of early assessment to support timely habilitation and optimize developmental outcomes.

Assessment↗
PubMed2026

Efficacy of pharmacological and microbiota-based therapies in preclinical models of autism spectrum disorder: a systematic review.

BACKGROUND: Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition in which pharmacological and microbiota-targeted interventions are emerging as promising therapeutic avenues. Animal models are the main tool to investigate etiology, molecular mechanisms and screening for pharmacological therapies. Methodological differences, outcome measure variability, incomplete reporting, biological confounders, and overgeneralization of the results made evaluating innovative pharmacological agents challenging. These limitations in the field highlight a need for systematic and standardized research to reliably assess and translate pharmacological interventions from ASD animal models to human clinical relevance. SUBJECTS: This systematic review synthesized efficacy evidence for pharmacological and microbiota-based therapies across established ASD animal models. RESULTS: We identified 52 recent (2010-2025) studies that reported key ASD behavioral outcomes after pharmacological or microbiota-focused treatments. Interventions were grouped into therapeutic classes - including oxytocinergic agents, E/I balance therapeutic targets, metabolic drugs, cannabinoids, purine-based interventions and emerging targets - alongside microbiota-directed strategies such as probiotics, prebiotics, and fecal microbiota transplantation. By integrating effect directions and robustness across models, we identified most potential drug candidates, evaluated the efficacy of novel strategies, and recognized critical translational gaps. The reviewed studies demonstrate that ASD-like behavioral deficits in preclinical models can be modulated through interventions targeting diverse biological systems, including neurotransmission, neuroinflammation, metabolism, and the gut-brain axis. CONCLUSIONS: These findings support the multifactorial nature of ASD pathophysiology which arises from a network of interacting systemic processes rather than a single molecular defect. It could explain the limited success of traditionally narrowly targeted interventions and suggest a paradigm shift into a more systemic approach.

Animals↗
PubMed2025

Prematurity and Genetic Liability for Autism Spectrum Disorder.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by diverse presentations and a strong genetic component. Environmental factors, such as prematurity, have also been linked to increased liability for ASD, though the interaction between genetic predisposition and prematurity remains unclear. This study aims to investigate the impact of genetic liability and preterm birth on ASD conditions. METHODS: We analyzed phenotype and genetic data from two large ASD cohorts, the Simons Foundation Powering Autism Research for Knowledge (SPARK) and Simons Simplex Collection (SSC), encompassing 78,559 individuals for phenotype analysis, 12,519 individuals with genome sequencing data, and 8,104 individuals with exome sequencing data. Statistical significance of differences in clinical measures was evaluated between individuals with different ASD and preterm status. We assessed the rare variants burden using generalized estimating equations (GEE) models and polygenic load using ASD-associated polygenic risk score (PRS). Furthermore, we developed a machine learning model to predict ASD in preterm children using phenotype and genetic features available at birth. RESULTS: Individuals with both preterm birth and ASD exhibit more severe phenotypic outcomes despite similar levels of genetic liability for ASD across the term and preterm groups. Notably, preterm ASD individuals showed an elevated rate of de novo variants identified in exome sequencing (GEE model, p=0.005) in comparison to the non-ASD preterm group. Additionally, a GEE model showed that a higher ASD PRS, preterm birth, and male sex were positively associated with a higher predicted probability for ASD, reaching a probability close to 90% in SPARK. Lastly, we developed a machine learning model using phenotype and genetic features available at birth with limited predictive power (AUROC = 0.65). CONCLUSIONS: Preterm birth may exacerbate the multimorbidity present in ASD, which was not due to the ASD genetic factors. However, increased genetic factors may elevate the likelihood of a preterm child being diagnosed with ASD. Additionally, a polygenic load of ASD-associated variants had an additive role with preterm birth in the predicted probability for ASD, especially for boys. We propose that incorporating genetic assessment into neonatal care could benefit early ASD identification and intervention for preterm infants.

Autism Spectrum Disorder↗
PubMed2025

Mapping Cerebellar Morphology in 15q11.2 CNV Carriers Using Normative Modeling.

Copy number variations (CNVs) at the 15q11.2 locus of the human genome have been associated with altered brain structure and increased risk for neurodevelopmental and neuropsychiatric disorders. The cerebellum is increasingly seen as a crucial brain region for neurodevelopmental conditions, yet the effects of 15q11.2 CNVs on cerebellar morphology remain largely unclear. Importantly, 15q11.2 CNVs shows reduced or incomplete penetrance (meaning that not all CNV carriers are affected) and variable expressivity (meaning that symptoms may differ between individuals with the same genetic alteration). Thus, there is a need to not only assess group differences, but also to quantify anatomical variability at the individual level. Here, we address these issues using normative models of brain anatomy trained on large datasets (n > 52k, age range: 3-85) to assess both group and individual-level deviations in cerebellar anatomy in carriers of 15q11.2 deletions (n = 120, mean [SD] age= 64.95 [7.58]) and duplications (n = 149, mean [SD] age=64.31 [7.21]), compared to non-carriers (n = 19,028, mean [SD] age=64.31 [7.58]). Group-level case-control analyses revealed significantly smaller total and regional cerebellar volumes in both deletion and duplication carriers, though with small effect sizes. Individual-level deviation analyses, capturing pronounced alterations in specific individuals, revealed a heterogeneous pattern among carriers. Overall, our findings suggest that CNVs at the 15q11.2 locus exert modest and highly individualized effects on cerebellar morphology.

15q11.2↗
PubMed2024

Variants in HCFC1 and MN1 genes causing intellectual disability in two Pakistani families.

BACKGROUND: Intellectual disability (ID) is a neurodevelopmental condition affecting around 2% of children and young adults worldwide, characterized by deficits in intellectual functioning and adaptive behavior. Genetic factors contribute to the development of ID phenotypes, including mutations and structural changes in chromosomes. Pathogenic variants in the HCFC1 gene cause X-linked mental retardation syndrome, also known as Siderius type X-linked mental retardation. The MN1 gene is necessary for palate development, and mutations in this gene result in a genetic condition called CEBALID syndrome. METHODS: Exome sequencing was used to identify the disease-causing variants in two affected families, A and B, from various regions of Pakistan. Affected individuals in these two families presented ID, developmental delay, and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing. RESULTS: In an X-linked family A, a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) in the HCFC1 gene (NM_005334.3) was identified, while in family B exome sequencing revealed a heterozygous nonsense variant (c.3680 G > A; p. Trp1227Ter) in exon-1 of the MN1 gene (NM_032581.4). Sanger sequencing confirmed the segregation of these variants with ID in each family. CONCLUSIONS: The investigation of two Pakistani families revealed pathogenic genetic variants in the HCFC1 and MN1 genes, which cause ID and expand the mutational spectrum of these genes.

Humans↗