Genomic architecture of autism from comprehensive whole-genome sequence annotation

Trost, Brett; Thiruvahindrapuram, Bhooma; Chan, Ada J.S.; Engchuan, Worrawat; Higginbotham, Edward J; Howe, Jennifer; Loureiro, Lívia O.; Reuter, Miriam S.; Roshandel, Delnaz; Whitney, J. Andrew; Zarrei, Mehdi; Bookman, Matthew; Somerville, Cherith; Shaath, Rulan; Abdi, Mona; Aliyev, Elbay; Patel, Rohan; Nalpathamkalam, Thomas; Pellecchia, Giovanna; Omar, Hamdan; Kaur, Gaganjot; Wang, Zhuozhi; MacDonald, Jeffrey R.; Wei, John; Sung, Wilson W L; Lamoureux, Sylvia; Hoang, Ny; Selvanayagam, Thanuja; Deflaux, Nicole; Geng, Melissa; Ghaffari, Siavash; Bates, John E.; Young, Edwin J.; Ding, Qiliang; Shum, Carole; D’Abate, Lia; Bradley, Clarrisa A.; Rutherford, Annabel; Aguda, Vernie; Apresto, Beverly; Chen, Nan; Desai, Sachin; Du, Xiaoyan; Fong, Matthew L.Y.; Pullenayegum, Sanjeev; Samler, Kozue; Wang, Ting; Ho, Karen; Paton, Tara; Pereira, Sérgio Luiz; Herbrick, Jo-Anne; Wintle, Richard F.; Fuerth, Jonathan; Noppornpitak, Juti; Ward, Heather; Magee, Patrick; Baz, Ayman Al; Kajendirarajah, Usanthan; Kapadia, Sharvari; Vlasblom, Jim; Valluri, Monica; Green, Joseph; Seifer, Vicki; Quirbach, Morgan; Rennie, Olivia; Kelley, Elizabeth; Masjedi, Nina; Lord, Catherine; Szego, Michael J.; Zawati, Ma’n H.; Lang, Michael; Strug, Lisa J.; Marshall, Christian R.; Costain, Gregory; Calli, Kristina; Iaboni, Alana; Yusuf, Afiqah; Ambrozewicz, Patricia; Gallagher, Louise; Amaral, David G.; Brian, Jessica; Elsabbagh, Mayada; Georgiades, Stelios; Messinger, Daniel S.; Ozonoff, Sally J; Sebat, Jonathan; Sjaarda, Calvin; Smith, Isabel M.; Szatmári, Péter; Zwaigenbaum, Lonnie; Kushki, Azadeh; Frazier, Thomas; Vorstman, Jacob; Fakhro, Khalid; Fernandez, Bridget A.; Lewis, M E Suzanne; Weksberg, Rosanna; Fiume, Marc; Yuen, Ryan K.C.; Anagnostou, Evdokia; Sondheimer, Neal; Glazer, David; Hartley, Dean M.; Scherer, Stephen W.

doi:10.1016/j.cell.2022.10.009

Cited by 98 publications

(100 citation statements)

References 118 publications

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“…It has been further categorized into gene expression regulation groups and more frequently mutated in NDDs-ascertained cohorts. In the latest release of whole-genome sequencing (WGS) data from the Autism Speaks MSSNG resource ( https://research.mss.ng , 5,100 individuals with ASD and 6,212 non-ASD parents and siblings), CTNNB1 (FDR 0.001 to 0.0001) was further identified as one of the 134 ASD-associated genes ( 54 ). Based on another single-cell nuclei transcriptomic data ( 55 ), 615 NDDs candidate genes (FDR < 0.05) had been identified and CTNNB1 was recognized as high-risk ASD genes in 46,612 trios by de novo enrichment analysis.…”

Section: Ctnnb1-related Ndds In Human Studiesmentioning

confidence: 99%

CTNNB1 in neurodevelopmental disorders

Zhuang

Wang

et al. 2023

Front. Psychiatry

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CTNNB1 is the gene that encodes β-catenin which acts as a key player in the Wnt signaling pathway and regulates cellular homeostasis. Most CTNNB1-related studies have been mainly focused on its role in cancer. Recently, CTNNB1 has also been found involved in neurodevelopmental disorders (NDDs), such as intellectual disability, autism, and schizophrenia. Mutations of CTNNB1 lead to the dysfunction of the Wnt signaling pathway that regulates gene transcription and further disturbs synaptic plasticity, neuronal apoptosis, and neurogenesis. In this review, we discuss a wide range of aspects of CTNNB1 and its physiological and pathological functions in the brain. We also provide an overview of the most recent research regarding CTNNB1 expression and its function in NDDs. We propose that CTNNB1 would be one of the top high-risk genes for NDDs. It could also be a potential therapeutic target for the treatment of NDDs.

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Section: Ctnnb1-related Ndds In Human Studiesmentioning

confidence: 99%

CTNNB1 in neurodevelopmental disorders

Zhuang

Wang

et al. 2023

Front. Psychiatry

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“…In recent years, huge effort has been devoted to studying the genetic basis of neurodevelopmental disorders. Exome sequencing of tens of thousands of affected individuals has identified numerous genes that are mutated in these conditions [44][45][46] . Despite this progress, understanding of the molecular mechanisms perturbed in many www.nature.com/scientificreports/ of these disorders remains sparse, and even in cases where detailed understanding is available, such knowledge has not been translated into pharmacological interventions.…”

Section: Discussionmentioning

confidence: 99%

A screen for MeCP2-TBL1 interaction inhibitors using a luminescence-based assay

Alexander-Howden

Zhang

Sloot

et al. 2023

Sci Rep

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Understanding the molecular pathology of neurodevelopmental disorders should aid the development of therapies for these conditions. In MeCP2 duplication syndrome (MDS)—a severe autism spectrum disorder—neuronal dysfunction is caused by increased levels of MeCP2. MeCP2 is a nuclear protein that binds to methylated DNA and recruits the nuclear co-repressor (NCoR) complex to chromatin via an interaction with the WD repeat-containing proteins TBL1 and TBLR1. The peptide motif in MeCP2 that binds to TBL1/TBLR1 is essential for the toxicity of excess MeCP2 in animal models of MDS, suggesting that small molecules capable of disrupting this interaction might be useful therapeutically. To facilitate the search for such compounds, we devised a simple and scalable NanoLuc luciferase complementation assay for measuring the interaction of MeCP2 with TBL1/TBLR1. The assay allowed excellent separation between positive and negative controls, and had low signal variance (Z-factor = 0.85). We interrogated compound libraries using this assay in combination with a counter-screen based on luciferase complementation by the two subunits of protein kinase A (PKA). Using this dual screening approach, we identified candidate inhibitors of the interaction between MeCP2 and TBL1/TBLR1. This work demonstrates the feasibility of future screens of large compound collections, which we anticipate will enable the development of small molecule therapeutics to ameliorate MDS.

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“…Using MRI data from the study entry time point (2-3½ years of age) 33 , we identified 11/89 WGS sequenced individuals in the APP cohort that met the criteria for ASD-DM, defined as a cerebral volume to height ratio >1.5 standard deviations above the mean compared to TD age-matched controls. Through a collaboration with MSSNG 35,36 , WGS and variant identification/annotation was performed for the autistic probands and a subset of family members, for which we also had blood specimens, including six trios and five non-trio probands yielding over 200 thousand variants. From this, we identified two exonic, de novo, LoF variants from trio families, including one singlenucleotide variant (SNV) splice-site variant impacting RYR3 and one 109-kbp duplication of YTHDF2 and GMEB1.…”

Section: Asd-dm Candidate Gene Discoverymentioning

confidence: 99%

A Subphenotype-to-Genotype Approach Reveals Disproportionate Megalencephaly Autism Risk Genes

Nishizaki

Mariano

et al. 2022

Preprint

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Among autistic individuals, a subphenotype with brain enlargement disproportionate to height (autism with disproportionate megalencephaly, or ASD-DM) seen at three years of age is associated with co-occurring intellectual disability and poorer prognoses later in life. However, many of the genes contributing to ASD-DM have yet to be delineated. In this study, we aim to identify additional ASD-DM associated genes to better define the genetic etiology of this subphenotype of autism. Here, we expand the previously studied sample size of ASD-DM individuals ten-fold by including probands from the Autism Phenome Project and Simons Simplex Collection, totaling 766 autistic individuals meeting the criteria for megalencephaly or macrocephaly and revealing 153 candidate ASD-DM genes harboring de novo protein-impacting variants. Our findings include thirteen high confidence autism genes and seven genes previously associated with DM. Five impacted genes have previously been associated with both autism and DM, including CHD8 and PTEN. By performing functional network analysis, we also narrowed in on additional candidate genes, including one previously implicated in ASD-DM (PIK3CA) as well as 184 additional genes previously implicated in ASD or DM alone. Using zebrafish as a model, we performed CRISPR gene editing to generate knockout animals for seven of candidate genes and assessed head-size and induced seizure activity differences. From this analysis, we identified significant morphological changes in zebrafish knockout models of two genes, ythdf2 and ryr3. While zebrafish knockout mutants model haploinsufficiency of assayed genes, we identified a de novo tandem duplication impacting YTHDF2 in an ASD-DM proband. Therefore, we also transiently overexpressed YTHDF2 by injection of in vitro transcribed human mRNA to simulate the patient-identified duplication. Following this, we observed increased head and brain size in the YTHDF2 overexpression zebrafish matching that of the proband, providing a functional link between YTHDF2 mutations and DM. Though discovery of additional mutations of ASD-DM candidate genes are required in order to fully elucidate the genetics associated with this severe form of autism, our study was able to provide support for YTHDF2 as a novel putative ASD-DM gene.

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Genomic architecture of autism from comprehensive whole-genome sequence annotation

Cited by 98 publications

References 118 publications

CTNNB1 in neurodevelopmental disorders

CTNNB1 in neurodevelopmental disorders

A screen for MeCP2-TBL1 interaction inhibitors using a luminescence-based assay

A Subphenotype-to-Genotype Approach Reveals Disproportionate Megalencephaly Autism Risk Genes

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