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Nature Sep 2023The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders. Cerebral organoids...
The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders. Cerebral organoids enable the study of neurodevelopmental disorders in a human context. We have developed the CRISPR-human organoids-single-cell RNA sequencing (CHOOSE) system, which uses verified pairs of guide RNAs, inducible CRISPR-Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Here we show that perturbation of 36 high-risk autism spectrum disorder genes related to transcriptional regulation uncovers their effects on cell fate determination. We find that dorsal intermediate progenitors, ventral progenitors and upper-layer excitatory neurons are among the most vulnerable cell types. We construct a developmental gene regulatory network of cerebral organoids from single-cell transcriptomes and chromatin modalities and identify autism spectrum disorder-associated and perturbation-enriched regulatory modules. Perturbing members of the BRG1/BRM-associated factor (BAF) chromatin remodelling complex leads to enrichment of ventral telencephalon progenitors. Specifically, mutating the BAF subunit ARID1B affects the fate transition of progenitors to oligodendrocyte and interneuron precursor cells, a phenotype that we confirmed in patient-specific induced pluripotent stem cell-derived organoids. Our study paves the way for high-throughput phenotypic characterization of disease susceptibility genes in organoid models with cell state, molecular pathway and gene regulatory network readouts.
Topics: Humans; Autism Spectrum Disorder; Autistic Disorder; Brain; Cell Lineage; Chromatin; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Developmental Disabilities; Gene Editing; Loss of Function Mutation; Mosaicism; Neurons; Organoids; RNA, Guide, CRISPR-Cas Systems; Single-Cell Gene Expression Analysis; Transcription, Genetic
PubMed: 37704762
DOI: 10.1038/s41586-023-06473-y -
JAMA Pediatrics Oct 2023Whether some domains of child development are specifically associated with screen time and whether the association continues with age remain unknown.
IMPORTANCE
Whether some domains of child development are specifically associated with screen time and whether the association continues with age remain unknown.
OBJECTIVE
To examine the association between screen time exposure among children aged 1 year and 5 domains of developmental delay (communication, gross motor, fine motor, problem-solving, and personal and social skills) at age 2 and 4 years.
DESIGN, PARTICIPANTS, AND SETTING
This cohort study was conducted under the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study. Pregnant women at 50 obstetric clinics and hospitals in the Miyagi and Iwate prefectures in Japan were recruited into the study between July 2013 and March 2017. The information was collected prospectively, and 7097 mother-child pairs were included in the analysis. Data analysis was performed on March 20, 2023.
EXPOSURE
Four categories of screen time exposure were identified for children aged 1 year (<1, 1 to <2, 2 to <4, or ≥4 h/d).
MAIN OUTCOMES AND MEASURES
Developmental delays in the 5 domains for children aged 2 and 4 years were assessed using the Japanese version of the Ages & Stages Questionnaires, Third Edition. Each domain ranged from 0 to 60 points. Developmental delay was defined if the total score for each domain was less than 2 SDs from its mean score.
RESULTS
Of the 7097 children in this study, 3674 were boys (51.8%) and 3423 were girls (48.2%). With regard to screen time exposure per day, 3440 children (48.5%) had less than 1 hour, 2095 (29.5%) had 1 to less than 2 hours, 1272 (17.9%) had 2 to less than 4 hours, and 290 (4.1%) had 4 or more hours. Children's screen time was associated with a higher risk of developmental delay at age 2 years in the communication (odds ratio [OR], 1.61 [95% CI, 1.23-2.10] for 1 to <2 h/d; 2.04 [1.52-2.74] for 2 to <4 h/d; 4.78 [3.24-7.06] for ≥4 vs <1 h/d), fine motor (1.74 [1.09-2.79] for ≥4 vs <1 h/d), problem-solving (1.40 [1.02-1.92] for 2 to <4 h/d; 2.67 [1.72-4.14] for ≥4 vs <1 h/d), and personal and social skills (2.10 [1.39-3.18] for ≥4 vs <1 h/d) domains. Regarding risk of developmental delay at age 4 years, associations were identified in the communication (OR, 1.64 [95% CI, 1.20-2.25] for 2 to <4 h/d; 2.68 [1.68-4.27] for ≥4 vs <1 h/d) and problem-solving (1.91 [1.17-3.14] for ≥4 vs <1 h/d) domains.
CONCLUSIONS AND RELEVANCE
In this study, greater screen time for children aged 1 year was associated with developmental delays in communication and problem-solving at ages 2 and 4 years. These findings suggest that domains of developmental delay should be considered separately in future discussions on screen time and child development.
Topics: Child, Preschool; Female; Humans; Infant; Male; Pregnancy; Child Development; Cohort Studies; Communication; Japan; Screen Time; Developmental Disabilities; Communication Disorders; Problem Solving; Learning Disabilities
PubMed: 37603356
DOI: 10.1001/jamapediatrics.2023.3057 -
Research in Developmental Disabilities Sep 2023
Topics: Child; Humans; Developmental Disabilities; Developing Countries
PubMed: 37634265
DOI: 10.1016/j.ridd.2023.104589 -
Radiologie (Heidelberg, Germany) May 2024
Topics: Adolescent; Child; Child, Preschool; Humans; Infant; Infant, Newborn; Developmental Disabilities
PubMed: 38689011
DOI: 10.1007/s00117-024-01292-2 -
Nature Nov 2023Mouse models are a critical tool for studying human diseases, particularly developmental disorders. However, conventional approaches for phenotyping may fail to detect...
Mouse models are a critical tool for studying human diseases, particularly developmental disorders. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be 'decomposable' through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.
Topics: Animals; Mice; Cell Nucleus; Developmental Disabilities; Embryo, Mammalian; Gain of Function Mutation; Genotype; Loss of Function Mutation; Models, Genetic; Mutation; Phenotype; Single-Cell Gene Expression Analysis; Disease Models, Animal
PubMed: 37968388
DOI: 10.1038/s41586-023-06548-w -
Scientific Reports Oct 2023Developmental disabilities prevalence seem to be high in countries around the world. It's worth understanding the most recent prevalence and trends of developmental...
Developmental disabilities prevalence seem to be high in countries around the world. It's worth understanding the most recent prevalence and trends of developmental disabilities. The objective of this study is to examine the prevalence and trends of developmental disabilities of US children and adolescents. A total of 26,422 individuals aged 3-17 years were included. Annual data were examined from the National Health Interview Survey (2018-2021). Weighted prevalence for each of the selected developmental disabilities were calculated. The prevalence of any developmental disabilities in individuals was 16.65% (95% CI 16.03-17.26%), prevalence of attention deficit/hyperactivity disorder (ADHD), learning disability (LD), autism spectrum disorder (ASD), intellectual disability (ID), and other developmental delay were 9.57% (95% CI 9.09-10.06%), 7.45% (95% CI 7.00-7.89%), 2.94% (95% CI 2.67-3.21%), 1.72% (95% CI 1.51-1.93%), and 5.24% (95% CI 4.89-5.59%), respectively. Significant increases were observed for other developmental delay (4.02-6.05%) and co-occurring LD & ID (1.03-1.82%). Findings form this study highlight a high prevalence of any developmental disabilities, although no significant increase was observed. The prevalence of other developmental delay and co-occurring LD & ID were significantly increased. Further investigation is warranted to assess potentially modifiable risk factors and causes of developmental disabilities.
Topics: Humans; Child; Adolescent; Developmental Disabilities; Autism Spectrum Disorder; Prevalence; Learning Disabilities; Attention Deficit Disorder with Hyperactivity; Intellectual Disability
PubMed: 37828147
DOI: 10.1038/s41598-023-44472-1 -
The Lancet. Oncology Apr 2024
Topics: Child; Humans; Developmental Disabilities; Neoplasms; Intellectual Disability
PubMed: 38547885
DOI: 10.1016/S1470-2045(24)00146-3 -
Assessment Jan 2024Developmental disorders are diverse, common, and impairing; still, many clinicians lack comprehensive training in their assessment. This review presents thorough... (Review)
Review
Developmental disorders are diverse, common, and impairing; still, many clinicians lack comprehensive training in their assessment. This review presents thorough guidelines for the evaluation and diagnosis of common communication, sleeping, feeding, and elimination disorders that often onset in the early developmental period and that are commonly encountered in clinical practice. Thorough guidance on the evidence-based assessment of developmental disorders is critical, as they are prevalent, impairing, and commonly comorbid with other psychiatric disorders of childhood. This review is the first of its kind-providing critically needed, step-by-step guidance on the existing evidence-based methodologies and assessment tools available for diagnosis. This review also makes clear the dire need for further development and validation of relevant screening and diagnostic measure and calls for specific attention to the development of specific screening and diagnostic assessment measures for feeding disorders and elimination disorders in particular. Clinicians and researchers alike may find this article useful in guiding diagnostic, treatment, and research procedures.
Topics: Child; Humans; Developmental Disabilities; Evidence-Based Practice
PubMed: 37303168
DOI: 10.1177/10731911231178290 -
American Journal on Intellectual and... Sep 2023In "Toward Equity in Research on Intellectual and Developmental Disabilities," we sought to make entrenched assumptions and practices of intellectual and developmental...
In "Toward Equity in Research on Intellectual and Developmental Disabilities," we sought to make entrenched assumptions and practices of intellectual and developmental disabilities research visible by explicitly describing the status quo in terms of models of disability, participant and researcher identities, research priorities, and biases in measurement and treatment approaches. We then curated individual- and systems-level actions drawn from disability justice and broader social justice lenses to offer a way forward. We focused on three major areas (i.e., intersectionality and person-centered approaches, participatory research, and interprofessional collaboration), depicting influences, methods, and actions in a framework of disability, identity, and culture. In this Author Response, we address five commentaries that critique and extend that synthesis.
Topics: Child; Humans; Developmental Disabilities; Diversity, Equity, Inclusion; Biomedical Research
PubMed: 37644864
DOI: 10.1352/1944-7558-128.5.388 -
Clinical Genetics Aug 2023POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and...
POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.
Topics: Humans; Child; Intellectual Disability; Autistic Disorder; Phenotype; Epilepsy; Mutation, Missense; Developmental Disabilities; POU Domain Factors
PubMed: 37165752
DOI: 10.1111/cge.14353