Enhancer-targeted CRISPR-Activation Rescues Haploinsufficient Autism Susceptibility Genes DOI Open Access
George Chen,

Gayatri Nair,

Aubrey J. Osorio

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 14, 2024

Abstract Autism Spectrum Disorder (ASD) is a highly heritable condition with diverse clinical presentations. Approximately 20% of ASD’s genetic susceptibility imparted by de novo mutations major effect, most which cause haploinsufficiency. We mapped enhancers two high confidence autism genes – CHD8 and SCN2A used CRISPR-based gene activation (CRISPR-A) in hPSC-derived excitatory neurons cerebral forebrain organoids to correct the effects haploinsufficiency, taking advantage presence wildtype allele each endogenous regulation. found that CRISPR-A induced sustained increase expression treated organoids, rescue levels mutation-associated phenotypes, including physiology. These data support via targeting haploinsufficient genes, as therapeutic intervention ASD other neurodevelopmental disorders.

Language: Английский

Microglial over-pruning of synapses during development in autism-associated SCN2A-deficient mice and human cerebral organoids DOI
Jiaxiang Wu, Jingliang Zhang, Xiaoling Chen

et al.

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(8), P. 2424 - 2437

Published: March 18, 2024

Language: Английский

Citations

19
Multikingdom and functional gut microbiota markers for autism spectrum disorder DOI
Qi Su, Oscar W.H. Wong,

Wenqi Lu

et al.

Nature Microbiology, Journal Year: 2024, Volume and Issue: 9(9), P. 2344 - 2355

Published: July 8, 2024

Language: Английский

Citations

12
Functional neurogenomics in autism spectrum disorders: A decade of progress DOI
Lucy Bicks, Daniel H. Geschwind

Current Opinion in Neurobiology, Journal Year: 2024, Volume and Issue: 86, P. 102858 - 102858

Published: March 27, 2024

Language: Английский

Citations

9
Lipidomic profiling of mouse brain and human neuron cultures reveals a role for Mboat7 in mTOR-dependent neuronal migration DOI

Isaac Tang,

Ashna Nisal, Alex Reed

et al.

Science Translational Medicine, Journal Year: 2025, Volume and Issue: 17(779)

Published: Jan. 1, 2025

Mutations in lipid regulator genes are a frequent cause of autism spectrum disorder, including those regulating phosphatidylinositol (PI) and phosphoinositide 3-kinase signaling. MBOAT7 encodes key acyltransferase PI synthesis is mutated an autism-related condition with neurodevelopmental delay epilepsy. Using liquid chromatography–tandem mass spectrometry, we analyzed the PI-associated glycerolipidome mice humans during neurodevelopment found dynamic regulation at times corresponding to neural apoptosis brains Mboat7 knockout mice. function was necessary for polyunsaturated cortical migration, loss resulted massive accumulation precursor lysophosphatidylinositol hyperactive mTOR Inhibiting signaling rescued migration defects. Our findings demonstrate roles remodeling implicate neuronal revealing potential paths treatment deficiency.

Language: Английский

Citations

1
Polygenic scores for autism are associated with reduced neurite density in adults and children from the general population DOI Creative Commons
Yuanjun Gu, Eva-Maria Stauffer, Saashi A. Bedford

et al.

Molecular Psychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Abstract Genetic variants linked to autism are thought change cognition and behaviour by altering the structure function of brain. Although a substantial body literature has identified structural brain differences in autism, it is unknown whether autism-associated common genetic changes cortical macro- micro-structure. We investigated this using neuroimaging data from adults (UK Biobank, N = 31,748) children (ABCD, 4928). Using polygenic scores correlations we observe robust negative association between for magnetic resonance imaging derived phenotype neurite density (intracellular volume fraction) general population. This result consistent across both adults, cortex white matter tracts, confirmed correlations. There were no sex association. Mendelian randomisation analyses provide evidence causal relationship intracellular fraction, although should be revisited better powered instruments. Overall, study provides shared variant genetics density.

Language: Английский

Citations

1
Genomic and Developmental Models to Predict Cognitive and Adaptive Outcomes in Autistic Children DOI
Vincent-Raphaël Bourque,

Zoe Schmilovich,

Guillaume Huguet

et al.

JAMA Pediatrics, Journal Year: 2025, Volume and Issue: unknown

Published: April 21, 2025

Importance Although early signs of autism are often observed between 18 and 36 months age, there is considerable uncertainty regarding future development. Clinicians lack predictive tools to identify those who will later be diagnosed with co-occurring intellectual disability (ID). Objective To predict ID in children autism. Design, Setting, Participants This prognostic study involved the development validation models integrating genetic variants developmental milestones ID. Models were trained, cross-validated, tested for generalizability across 3 cohorts: Simons Foundation Powering Autism Research (SPARK), Simplex Collection, MSSNG. Autistic participants assessed older than 6 years age Study data analyzed from January 2023 July 2024. Exposures Ages at attaining milestones, occurrence language regression, polygenic scores cognitive ability autism, rare copy number variants, de novo loss-of-function missense impacting constrained genes. Main Outcomes Measures The out-of-sample performance was using area under receiver operating characteristic curve (AUROC), positive values (PPVs), negative (NPVs). Results A total 5633 autistic (4574 male [81.2%]) included this analysis. On average, 4 (IQR, 3-7) 11 (8-14) 1159 (20.6%) being model all predictors yielded an AUROC 0.653 (95% CI, 0.625-0.681), cross-validated generalized cohorts. modest reflected that only a subset individuals carried large-effect high scores, or presented delayed milestones. However, combinations typically not considered clinically relevant by diagnostic laboratories achieved PPVs 55% correctly identified 10% developing addition specifically improved NPVs rather PPVs. Notably, stratify probabilities up 2-fold higher compared typical Conclusions Relevance suggest growing neurodevelopmental condition–associated cannot, most cases, used alone predicting combining different classes provide individual-level predictions could useful targeting interventions.

Language: Английский

Citations

1
Dissecting the contribution of common variants to risk of rare neurodevelopmental conditions DOI Creative Commons
Qin Qin Huang, Emilie M. Wigdor,

Patrick Campbell

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: March 6, 2024

Abstract Although rare neurodevelopmental conditions have a large Mendelian component, common genetic variants also contribute to risk. However, little is known about how this polygenic risk distributed among patients with these and their parents, its interplay variants, whether parents’ background contributes children’s beyond the direct effect of transmitted child (i.e. via indirect effects potentially mediated through prenatal environment or ‘genetic nurture’). Here, we addressed questions using data from 11,573 conditions, 9,128 parents 26,869 controls. Common explained ∼10% variance in overall Patients monogenic diagnosis had significantly less than those without, supporting liability threshold model, while both genetically undiagnosed diagnosed affected more In trio-based score for but not non-transmitted parental alleles were associated risk, indicating effect. contrast, observed no scores educational attainment cognitive performance, saw significant correlation between child’s due and/or assortment traits. Indeed, as expected under assortment, show that variant predisposition correlated component Our findings thus suggest future studies should investigate possible role nature on consider contribution simultaneously when studying cognition-related phenotypes.

Language: Английский

Citations

6
Unravelling the Cerebellar Involvement in Autism Spectrum Disorders: Insights into Genetic Mechanisms and Developmental Pathways DOI Creative Commons
Marika Guerra, Vanessa Medici, Gina La Sala

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(14), P. 1176 - 1176

Published: July 10, 2024

Autism spectrum disorders (ASDs) are complex neurodevelopmental conditions characterized by deficits in social interaction and communication, as well repetitive behaviors. Although the etiology of ASD is multifactorial, with both genetic environmental factors contributing to its development, a strong basis widely recognized. Recent research has identified numerous mutations genomic rearrangements associated ASD-characterizing genes involved brain development. Alterations developmental programs particularly harmful during critical periods Notably, studies have indicated that disruptions occurring second trimester pregnancy affect cortical while disturbances perinatal early postnatal period cerebellar The defects must be viewed context role cerebellum cognitive processes, which now established. present review emphasizes complexity neuropathological mechanisms underlying aims provide insights into involvement disorder, focusing on recent advances molecular landscape governing development humans. Furthermore, we highlight when neurons ASD-associated may play cortico–cerebellar circuits. Finally, discuss improvements protocols for generating organoids recapitulate long maturation this organ. These models, if generated from patient-induced pluripotent stem cells (iPSC), could valuable approach elucidate contribution defective pathology inform diagnostic therapeutic strategies.

Language: Английский

Citations

6
ADNP dysregulates methylation and mitochondrial gene expression in the cerebellum of a Helsmoortel–Van der Aa syndrome autopsy case DOI Creative Commons
Claudio Peter D’Incal, Anke Van Dijck, Joe Ibrahim

et al.

Acta Neuropathologica Communications, Journal Year: 2024, Volume and Issue: 12(1)

Published: April 18, 2024

Abstract Background Helsmoortel–Van der Aa syndrome is a neurodevelopmental disorder in which patients present with autism, intellectual disability, and frequent extra-neurological features such as feeding gastrointestinal problems, visual impairments, cardiac abnormalities. All exhibit heterozygous de novo nonsense or frameshift stop mutations the Activity-Dependent Neuroprotective Protein ( ADNP ) gene, accounting for prevalence of 0.2% all autism cases worldwide. fulfills an essential chromatin remodeling function during brain development. In this study, we investigated cerebellum died 6-year-old male patient c.1676dupA/p.His559Glnfs*3 mutation. Results The clinical presentation was representative syndrome. During his lifespan, he underwent two liver transplantations after child because multiple organ failure. An autopsy performed, various tissue samples were taken further analysis. We performed molecular characterization cerebellum, region involved motor coordination, known its highest expression compared it to age-matched control subject. Importantly, epigenome-wide analysis identified CpG methylation differences pathways causing delay. Interestingly, transcription factor motif enrichment differentially methylated genes showed that binding most significantly enriched. RNA sequencing downregulation WNT signaling pathway autophagy defects possible causes Ultimately, label-free quantification mass spectrometry expressed proteins mitochondrial stress sirtuin amongst others. Protein–protein interaction revealed network including remodelers (ADNP, SMARCC2, HDAC2 YY1), autophagy-related (LAMP1, BECN1 LC3) well key histone deacetylating enzyme SIRT1, energy metabolism. protein SIRT1 biochemically validated through microtubule-end EB1/EB3 by direct co-immunoprecipitation mouse suggesting important mito-epigenetic crosstalk between metabolism linked responses. This supported activity assays stainings patient-derived fibroblasts suggest dysfunctions deficient human brain. Conclusion study forms baseline providing novel insights disease mechanisms By combining multi-omic biochemical approaches, SIRT1-EB1/EB3-ADNP complex may contribute autophagic flux alterations impaired holds promise new therapeutic target. Graphical abstract

Language: Английский

Citations

5
Whole genome sequencing analysis identifies sex differences of familial pattern contributing to phenotypic diversity in autism DOI Creative Commons

Soo-Whee Kim,

Hyeji Lee,

Da Yea Song

et al.

Genome Medicine, Journal Year: 2024, Volume and Issue: 16(1)

Published: Sept. 27, 2024

Language: Английский

Citations

5