Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intellectual developmental disorder (IDD), are highly prevalent and lack effective treatments, posing significant health challenges. These disorders are frequently comorbid with disruptions in sleep rhythms, and sleep-related indicators are often used to assess disease severity and treatment efficacy. Recent evidence has highlighted the crucial roles of circadian rhythm disturbances and circadian clock gene mutations in the pathogenesis of NDDs. This review focuses on the mechanisms by which circadian rhythm disruptions and circadian clock gene mutations contribute to cognitive, behavioral, and emotional disorders associated with NDDs, particularly through the dysregulation of dopamine system. Additionally, we discussed the potential of targeting the circadian system as novel therapeutic strategies for the treatment of NDDs.
Humans ; Neurodevelopmental Disorders/genetics* ; Attention Deficit Disorder with Hyperactivity/genetics* ; Circadian Rhythm/genetics* ; Autism Spectrum Disorder/genetics* ; Mutation ; Intellectual Disability/genetics* ; Circadian Clocks/physiology* ; Dopamine/metabolism*

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairments, repetitive behaviors, and restricted interests. Studies have shown that it is more prevalent in males than females. Although this issue has attracted academic attention since the 20th century, the specific mechanisms underlying the gender differences in ASD remain unclear. This paper reviews the impact of gender differences in ASD, focusing on the female protective effect, DNA methylation, hormone levels, and clinical manifestations. It also discusses corresponding treatment options, particularly suggesting improvements in the diagnostic process, which is often overlooked, in order to provide valuable references for the clinical diagnosis and treatment of ASD.
Humans ; Autism Spectrum Disorder/genetics* ; Female ; Male ; DNA Methylation ; Sex Factors ; Sex Characteristics

OBJECTIVES: To evaluate the causal association between circulating levels of zinc, magnesium, and other minerals and autism spectrum disorder (ASD). METHODS: A two-sample Mendelian randomization (MR) analysis was performed using summary statistics from large-scale genome-wide association studies of European populations, including 18 382 ASD cases and 27 969 controls. Genetic data for iron, calcium, and magnesium were obtained from the UK Biobank, and data for zinc and selenium were sourced from an Australian-British cohort. A total of 351 genetic instrumental variables were selected. Causal inference was performed using inverse-variance weighting as the primary analysis method. Sensitivity analyses were performed by Cochran's Q test and MR-PRESSO global test to assess the robustness of the findings. RESULTS: No statistically significant causal effect was observed for circulating zinc, magnesium, calcium, selenium, or iron levels on ASD risk (all P>0.05). The odds ratios and 95% confidence intervals from the inverse-variance weighting analysis were 0.934 (0.869-1.003) for zinc, 1.315 (0.971-1.850) for magnesium, 1.055 (0.960-1.159) for calcium, 1.015 (0.953-1.080) for selenium, and 0.946 (0.687-1.303) for iron. Sensitivity analysis revealed significant heterogeneity in the causal association between circulating calcium and ASD (P=0.006), while the effect estimate remained stable after MR-PRESSO correction (P=0.487). The causal effect estimates for the remaining minerals demonstrated good robustness. CONCLUSIONS This study did not find significant evidence supporting a causal association between circulating zinc, magnesium, calcium, selenium, or iron levels and ASD risk, providing important clues for the etiology of ASD and precision nutritional interventions.
Humans ; Mendelian Randomization Analysis ; Autism Spectrum Disorder/genetics* ; Magnesium/blood* ; Zinc/blood* ; Minerals/blood* ; Genome-Wide Association Study ; Selenium/blood*

Autism Spectrum Disorders (ASDs) are reported as a group of neurodevelopmental disorders. The structural changes of brain regions including the hippocampus were widely reported in autistic patients and mouse models with dysfunction of ASD risk genes, but the underlying mechanisms are not fully understood. Here, we report that deletion of Trio, a high-susceptibility gene of ASDs, causes a postnatal dentate gyrus (DG) hypoplasia with a zigzagged suprapyramidal blade, and the Trio-deficient mice display autism-like behaviors. The impaired morphogenesis of DG is mainly caused by disturbing the postnatal distribution of postmitotic granule cells (GCs), which further results in a migration deficit of neural progenitors. Furthermore, we reveal that Trio plays different roles in various excitatory neural cells by spatial transcriptomic sequencing, especially the role of regulating the migration of postmitotic GCs. In summary, our findings provide evidence of cellular mechanisms that Trio is involved in postnatal DG morphogenesis.
Animals ; Dentate Gyrus/metabolism* ; Mice ; Morphogenesis/physiology* ; Neurons/pathology* ; Cell Movement ; Mice, Inbred C57BL ; Autism Spectrum Disorder/pathology* ; Mice, Knockout ; Neural Stem Cells ; Male ; Neurogenesis ; Autistic Disorder/genetics*

Autism Spectrum Disorder (ASD) is marked by early-onset neurodevelopmental anomalies, yet the temporal dynamics of genetic contributions to these processes remain insufficiently understood. This study aimed to elucidate the role of the Shank3 gene, known to be associated with monogenic causes of autism, in early developmental processes to inform the timing and mechanisms for potential interventions for ASD. Utilizing the Shank3B knockout (KO) mouse model, we examined Shank3 expression and its impact on neuronal maturation through Golgi staining for dendritic morphology and electrophysiological recordings to measure synaptic function in the anterior cingulate cortex (ACC) across different postnatal stages. Our longitudinal analysis revealed that, while Shank3B KO mice displayed normal neuronal morphology at one week postnatal, significant impairments in dendritic growth and synaptic activity emerged by two to three weeks. These findings highlight the critical developmental window during which Shank3 is essential for neuronal and synaptic maturation in the ACC.
Animals ; Nerve Tissue Proteins/metabolism* ; Mice, Knockout ; Dendrites/metabolism* ; Mice ; Synapses/metabolism* ; Gyrus Cinguli/metabolism* ; Male ; Mice, Inbred C57BL ; Autism Spectrum Disorder/genetics* ; Microfilament Proteins

OBJECTIVE: To assess the value of copy number variation sequencing (CNV-seq) for the diagnosis of children with intellectual disability (ID), developmental delay (DD), and autistic spectrum disorder (ASD). METHODS: Forty patients with ID/DD/ASD referred to Nanshan Maternity and Child Health Care Hospital from September 2018 to January 2022 were enrolled. G-banded karyotyping analysis was carried out for the patients. Genomic DNA was extracted from peripheral blood samples and subjected to CNV-Seq analysis to detect chromosome copy number variations (CNVs) in such patients. ClinVar, DECIPHER, OMIM and other database were searched for data annotation. RESULTS: Among the 40 patients (including 30 males and 10 females), 16, 15 and 6 were diagnosed with ID, DD and ASD, respectively. One patient had combined symptoms of ID and DD, whilst the remaining two had combined ID and ASD. Four patients were found with abnormal karyotypes, including 47,XY,+mar, 46,XY,inv(8)(p11.2q21.2), 46,XX,del(5)(p14) and 46,XX[76]/46,X,dup(X)(p21.1q12). Chromosome polymorphism was also found in two other patients. CNV-seq analysis has detected 32 CNVs in 20 patients (50.0%, 20/40). Pathogenic CNVs were found in 10 patients (25.0%), 15 CNVs of uncertain clinical significance were found in 12 patients (30.0%), and 7 likely benign CNVs were found in 4 patients (10.0%). CONCLUSION Chromosome CNVs play an important role in the pathogenesis of ID/DD/ASD. CNV-seq can detect chromosomal abnormalities including microdeletions and microduplications, which could provide a powerful tool for revealing the genetic etiology of ID/DD/ASD patients.
Pregnancy ; Child ; Male ; Humans ; Female ; DNA Copy Number Variations ; Intellectual Disability/genetics* ; Autism Spectrum Disorder/genetics* ; Developmental Disabilities/genetics* ; Abnormal Karyotype

Brain size abnormality is correlated with an increased frequency of autism spectrum disorder (ASD) in offspring. Genetic analysis indicates that heterozygous mutations of the WD repeat domain 62 (WDR62) are associated with ASD. However, biological evidence is still lacking. Our study showed that Wdr62 knockout (KO) led to reduced brain size with impaired learning and memory, as well as ASD-like behaviors in mice. Interestingly, Wdr62 Nex-cKO mice (depletion of WDR62 in differentiated neurons) had a largely normal brain size but with aberrant social interactions and repetitive behaviors. WDR62 regulated dendritic spinogenesis and excitatory synaptic transmission in cortical pyramidal neurons. Finally, we revealed that retinoic acid gavages significantly alleviated ASD-like behaviors in mice with WDR62 haploinsufficiency, probably by complementing the expression of ASD and synapse-related genes. Our findings provide a new perspective on the relationship between the microcephaly gene WDR62 and ASD etiology that will benefit clinical diagnosis and intervention of ASD.
Mice ; Animals ; Microcephaly/genetics* ; Autistic Disorder/metabolism* ; Autism Spectrum Disorder/metabolism* ; Nerve Tissue Proteins/metabolism* ; Brain/metabolism* ; Mice, Knockout ; Cell Cycle Proteins/metabolism*

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder characterized by deficits in social interactions and repetitive behaviors. Although hundreds of ASD risk genes, implicated in synaptic formation and transcriptional regulation, have been identified through human genetic studies, the East Asian ASD cohorts are still under-represented in genome-wide genetic studies. Here, we applied whole-exome sequencing to 369 ASD trios including probands and unaffected parents of Chinese origin. Using a joint-calling analytical pipeline based on GATK toolkits, we identified numerous de novo mutations including 55 high-impact variants and 165 moderate-impact variants, as well as de novo copy number variations containing known ASD-related genes. Importantly, combined with single-cell sequencing data from the developing human brain, we found that the expression of genes with de novo mutations was specifically enriched in the pre-, post-central gyrus (PRC, PC) and banks of the superior temporal (BST) regions in the human brain. By further analyzing the brain imaging data with ASD and healthy controls, we found that the gray volume of the right BST in ASD patients was significantly decreased compared to healthy controls, suggesting the potential structural deficits associated with ASD. Finally, we found a decrease in the seed-based functional connectivity between BST/PC/PRC and sensory areas, the insula, as well as the frontal lobes in ASD patients. This work indicated that combinatorial analysis with genome-wide screening, single-cell sequencing, and brain imaging data reveal the brain regions contributing to the etiology of ASD.
Humans ; Autism Spectrum Disorder/metabolism* ; Autistic Disorder ; Exome Sequencing ; DNA Copy Number Variations ; East Asian People ; Brain/metabolism* ; Mutation/genetics* ; Genetic Predisposition to Disease/genetics*

OBJECTIVE: To explore the clinical characteristics and genetic basis of a child with Mental retardation autosomal dominant 51 (MRD51). METHODS: A child with MRD51 who was hospitalized at Guangzhou Women and Children's Medical Center on March 4, 2022 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her parents were collected and subjected to whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing and bioinformatic analysis. RESULTS: The child, a 5-year-and-3-month-old girl, had manifested autism spectrum disorder (ASD), mental retardation (MR), recurrent febrile convulsions and facial dysmorphism. WES revealed that she has harbored a novel heterozygous variant of c.142G>T (p.Glu48Ter) in the KMT5B gene. Sanger sequencing confirmed that neither of her parents has carried the same variant. The variant has not been recorded in the ClinVar, OMIM and HGMD, ESP, ExAC and 1000 Genomes databases. Analysis with online software including Mutation Taster, GERP++ and CADD indicated it to be pathogenic. Prediction with SWISS-MODEL online software suggested that the variant may have a significant impact on the structure of KMT5B protein. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic. CONCLUSION The c.142G>T (p.Glu48Ter) variant of the KMT5B gene probably underlay the MRD51 in this child. Above finding has expanded the spectrum of KMT5B gene mutations and provided a reference for clinical diagnosis and genetic counseling for this family.
Humans ; Female ; Child, Preschool ; Intellectual Disability/genetics* ; Autism Spectrum Disorder/genetics* ; Mutation

OBJECTIVE: To explore the clinical characteristics and genetic basis of a child with autism spectrum disorder (ASD) in conjunct with congenital heart disease (CHD). METHODS: A child who was hospitalized at the Third People's Hospital of Chengdu on April 13, 2021 was selected as the study subject. Clinical data of the child were collected. Peripheral blood samples of the child and his parents were collected and subjected to whole exome sequencing (WES). A GTX genetic analysis system was used to analyze the WES data and screen candidate variants for ASD. Candidate variant was verified by Sanger sequencing and bioinformatics analysis. Real-time fluorescent quantitative PCR (qPCR) was carried out to compare the expression of mRNA of the NSD1 gene between this child and 3 healthy controls and 5 other children with ASD. RESULTS: The patient, an 8-year-old male, has manifested with ASD, mental retardation and CHD. WES analysis revealed that he has harbored a heterozygous c.3385+2T>C variant in the NSD1 gene, which may affect the function of its protein product. Sanger sequencing showed that neither of his parent has carried the same variant. By bioinformatic analysis, the variant has not been recorded in the ESP, 1000 Genomes and ExAC databases. Analysis with Mutation Taster online software indicated it to be disease causing. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was predicted to be pathogenic. By qPCR analysis, the expression level of mRNA of the NSD1 gene in this child and 5 other children with ASD was significantly lower than that of the healthy controls (P < 0.001). CONCLUSION The c.3385+2T>C variant of the NSD1 gene can significantly reduce its expression, which may predispose to ASD. Above finding has enriched the mutational spectrum the NSD1 gene.
Male ; Child ; Humans ; Autism Spectrum Disorder/genetics* ; Heart Defects, Congenital/genetics* ; Computational Biology ; Genomics ; Mutation ; RNA, Messenger/genetics* ; Histone-Lysine N-Methyltransferase/genetics*