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315 results on '"De Rubeis, Silvia"'

1. Neuronal diversity and stereotypy at multiple scales through whole brain morphometry

Author

Liu, Yufeng, Jiang, Shengdian, Li, Yingxin, Zhao, Sujun, Yun, Zhixi, Zhao, Zuo-Han, Zhang, Lingli, Wang, Gaoyu, Chen, Xin, Manubens-Gil, Linus, Hang, Yuning, Gong, Qiaobo, Li, Yuanyuan, Qian, Penghao, Qu, Lei, Garcia-Forn, Marta, Wang, Wei, De Rubeis, Silvia, Wu, Zhuhao, Osten, Pavel, Gong, Hui, Hawrylycz, Michael, Mitra, Partha, Dong, Hongwei, Luo, Qingming, Ascoli, Giorgio A., Zeng, Hongkui, Liu, Lijuan, and Peng, Hanchuan

Published
2024
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2. Nuclear RNA catabolism controls endogenous retroviruses, gene expression asymmetry, and dedifferentiation.

Author

Torre, Denis, Fstkchyan, Yesai, Ho, Jessica, Cheon, Youngseo, Patel, Roosheel, Degrace, Emma, Mzoughi, Slim, Schwarz, Megan, Mohammed, Kevin, Seo, Ji-Seon, Romero-Bueno, Raquel, Demircioglu, Deniz, Hasson, Dan, Tang, Weijing, Mahajani, Sameehan, Campisi, Laura, Zheng, Simin, Song, Won-Suk, Wang, Ying-Chih, Shah, Hardik, Francoeur, Nancy, Soto, Juan, Salfati, Zelda, Weirauch, Matthew, Warburton, Peter, Beaumont, Kristin, Smith, Melissa, Mulder, Lubbertus, Jang, Cholsoon, Lee, Daeyoup, De Rubeis, Silvia, Cobos, Inma, Tam, Oliver, Hammell, Molly, Seldin, Marcus, Sebra, Robert, Rosenberg, Brad, Benner, Chris, Guccione, Ernesto, Basu, Uttiya, Sebastiano, Vittorio, Shi, Yongsheng, Kessenbrock, Kai, Villalta, Sergio, Marazzi, Ivan, and Byun, Minji

Subjects
2CLC, Integrator, MERVL, RNA catabolism, elongation, endogenous retrovirus, non-coding RNA, stem cell, totipotent-like cells, transcription-associated RNA degradation, Endogenous Retroviruses, RNA, Nuclear, Epigenesis, Genetic, Heterochromatin, Gene Expression
Abstract

Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.

Published
2023

4. Skewed X-chromosome inactivation in unsolved neurodevelopmental disease cases can guide re-evaluation For X-linked genes

Author

Giovenino, Chiara, Trajkova, Slavica, Pavinato, Lisa, Cardaropoli, Simona, Pullano, Verdiana, Ferrero, Enza, Sukarova-Angelovska, Elena, Carestiato, Silvia, Salmin, Paola, Rinninella, Antonina, Battaglia, Anthony, Bertoli, Luca, Fadda, Antonio, Palermo, Flavia, Carli, Diana, Mussa, Alessandro, Dimartino, Paola, Bruselles, Alessandro, Froukh, Tawfiq, Mandrile, Giorgia, Pasini, Barbara, De Rubeis, Silvia, Buxbaum, Joseph D., Pippucci, Tommaso, Tartaglia, Marco, Rossato, Marzia, Delledonne, Massimo, Ferrero, Giovanni Battista, and Brusco, Alfredo

Published
2023
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5. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

Author

Fu, Jack M, Satterstrom, F Kyle, Peng, Minshi, Brand, Harrison, Collins, Ryan L, Dong, Shan, Wamsley, Brie, Klei, Lambertus, Wang, Lily, Hao, Stephanie P, Stevens, Christine R, Cusick, Caroline, Babadi, Mehrtash, Banks, Eric, Collins, Brett, Dodge, Sheila, Gabriel, Stacey B, Gauthier, Laura, Lee, Samuel K, Liang, Lindsay, Ljungdahl, Alicia, Mahjani, Behrang, Sloofman, Laura, Smirnov, Andrey N, Barbosa, Mafalda, Betancur, Catalina, Brusco, Alfredo, Chung, Brian HY, Cook, Edwin H, Cuccaro, Michael L, Domenici, Enrico, Ferrero, Giovanni Battista, Gargus, J Jay, Herman, Gail E, Hertz-Picciotto, Irva, Maciel, Patricia, Manoach, Dara S, Passos-Bueno, Maria Rita, Persico, Antonio M, Renieri, Alessandra, Sutcliffe, James S, Tassone, Flora, Trabetti, Elisabetta, Campos, Gabriele, Cardaropoli, Simona, Carli, Diana, Chan, Marcus CY, Fallerini, Chiara, Giorgio, Elisa, Girardi, Ana Cristina, Hansen-Kiss, Emily, Lee, So Lun, Lintas, Carla, Ludena, Yunin, Nguyen, Rachel, Pavinato, Lisa, Pericak-Vance, Margaret, Pessah, Isaac N, Schmidt, Rebecca J, Smith, Moyra, Costa, Claudia IS, Trajkova, Slavica, Wang, Jaqueline YT, Yu, Mullin HC, Cutler, David J, De Rubeis, Silvia, Buxbaum, Joseph D, Daly, Mark J, Devlin, Bernie, Roeder, Kathryn, Sanders, Stephan J, and Talkowski, Michael E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Autism, Brain Disorders, Pediatric, Biotechnology, Intellectual and Developmental Disabilities (IDD), Human Genome, Mental Health, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Mental health, Autism Spectrum Disorder, Autistic Disorder, DNA Copy Number Variations, Genetic Predisposition to Disease, Humans, Mutation, Autism Sequencing Consortium, Broad Institute Center for Common Disease Genomics, iPSYCH-BROAD Consortium, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Some individuals with autism spectrum disorder (ASD) carry functional mutations rarely observed in the general population. We explored the genes disrupted by these variants from joint analysis of protein-truncating variants (PTVs), missense variants and copy number variants (CNVs) in a cohort of 63,237 individuals. We discovered 72 genes associated with ASD at false discovery rate (FDR) ≤ 0.001 (185 at FDR ≤ 0.05). De novo PTVs, damaging missense variants and CNVs represented 57.5%, 21.1% and 8.44% of association evidence, while CNVs conferred greatest relative risk. Meta-analysis with cohorts ascertained for developmental delay (DD) (n = 91,605) yielded 373 genes associated with ASD/DD at FDR ≤ 0.001 (664 at FDR ≤ 0.05), some of which differed in relative frequency of mutation between ASD and DD cohorts. The DD-associated genes were enriched in transcriptomes of progenitor and immature neuronal cells, whereas genes showing stronger evidence in ASD were more enriched in maturing neurons and overlapped with schizophrenia-associated genes, emphasizing that these neuropsychiatric disorders may share common pathways to risk.

Published
2022

6. Author Correction: Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4

Author

Campisi, Laura, Chizari, Shahab, Ho, Jessica SY, Gromova, Anastasia, Arnold, Frederick J, Mosca, Lorena, Mei, Xueyan, Fstkchyan, Yesai, Torre, Denis, Beharry, Cindy, Garcia-Forn, Marta, Jiménez-Alcázar, Miguel, Korobeynikov, Vladislav A, Prazich, Jack, Fayad, Zahi A, Seldin, Marcus M, De Rubeis, Silvia, Bennett, Craig L, Ostrow, Lyle W, Lunetta, Christian, Squatrito, Massimo, Byun, Minji, Shneider, Neil A, Jiang, Ning, La Spada, Albert R, and Marazzi, Ivan

Subjects
General Science & Technology
Published
2022

7. Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4

Author

Campisi, Laura, Chizari, Shahab, Ho, Jessica SY, Gromova, Anastasia, Arnold, Frederick J, Mosca, Lorena, Mei, Xueyan, Fstkchyan, Yesai, Torre, Denis, Beharry, Cindy, Garcia-Forn, Marta, Jiménez-Alcázar, Miguel, Korobeynikov, Vladislav A, Prazich, Jack, Fayad, Zahi A, Seldin, Marcus M, De Rubeis, Silvia, Bennett, Craig L, Ostrow, Lyle W, Lunetta, Christian, Squatrito, Massimo, Byun, Minji, Shneider, Neil A, Jiang, Ning, La Spada, Albert R, and Marazzi, Ivan

Subjects
Biomedical and Clinical Sciences, Immunology, ALS, Rare Diseases, Neurodegenerative, Neurosciences, Brain Disorders, Genetics, 2.1 Biological and endogenous factors, Aetiology, Neurological, Animals, Mice, Amyotrophic Lateral Sclerosis, CD8-Positive T-Lymphocytes, Clone Cells, DNA Helicases, Gene Knock-In Techniques, Motor Neurons, Multifunctional Enzymes, Mutation, RNA Helicases, Humans, General Science & Technology
Abstract

Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control1. ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS1. Although several ALS-associated genes have been shown to affect immune functions2, whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression3. Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene (SETX). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (TEMRA) CD8 T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8 T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded TEMRA CD8 T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8 T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state.

Published
2022

9. Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder

Author

Pavinato, Lisa, Stanic, Jennifer, Barzasi, Marta, Gurgone, Antonia, Chiantia, Giuseppe, Cipriani, Valentina, Eberini, Ivano, Palazzolo, Luca, Di Luca, Monica, Costa, Alex, Marcantoni, Andrea, Biamino, Elisa, Spada, Marco, Hiatt, Susan M., Kelley, Whitley V., Vestito, Letizia, Sisodiya, Sanjay M., Efthymiou, Stephanie, Chand, Prem, Kaiyrzhanov, Rauan, Bruselles, Alessandro, Cardaropoli, Simona, Tartaglia, Marco, De Rubeis, Silvia, Buxbaum, Joseph D., Smedley, Damian, Ferrero, Giovanni Battista, Giustetto, Maurizio, Gardoni, Fabrizio, and Brusco, Alfredo

Published
2023
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10. Episignatures Stratifying Helsmoortel-Van Der Aa Syndrome Show Modest Correlation with Phenotype

Author

Breen, Michael S, Garg, Paras, Tang, Lara, Mendonca, Danielle, Levy, Tess, Barbosa, Mafalda, Arnett, Anne B, Kurtz-Nelson, Evangeline, Agolini, Emanuele, Battaglia, Agatino, Chiocchetti, Andreas G, Freitag, Christine M, Garcia-Alcon, Alicia, Grammatico, Paola, Hertz-Picciotto, Irva, Ludena-Rodriguez, Yunin, Moreno, Carmen, Novelli, Antonio, Parellada, Mara, Pascolini, Giulia, Tassone, Flora, Grice, Dorothy E, Di Marino, Daniele, Bernier, Raphael A, Kolevzon, Alexander, Sharp, Andrew J, Buxbaum, Joseph D, Siper, Paige M, and De Rubeis, Silvia

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, Brain Disorders, Basic Behavioral and Social Science, Intellectual and Developmental Disabilities (IDD), Mental Health, Behavioral and Social Science, Autism, Neurosciences, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Autism Spectrum Disorder, Child, DNA Methylation, Developmental Disabilities, Epigenesis, Genetic, Female, Homeodomain Proteins, Humans, Intellectual Disability, Male, Mutation, Nerve Tissue Proteins, Neurodevelopmental Disorders, Phenotype, Transcriptome, ADNP, DNA methylation, Helsmoortel-Van der Aa syndrome, autism spectrum disorder, biomarkers, epigenetic signature, episignature, genotype-phenotype correlations, intellectual disability, neurodevelopmental disorders, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Helsmoortel-Van der Aa syndrome (HVDAS) is a neurodevelopmental condition associated with intellectual disability/developmental delay, autism spectrum disorder, and multiple medical comorbidities. HVDAS is caused by mutations in activity-dependent neuroprotective protein (ADNP). A recent study identified genome-wide DNA methylation changes in 22 individuals with HVDAS, adding to the group of neurodevelopmental disorders with an epigenetic signature. This methylation signature segregated those with HVDAS into two groups based on the location of the mutations. Here, we conducted an independent study on 24 individuals with HVDAS and replicated the existence of the two mutation-dependent episignatures. To probe whether the two distinct episignatures correlate with clinical outcomes, we used deep behavioral and neurobiological data from two prospective cohorts of individuals with a genetic diagnosis of HVDAS. We found limited phenotypic differences between the two HVDAS-affected groups and no evidence that individuals with more widespread methylation changes are more severely affected. Moreover, in spite of the methylation changes, we observed no profound alterations in the blood transcriptome of individuals with HVDAS. Our data warrant caution in harnessing methylation signatures in HVDAS as a tool for clinical stratification, at least with regard to behavioral phenotypes.

Published
2020

11. Publisher Correction: Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Author

Lim, Elaine T, Uddin, Mohammed, De Rubeis, Silvia, Chan, Yingleong, Kamumbu, Anne S, Zhang, Xiaochang, D’Gama, Alissa M, Kim, Sonia N, Hill, Robert Sean, Goldberg, Arthur P, Poultney, Christopher, Minshew, Nancy J, Kushima, Itaru, Aleksic, Branko, Ozaki, Norio, Parellada, Mara, Arango, Celso, Penzol, Maria J, Carracedo, Angel, Kolevzon, Alexander, Hultman, Christina M, Weiss, Lauren A, Fromer, Menachem, Chiocchetti, Andreas G, Freitag, Christine M, Church, George M, Scherer, Stephen W, Buxbaum, Joseph D, and Walsh, Christopher A

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Autism Sequencing Consortium, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

12. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author

Satterstrom, F Kyle, Kosmicki, Jack A, Wang, Jiebiao, Breen, Michael S, De Rubeis, Silvia, An, Joon-Yong, Peng, Minshi, Collins, Ryan, Grove, Jakob, Klei, Lambertus, Stevens, Christine, Reichert, Jennifer, Mulhern, Maureen S, Artomov, Mykyta, Gerges, Sherif, Sheppard, Brooke, Xu, Xinyi, Bhaduri, Aparna, Norman, Utku, Brand, Harrison, Schwartz, Grace, Nguyen, Rachel, Guerrero, Elizabeth E, Dias, Caroline, Consortium, Autism Sequencing, Aleksic, Branko, Anney, Richard, Barbosa, Mafalda, Bishop, Somer, Brusco, Alfredo, Bybjerg-Grauholm, Jonas, Carracedo, Angel, Chan, Marcus CY, Chiocchetti, Andreas G, Chung, Brian HY, Coon, Hilary, Cuccaro, Michael L, Curró, Aurora, Bernardina, Bernardo Dalla, Doan, Ryan, Domenici, Enrico, Dong, Shan, Fallerini, Chiara, Fernández-Prieto, Montserrat, Ferrero, Giovanni Battista, Freitag, Christine M, Fromer, Menachem, Gargus, J Jay, Geschwind, Daniel, Giorgio, Elisa, González-Peñas, Javier, Guter, Stephen, Halpern, Danielle, Hansen-Kiss, Emily, He, Xin, Herman, Gail E, Hertz-Picciotto, Irva, Hougaard, David M, Hultman, Christina M, Ionita-Laza, Iuliana, Jacob, Suma, Jamison, Jesslyn, Jugessur, Astanand, Kaartinen, Miia, Knudsen, Gun Peggy, Kolevzon, Alexander, Kushima, Itaru, Lee, So Lun, Lehtimäki, Terho, Lim, Elaine T, Lintas, Carla, Lipkin, W Ian, Lopergolo, Diego, Lopes, Fátima, Ludena, Yunin, Maciel, Patricia, Magnus, Per, Mahjani, Behrang, Maltman, Nell, Manoach, Dara S, Meiri, Gal, Menashe, Idan, Miller, Judith, Minshew, Nancy, Montenegro, Eduarda MS, Moreira, Danielle, Morrow, Eric M, Mors, Ole, Mortensen, Preben Bo, Mosconi, Matthew, Muglia, Pierandrea, Neale, Benjamin M, Nordentoft, Merete, Ozaki, Norio, Palotie, Aarno, Parellada, Mara, Passos-Bueno, Maria Rita, Pericak-Vance, Margaret, Persico, Antonio M, and Pessah, Isaac

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Brain Disorders, Mental Health, Pediatric, Human Genome, Clinical Research, Autism, Intellectual and Developmental Disabilities (IDD), Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Mental health, Neurological, Autistic Disorder, Case-Control Studies, Cell Lineage, Cerebral Cortex, Cohort Studies, Exome, Female, Gene Expression Regulation, Developmental, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Mutation, Missense, Neurobiology, Neurons, Phenotype, Sex Factors, Single-Cell Analysis, Exome Sequencing, Autism Sequencing Consortium, iPSYCH-Broad Consortium, autism spectrum disorder, cell type, cytoskeleton, excitatory neurons, excitatory-inhibitory balance, exome sequencing, genetics, inhibitory neurons, liability, neurodevelopment, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n = 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

Published
2020

14. Identification of common genetic risk variants for autism spectrum disorder

Author

Grove, Jakob, Ripke, Stephan, Als, Thomas D, Mattheisen, Manuel, Walters, Raymond K, Won, Hyejung, Pallesen, Jonatan, Agerbo, Esben, Andreassen, Ole A, Anney, Richard, Awashti, Swapnil, Belliveau, Rich, Bettella, Francesco, Buxbaum, Joseph D, Bybjerg-Grauholm, Jonas, Bækvad-Hansen, Marie, Cerrato, Felecia, Chambert, Kimberly, Christensen, Jane H, Churchhouse, Claire, Dellenvall, Karin, Demontis, Ditte, De Rubeis, Silvia, Devlin, Bernie, Djurovic, Srdjan, Dumont, Ashley L, Goldstein, Jacqueline I, Hansen, Christine S, Hauberg, Mads Engel, Hollegaard, Mads V, Hope, Sigrun, Howrigan, Daniel P, Huang, Hailiang, Hultman, Christina M, Klei, Lambertus, Maller, Julian, Martin, Joanna, Martin, Alicia R, Moran, Jennifer L, Nyegaard, Mette, Nærland, Terje, Palmer, Duncan S, Palotie, Aarno, Pedersen, Carsten Bøcker, Pedersen, Marianne Giørtz, dPoterba, Timothy, Poulsen, Jesper Buchhave, Pourcain, Beate St, Qvist, Per, Rehnström, Karola, Reichenberg, Abraham, Reichert, Jennifer, Robinson, Elise B, Roeder, Kathryn, Roussos, Panos, Saemundsen, Evald, Sandin, Sven, Satterstrom, F Kyle, Davey Smith, George, Stefansson, Hreinn, Steinberg, Stacy, Stevens, Christine R, Sullivan, Patrick F, Turley, Patrick, Walters, G Bragi, Xu, Xinyi, Stefansson, Kari, Geschwind, Daniel H, Nordentoft, Merete, Hougaard, David M, Werge, Thomas, Mors, Ole, Mortensen, Preben Bo, Neale, Benjamin M, Daly, Mark J, and Børglum, Anders D

Subjects
Intellectual and Developmental Disabilities (IDD), Human Genome, Pediatric, Brain Disorders, Autism, Biotechnology, Genetics, Mental Health, Prevention, 2.3 Psychological, social and economic factors, Aetiology, 2.1 Biological and endogenous factors, Mental health, Adolescent, Autism Spectrum Disorder, Case-Control Studies, Child, Child, Preschool, Denmark, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Risk Factors, Autism Spectrum Disorder Working Group of the Psychiatric Genomics Consortium, BUPGEN, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, 23andMe Research Team, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.

Published
2019

15. De Novo Sequence and Copy Number Variants Are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis.

Author

Wang, Sheng, Mandell, Jeffrey D, Kumar, Yogesh, Sun, Nawei, Morris, Montana T, Arbelaez, Juan, Nasello, Cara, Dong, Shan, Duhn, Clif, Zhao, Xin, Yang, Zhiyu, Padmanabhuni, Shanmukha S, Yu, Dongmei, King, Robert A, Dietrich, Andrea, Khalifa, Najah, Dahl, Niklas, Huang, Alden Y, Neale, Benjamin M, Coppola, Giovanni, Mathews, Carol A, Scharf, Jeremiah M, Tourette International Collaborative Genetics Study (TIC Genetics), Tourette Syndrome Genetics Southern and Eastern Europe Initiative (TSGENESEE), Tourette Association of America International Consortium for Genetics (TAAICG), Fernandez, Thomas V, Buxbaum, Joseph D, De Rubeis, Silvia, Grice, Dorothy E, Xing, Jinchuan, Heiman, Gary A, Tischfield, Jay A, Paschou, Peristera, Willsey, A Jeremy, and State, Matthew W

Subjects
Tourette International Collaborative Genetics Study, Tourette Syndrome Genetics Southern and Eastern Europe Initiative, Tourette Association of America International Consortium for Genetics, Humans, Tourette Syndrome, Cadherins, Receptors, Cell Surface, Pedigree, Cell Polarity, Adult, Child, Female, Male, DNA Copy Number Variations, TIC Genetics, Tourette disorder, cell polarity, copy number variants, de novo variants, gene discovery, microarray genotyping, multiplex, simplex, whole exome sequencing, Clinical Research, Pediatric, Biotechnology, Genetics, Brain Disorders, Human Genome, Intellectual and Developmental Disabilities (IDD), Neurodegenerative, 2.1 Biological and endogenous factors, Aetiology, Biochemistry and Cell Biology, Medical Physiology
Abstract

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole-exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex, but not multiplex, families; we identify a high-confidence TD risk gene, CELSR3 (cadherin EGF LAG seven-pass G-type receptor 3); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.

Published
2018

16. Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Author

Lim, Elaine T, Uddin, Mohammed, De Rubeis, Silvia, Chan, Yingleong, Kamumbu, Anne S, Zhang, Xiaochang, D'Gama, Alissa M, Kim, Sonia N, Hill, Robert Sean, Goldberg, Arthur P, Poultney, Christopher, Minshew, Nancy J, Kushima, Itaru, Aleksic, Branko, Ozaki, Norio, Parellada, Mara, Arango, Celso, Penzol, Maria J, Carracedo, Angel, Kolevzon, Alexander, Hultman, Christina M, Weiss, Lauren A, Fromer, Menachem, Chiocchetti, Andreas G, Freitag, Christine M, Church, George M, Scherer, Stephen W, Buxbaum, Joseph D, and Walsh, Christopher A

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Brain Disorders, Autism, Genetics, Pediatric, Mental Health, Intellectual and Developmental Disabilities (IDD), 2.1 Biological and endogenous factors, Aetiology, Mental health, Autism Spectrum Disorder, Databases, Genetic, Genetic Predisposition to Disease, Genetic Variation, Humans, Mosaicism, Mutation, Missense, Zygote, Autism Sequencing Consortium, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

Published
2017

17. DDX3X syndrome: From clinical phenotypes to biological insights.

Author

von Mueffling, Alexa, Garcia‐Forn, Marta, and De Rubeis, Silvia

Subjects
RNA helicase, AUTISM spectrum disorders, NEURONAL differentiation, MOVEMENT disorders, GENETIC translation, RNA metabolism
Abstract

DDX3X syndrome is a neurodevelopmental disorder accounting for up to 3% of cases of intellectual disability (ID) and affecting primarily females. Individuals diagnosed with DDX3X syndrome can also present with behavioral challenges, motor delays and movement disorders, epilepsy, and congenital malformations. DDX3X syndrome is caused by mutations in the X‐linked gene DDX3X, which encodes a DEAD‐box RNA helicase with critical roles in RNA metabolism, including mRNA translation. Emerging discoveries from animal models are unveiling a fundamental role of DDX3X in neuronal differentiation and development, especially in the neocortex. Here, we review the current knowledge of genetic and neurobiological mechanisms underlying DDX3X syndrome and their relationship with clinical phenotypes. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Prospective and detailed behavioral phenotyping in DDX3X syndrome

Author

Tang, Lara, Levy, Tess, Guillory, Sylvia, Halpern, Danielle, Zweifach, Jessica, Giserman-Kiss, Ivy, Foss-Feig, Jennifer H., Frank, Yitzchak, Lozano, Reymundo, Belani, Puneet, Layton, Christina, Lerman, Bonnie, Frowner, Emanuel, Breen, Michael S., De Rubeis, Silvia, Kostic, Ana, Kolevzon, Alexander, Buxbaum, Joseph D., Siper, Paige M., and Grice, Dorothy E.

Published
2021
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22. Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes.

Author

He, Xin, Sanders, Stephan, Liu, Li, De Rubeis, Silvia, Lim, Elaine, Sutcliffe, James, Schellenberg, Gerard, Gibbs, Richard, Daly, Mark, Buxbaum, Joseph, State, Matthew, Devlin, Bernie, and Roeder, Kathryn

Subjects
Bayes Theorem, Case-Control Studies, Child Development Disorders, Pervasive, Exome, Genetic Predisposition to Disease, Genetic Variation, Humans, Likelihood Functions, Models, Theoretical, Mutation, Risk Factors, Sequence Analysis, DNA
Abstract

De novo mutations affect risk for many diseases and disorders, especially those with early-onset. An example is autism spectrum disorders (ASD). Four recent whole-exome sequencing (WES) studies of ASD families revealed a handful of novel risk genes, based on independent de novo loss-of-function (LoF) mutations falling in the same gene, and found that de novo LoF mutations occurred at a twofold higher rate than expected by chance. However successful these studies were, they used only a small fraction of the data, excluding other types of de novo mutations and inherited rare variants. Moreover, such analyses cannot readily incorporate data from case-control studies. An important research challenge in gene discovery, therefore, is to develop statistical methods that accommodate a broader class of rare variation. We develop methods that can incorporate WES data regarding de novo mutations, inherited variants present, and variants identified within cases and controls. TADA, for Transmission And De novo Association, integrates these data by a gene-based likelihood model involving parameters for allele frequencies and gene-specific penetrances. Inference is based on a Hierarchical Bayes strategy that borrows information across all genes to infer parameters that would be difficult to estimate for individual genes. In addition to theoretical development we validated TADA using realistic simulations mimicking rare, large-effect mutations affecting risk for ASD and show it has dramatically better power than other common methods of analysis. Thus TADAs integration of various kinds of WES data can be a highly effective means of identifying novel risk genes. Indeed, application of TADA to WES data from subjects with ASD and their families, as well as from a study of ASD subjects and controls, revealed several novel and promising ASD candidate genes with strong statistical support.

Published
2013

23. Recessive gene disruptions in autism spectrum disorder

Author

Doan, Ryan N., Lim, Elaine T., De Rubeis, Silvia, Betancur, Catalina, Cutler, David J., Chiocchetti, Andreas G., Overman, Lynne M., Soucy, Aubrie, Goetze, Susanne, Autism Sequencing Consortium, Freitag, Christine M., Daly, Mark J., Walsh, Christopher A., Buxbaum, Joseph D., and Yu, Timothy W.

Published
2019
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24. Differential usage of transcriptional start sites and polyadenylation sites in FMR1 premutation alleles

Author

Tassone, Flora, De Rubeis, Silvia, Carosi, Chiara, La Fata, Giorgio, Serpa, Gisele, Raske, Christopher, Willemsen, Rob, Hagerman, Paul J, and Bagni, Claudia

Subjects
Intellectual and Developmental Disabilities (IDD), Brain Disorders, Neurodegenerative, Mental Health, Neurosciences, Fragile X Syndrome, Genetics, Rare Diseases, Underpinning research, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Neurological, 3' Untranslated Regions, 5' Untranslated Regions, Alleles, Animals, Base Sequence, Brain, Fragile X Mental Retardation Protein, Humans, Mice, Molecular Sequence Data, Mutation, Polyadenylation, Transcription Initiation Site, Trinucleotide Repeats, Untranslated Regions, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Developmental Biology
Abstract

5'- and 3'-untranslated regions (UTRs) are important regulators of gene expression and play key roles in disease progression and susceptibility. The 5'-UTR of the fragile X mental retardation 1 (FMR1) gene contains a CGG repeat element that is expanded (>200 CGG repeats; full mutation) and methylated in fragile X syndrome (FXS), the most common form of inherited intellectual disability (ID) and known cause of autism. Significant phenotypic involvement has also emerged in some individuals with the premutation (55-200 CGG repeats), including fragile X-associated premature ovarian insufficiency (FXPOI) in females, and the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), in older adult carriers. Here, we show that FMR1 mRNA in human and mouse brain is expressed as a combination of multiple isoforms that use alternative transcriptional start sites and different polyadenylation sites. Furthermore, we have identified a novel human transcription start site used in brain but not in lymphoblastoid cells, and have detected FMR1 isoforms generated through the use of both canonical and non-canonical polyadenylation signals. Importantly, in both human and mouse, a specific regulation of the UTRs is observed in brain of FMR1 premutation alleles, suggesting that the transcript variants may play a role in premutation-related pathologies.

Published
2011

25. Full-Spectrum Neuronal Diversity and Stereotypy through Whole Brain Morphometry

Author

Peng, Hanchuan, primary, Liu, Yufeng, additional, Jiang, Shengdian, additional, Li, Yingxin, additional, Zhao, Sujun, additional, Yun, Zhixi, additional, Zhao, Zuo-Han, additional, Zhang, Lingli, additional, Wang, Gaoyu, additional, Chen, Xin, additional, Manubens-Gil, Linus, additional, Hang, Yuning, additional, Garcia-forn, Marta, additional, Wang, Wei, additional, De Rubeis, Silvia, additional, Wu, Zhuhao, additional, Osten, Pavel, additional, Gong, Hui, additional, Hawrylycz, Michael, additional, Mitra, Partha, additional, Dong, Hong-Wei, additional, Luo, Qingming, additional, Ascoli, Giorgio, additional, Zeng, Hongkui, additional, and Liu, Lijuan, additional

Published
2023
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26. Translational derepression of Elavl4 isoforms at their alternative 5′ UTRs determines neuronal development

Author

Popovitchenko, Tatiana, Park, Yongkyu, Page, Nicholas F., Luo, Xiaobing, Krsnik, Zeljka, Liu, Yuan, Salamon, Iva, Stephenson, Jessica D., Kraushar, Matthew L., Volk, Nicole L., Patel, Sejal M., Wijeratne, H. R. Sagara, Li, Diana, Suthar, Kandarp S., Wach, Aaron, Sun, Miao, Arnold, Sebastian J., Akamatsu, Wado, Okano, Hideyuki, Paillard, Luc, Zhang, Huaye, Buyske, Steven, Kostovic, Ivica, De Rubeis, Silvia, Hart, Ronald P., and Rasin, Mladen-Roko

Published
2020
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27. Altered striatal actin dynamics drives behavioral inflexibility in a mouse model of fragile X syndrome

Author

Mercaldo, Valentina, primary, Vidimova, Barbora, additional, Gastaldo, Denise, additional, Fernández, Esperanza, additional, Lo, Adrian C., additional, Cencelli, Giulia, additional, Pedini, Giorgia, additional, De Rubeis, Silvia, additional, Longo, Francesco, additional, Klann, Eric, additional, Smit, August B., additional, Grant, Seth G.N., additional, Achsel, Tilmann, additional, and Bagni, Claudia, additional

Published
2023
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28. The clinical and molecular spectrum of the KDM6B-related neurodevelopmental disorder

Author

Rots, Dmitrijs, primary, Jakub, Taryn E., additional, Keung, Crystal, additional, Jackson, Adam, additional, Banka, Siddharth, additional, Pfundt, Rolph, additional, de Vries, Bert B.A., additional, van Jaarsveld, Richard H., additional, Hopman, Saskia M.J., additional, van Binsbergen, Ellen, additional, Valenzuela, Irene, additional, Hempel, Maja, additional, Bierhals, Tatjana, additional, Kortüm, Fanny, additional, Lecoquierre, Francois, additional, Goldenberg, Alice, additional, Hertz, Jens Michael, additional, Andersen, Charlotte Brasch, additional, Kibæk, Maria, additional, Prijoles, Eloise J., additional, Stevenson, Roger E., additional, Everman, David B., additional, Patterson, Wesley G., additional, Meng, Linyan, additional, Gijavanekar, Charul, additional, De Dios, Karl, additional, Lakhani, Shenela, additional, Levy, Tess, additional, Wagner, Matias, additional, Wieczorek, Dagmar, additional, Benke, Paul J., additional, Lopez Garcia, María Soledad, additional, Perrier, Renee, additional, Sousa, Sergio B., additional, Almeida, Pedro M., additional, Simões, Maria José, additional, Isidor, Bertrand, additional, Deb, Wallid, additional, Schmanski, Andrew A., additional, Abdul-Rahman, Omar, additional, Philippe, Christophe, additional, Bruel, Ange-Line, additional, Faivre, Laurence, additional, Vitobello, Antonio, additional, Thauvin, Christel, additional, Smits, Jeroen J., additional, Garavelli, Livia, additional, Caraffi, Stefano G., additional, Peluso, Francesca, additional, Davis-Keppen, Laura, additional, Platt, Dylan, additional, Royer, Erin, additional, Leeuwen, Lisette, additional, Sinnema, Margje, additional, Stegmann, Alexander P.A., additional, Stumpel, Constance T.R.M., additional, Tiller, George E., additional, Bosch, Daniëlle G.M., additional, Potgieter, Stephanus T., additional, Joss, Shelagh, additional, Splitt, Miranda, additional, Holden, Simon, additional, Prapa, Matina, additional, Foulds, Nicola, additional, Douzgou, Sofia, additional, Puura, Kaija, additional, Waltes, Regina, additional, Chiocchetti, Andreas G., additional, Freitag, Christine M., additional, Satterstrom, F. Kyle, additional, De Rubeis, Silvia, additional, Buxbaum, Joseph, additional, Gelb, Bruce D., additional, Branko, Aleksic, additional, Kushima, Itaru, additional, Howe, Jennifer, additional, Scherer, Stephen W., additional, Arado, Alessia, additional, Baldo, Chiara, additional, Patat, Olivier, additional, Bénédicte, Demeer, additional, Lopergolo, Diego, additional, Santorelli, Filippo M., additional, Haack, Tobias B., additional, Dufke, Andreas, additional, Bertrand, Miriam, additional, Falb, Ruth J., additional, Rieß, Angelika, additional, Krieg, Peter, additional, Spranger, Stephanie, additional, Bedeschi, Maria Francesca, additional, Iascone, Maria, additional, Josephi-Taylor, Sarah, additional, Roscioli, Tony, additional, Buckley, Michael F., additional, Liebelt, Jan, additional, Dagli, Aditi I., additional, Aten, Emmelien, additional, Hurst, Anna C.E., additional, Hicks, Alesha, additional, Suri, Mohnish, additional, Aliu, Ermal, additional, Naik, Sunil, additional, Sidlow, Richard, additional, Coursimault, Juliette, additional, Nicolas, Gaël, additional, Küpper, Hanna, additional, Petit, Florence, additional, Ibrahim, Veyan, additional, Top, Deniz, additional, Di Cara, Francesca, additional, Louie, Raymond J., additional, Stolerman, Elliot, additional, Brunner, Han G., additional, Vissers, Lisenka E.L.M., additional, Kramer, Jamie M., additional, and Kleefstra, Tjitske, additional

Published
2023
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29. Altered striatal actin dynamics drives behavioral inflexibility in a mouse model of fragile X syndrome

Author

Mercaldo, Valentina, Vidimova, Barbora, Gastaldo, Denise, Fernández, Esperanza, Lo, Adrian C., Cencelli, Giulia, Pedini, Giorgia, De Rubeis, Silvia, Longo, Francesco, Klann, Eric, Smit, August B., Grant, Seth G.N., Achsel, Tilmann, Bagni, Claudia, Mercaldo, Valentina, Vidimova, Barbora, Gastaldo, Denise, Fernández, Esperanza, Lo, Adrian C., Cencelli, Giulia, Pedini, Giorgia, De Rubeis, Silvia, Longo, Francesco, Klann, Eric, Smit, August B., Grant, Seth G.N., Achsel, Tilmann, and Bagni, Claudia

Abstract

The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is fragile X syndrome (FXS), an NDD caused by the absence of the functional RNA-binding protein FMRP. Here, we demonstrate how the brain region-specific composition of postsynaptic density (PSD) contributes to FXS. In the striatum, the FXS mouse model shows an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, which is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.

Published
2023
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30. CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD

Author

Genetica, Genetica Sectie Genoomdiagnostiek, Pavinato, Lisa, Delle Vedove, Andrea, Carli, Diana, Ferrero, Marta, Carestiato, Silvia, Howe, Jennifer L, Agolini, Emanuele, Coviello, Domenico A, van de Laar, Ingrid, Au, Ping Yee Billie, Di Gregorio, Eleonora, Fabbiani, Alessandra, Croci, Susanna, Mencarelli, Maria Antonietta, Bruno, Lucia P, Renieri, Alessandra, Veltra, Danai, Sofocleous, Christalena, Faivre, Laurence, Mazel, Benoit, Safraou, Hana, Denommé-Pichon, Anne Sophie, van Slegtenhorst, Marjon A, Giesbertz, Noor, van Jaarsveld, Richard H, Childers, Anna, Rogers, R Curtis, Novelli, Antonio, De Rubeis, Silvia, Buxbaum, Joseph D, Scherer, Stephen W, Ferrero, Giovanni Battista, Wirth, Brunhilde, Brusco, Alfredo, Genetica, Genetica Sectie Genoomdiagnostiek, Pavinato, Lisa, Delle Vedove, Andrea, Carli, Diana, Ferrero, Marta, Carestiato, Silvia, Howe, Jennifer L, Agolini, Emanuele, Coviello, Domenico A, van de Laar, Ingrid, Au, Ping Yee Billie, Di Gregorio, Eleonora, Fabbiani, Alessandra, Croci, Susanna, Mencarelli, Maria Antonietta, Bruno, Lucia P, Renieri, Alessandra, Veltra, Danai, Sofocleous, Christalena, Faivre, Laurence, Mazel, Benoit, Safraou, Hana, Denommé-Pichon, Anne Sophie, van Slegtenhorst, Marjon A, Giesbertz, Noor, van Jaarsveld, Richard H, Childers, Anna, Rogers, R Curtis, Novelli, Antonio, De Rubeis, Silvia, Buxbaum, Joseph D, Scherer, Stephen W, Ferrero, Giovanni Battista, Wirth, Brunhilde, and Brusco, Alfredo

Published
2023

32. Polygenic risk score-based phenome-wide association study identifies novel associations for Tourette syndrome

Author

Jain, Pritesh, Miller-Fleming, Tyne, Topaloudi, Apostolia, Yu, Dongmei, Drineas, Petros, Georgitsi, Marianthi, Yang, Zhiyu, Rizzo, Renata, Müller-Vahl, Kirsten R., Tumer, Zeynep, Mol Debes, Nanette, Hartmann, Andreas, Depienne, Christel, Worbe, Yulia, Mir, Pablo, Cath, Danielle C., Boomsma, Dorret I., Roessner, Veit, Wolanczyk, Tomasz, Janik, Piotr, Szejko, Natalia, Zekanowski, Cezary, Barta, Csaba, Nemoda, Zsofia, Tarnok, Zsanett, Buxbaum, Joseph D., Grice, Dorothy, Glennon, Jeffrey, Stefansson, Hreinn, Hengerer, Bastian, Benaroya-Milshtein, Noa, Cardona, Francesco, Hedderly, Tammy, Heyman, Isobel, Huyser, Chaim, Morer, Astrid, Mueller, Norbert, Munchau, Alexander, Plessen, Kerstin J., Porcelli, Cesare, Walitza, Susanne, Schrag, Anette, Martino, Davide, Dietrich, Andrea, Mathews, Carol A., Scharf, Jeremiah M., Hoekstra, Pieter J., Davis, Lea K., Paschou, Peristera, Als, Thomas D., Aschauer, Harald, Atzmon, Gil, Bækvad-Hansen, Matie, Barr, Cathy L., Barzilai, Nir, Batterson, James R., Batterson, Robert, Benarroch, Fortu, Berlin, Cheston, Boberg, Julia, Bodmer, Benjamin, Bohnenpoll, Julia, Børglum, Anders D., Brown, Lawrence W., Bruun, Ruth, Budman, Cathy L., Buckner, Randy L., Bybjerg-Grauholm, Jonas, Cheon, Keun-Ah, Chouinard, Sylvain, Coffey, Barbara J., Coppola, Giovanni, Crowley, James J., Dahl, Niklas, Darrow, Sabrina M., Daly, Mark J., De Rubeis, Silvia, Dion, Yves, Djurfeldt, Diana R., Domenech-Salgado, Laura, Eapen, Valsamma, Elzerman, Lonneke, Fernandez, Thomas V., Freimer Carolin Fremer, Nelson B., Garcia-Delgar, Blanca, Garrido, Marcos, Gilbert, Donald L., Giusti-Rodriguez, Paola, Grados, Marco, Greenberg, Erica, Grove, Jakob, Hagstrom, Julie, Halvorsen, Matt, Hansen, Bjarne, Haavik, Jan, Hebebrand, Johannes, Heiman, Gary A., Herrera, Luis, Hinney, Anke, Hirschtritt, Matthew E., Sul, Jae Hoon, Hong, Hyun Ju, Hougaard, David M., Huang, Alden Y., Ibanez-Gomez, Laura, Ivankovic, Franjo, Jankovic, Joseph, Karlsson, Elinor K., Kaprio, Jakko A., Kim, Young Key, Kim, Young-Shin, King, Robert A., Knowles, James A., Koh, Yun-Joo, Kook, Sodham, Khalifa, Najah, Konstantinidis, Anastasios, Kuperman, Samuel, Kurlan, Roger, Kvale, Gerd, Leckman, James, Lee, Paul C., Leventhal, Bennett, Lichtenstein, Paul, Lindbald-Toh, Kerstin, Lowe, Thomas, Ludolph, Andrea, da Silva, Claudia Luhrs, Luðvigsson, Pétur, Luykx, Jurjen, Lyon, Gholson J., Mahjani, Behrang, Maras, Athanasios, Mataix-Cols, David, Mattheisen, Manuel, Malaty, Irene A., McMahon, William M., McQuillin, Andrew, Meier, Sandra M., Moessner, Rainald, Mortensen, Preben B., Mors, Ole, Mudgal, Poorva, Nagy, Peter, Naarden, Allan, Neale, Benjamin M., Nawaz, Muhammad S., Nissen, Judith Becker, Nöthen Merete Nordentoft, Markus M., Nordsletten, Ashley E., Okun, Michael S., Ophoff, Roel, Osiecki, Lisa, Palotie, Aarno, Palviainen, Teemu P., Pato Michele T. Pato, Carlos N., Pittenger, Christopher, Pollak, Yehuda, Posthuma, Danielle, Ramos, Eliana, Reichert, Jennifer, Robertson, Mary M., Roffman, Joshua L., Rouleau, Guy, Rück, Christian, Sæmundsen, Evald, Samuels, Jack, Sandin, Sven, Sandor, Paul, Schlögelhofer, Monika, Shin, Eun-Young, Singer, Harvey S., Smit, Jan, Smoller, Jordan W., State, Matthew, Solem, Stian, Song, Dong-Ho, Song, Jungeun, Stamenkovic, Mara, Stefansson, Kári, Strom, Nora, Stuhrmann, Manfred, Szatkiewicz, Jin, Szymanska, Urszula, Tischfield, Jay A., Tsetsos, Fotis, Thorarensen, Ólafur, Tubing, Jennifer, Visscher, Frank, Wagner, Michael, Wanderer, Sina, Wang, Sheng, Werge, Thomas, Willsey, Jeremy A., Wolancyk, Tomasz, Woods, Douglas W., Woods, Martin, Zelaya, Ivette, Zinner, Samuel H., Apter, Alan, Ball, Juliane, Bognar, Emese, Buse, Judith, Vela, Marta Correa, Fremer, Carolin, Gulisano, Mariangela, Hagen, Annelieke, Hagstrøm, Julie, Madruga-Garrido, Marcos, Pellico, Alessandra, Ruhrman, Daphna, Schnell, Jaana, Silvestri, Paola Rosaria, Skov, Liselotte, Steinberg, Tamar, Gloor, Friederike Tagwerker, Turner, Victoria L., Weidinger, Elif, Alexander, John, Aranyi, Tamas, Buisman, Wim R., Buitelaar, Jan K., Driessen, Nicole, Fan, Siyan, Forde, Natalie J., Gerasch, Sarah, van den Heuvel, Odile A., Jespersgaard, Cathrine, Kanaan, Ahmad S., Möller, Harald E., Nespoli, Ester, Pagliaroli, Luca, Poelmans, Geert, Pouwels, Petra J. W., Rizzo, Francesca, Veltman, Dick J., van der Werf, Ysbrand D., Widomska, Joanna, Zilhäo, Nuno R., Biological Psychology, Amsterdam Reproduction & Development, APH - Mental Health, APH - Methodology, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Dynamic Earth and Resources, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)

Subjects
Male, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Medizin, Autism Spectrum Disorder/genetics, Cellular and Molecular Neuroscience, Psychiatry and Mental health, Diabetes Mellitus, Type 2, Risk Factors, Diabetes Mellitus, Tourette Syndrome/genetics, Humans, Female, Attention Deficit Disorder with Hyperactivity/genetics, Type 2, Biological Psychiatry
Abstract

Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders. Tourette Syndrome (TS) is a complex neurodevelopmental disorder characterized by vocal and motor tics lasting more than a year. It is highly polygenic in nature with both rare and common previously associated variants. Epidemiological studies have shown TS to be correlated with other phenotypes, but large-scale phenome wide analyses in biobank level data have not been performed to date. In this study, we used the summary statistics from the latest meta-analysis of TS to calculate the polygenic risk score (PRS) of individuals in the UK Biobank data and applied a Phenome Wide Association Study (PheWAS) approach to determine the association of disease risk with a wide range of phenotypes. A total of 57 traits were found to be significantly associated with TS polygenic risk, including multiple psychosocial factors and mental health conditions such as anxiety disorder and depression. Additional associations were observed with complex non-psychiatric disorders such as Type 2 diabetes, heart palpitations, and respiratory conditions. Cross-disorder comparisons of phenotypic associations with genetic risk for other childhood-onset disorders (e.g.: attention deficit hyperactivity disorder [ADHD], autism spectrum disorder [ASD], and obsessive-compulsive disorder [OCD]) indicated an overlap in associations between TS and these disorders. ADHD and ASD had a similar direction of effect with TS while OCD had an opposite direction of effect for all traits except mental health factors. Sex-specific PheWAS analysis identified differences in the associations with TS genetic risk between males and females. Type 2 diabetes and heart palpitations were significantly associated with TS risk in males but not in females, whereas diseases of the respiratory system were associated with TS risk in females but not in males. This analysis provides further evidence of shared genetic and phenotypic architecture of different complex disorders.

Published
2023
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35. Skewed X-chromosome Inactivation in Unsolved Neurodevelopmental Disease Cases Can Guide Re-evaluation for X-linked Genes

Author

Brusco, Alfredo, primary, Giovenino, Chiara, additional, Trajkova, Slavica, additional, Pavinato, Lisa, additional, Cardaropoli, Simona, additional, Pullano, Verdiana, additional, Sukarova-Angelovska, Elena, additional, Carestiato, Silvia, additional, Salmin, Paola, additional, Rinninella, Antonina, additional, Battaglia, Anthony, additional, Bertoli, Luca, additional, Fadda, Antonio, additional, Palermo, Flavia, additional, Carli, Diana, additional, Mussa, Alessandro, additional, Dimartino, Paola, additional, Bruselles, Alessandro, additional, froukh, Tawfiq, additional, Mandrile, Giorgia, additional, Pasini, Barbara, additional, De Rubeis, Silvia, additional, Buxbaum, Joseph, additional, Pippucci, Tommaso, additional, Tartaglia, Marco, additional, Rossato, Marzia, additional, Delledonne, Massimo, additional, and Ferrero, Giovanni Battista, additional

Published
2022
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40. CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD

Author

Pavinato, Lisa, primary, Delle Vedove, Andrea, additional, Carli, Diana, additional, Ferrero, Marta, additional, Carestiato, Silvia, additional, Howe, Jennifer L, additional, Agolini, Emanuele, additional, Coviello, Domenico A, additional, van de Laar, Ingrid, additional, Au, Ping Yee Billie, additional, Di Gregorio, Eleonora, additional, Fabbiani, Alessandra, additional, Croci, Susanna, additional, Mencarelli, Maria Antonietta, additional, Bruno, Lucia P, additional, Renieri, Alessandra, additional, Veltra, Danai, additional, Sofocleous, Christalena, additional, Faivre, Laurence, additional, Mazel, Benoit, additional, Safraou, Hana, additional, Denommé-Pichon, Anne-Sophie, additional, van Slegtenhorst, Marjon A, additional, Giesbertz, Noor, additional, van Jaarsveld, Richard H, additional, Childers, Anna, additional, Rogers, R Curtis, additional, Novelli, Antonio, additional, De Rubeis, Silvia, additional, Buxbaum, Joseph D, additional, Scherer, Stephen W, additional, Ferrero, Giovanni Battista, additional, Wirth, Brunhilde, additional, and Brusco, Alfredo, additional

Published
2022
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41. Functional analysis of TLK2 variants and their proximal interactomes implicates impaired kinase activity and chromatin maintenance defects in their pathogenesis

Author

Pavinato, Lisa, Villamor-Paya, Marina, Sanchiz-Calvo, Maria, Andreoli, Cristina, Gay, Marina, Vilaseca, Marta, Arauz-Garofalo, Gianluca, Ciolfi, Andrea, Bruselles, Alessandro, Pippucci, Tommaso, Prota, Valentina, Carli, Diana, Giorgio, Elisa, Radio, Francesca Clementina, Antona, Vincenzo, Giuffre, Mario, Ranguin, Kara, Colson, Cindy, De Rubeis, Silvia, Dimartino, Paola, Buxbaum, Joseph D., Ferrero, Giovanni Battista, Tartaglia, Marco, Martinelli, Simone, Stracker, Travis H., Brusco, Alfredo, Pavinato, Lisa, Villamor-Paya, Marina, Sanchiz-Calvo, Maria, Andreoli, Cristina, Gay, Marina, Vilaseca, Marta, Arauz-Garofalo, Gianluca, Ciolfi, Andrea, Bruselles, Alessandro, Pippucci, Tommaso, Prota, Valentina, Carli, Diana, Giorgio, Elisa, Radio, Francesca Clementina, Antona, Vincenzo, Giuffre, Mario, Ranguin, Kara, Colson, Cindy, De Rubeis, Silvia, Dimartino, Paola, Buxbaum, Joseph D., Ferrero, Giovanni Battista, Tartaglia, Marco, Martinelli, Simone, Stracker, Travis H., and Brusco, Alfredo

Abstract

Introduction The Tousled-like kinases 1 and 2 (TLK1 and TLK2) are involved in many fundamental processes, including DNA replication, cell cycle checkpoint recovery and chromatin remodelling. Mutations in TLK2 were recently associated with 'Mental Retardation Autosomal Dominant 57' (MRD57, MIM# 618050), a neurodevelopmental disorder characterised by a highly variable phenotype, including mild-to-moderate intellectual disability, behavioural abnormalities, facial dysmorphisms, microcephaly, epilepsy and skeletal anomalies. Methods We re-evaluate whole exome sequencing and array-CGH data from a large cohort of patients affected by neurodevelopmental disorders. Using spatial proteomics (BioID) and single-cell gel electrophoresis, we investigated the proximity interaction landscape of TLK2 and analysed the effects of p.(Asp551Gly) and a previously reported missense variant (c.1850C>T; p.(Ser617Leu)) on TLK2 interactions, localisation and activity. Results We identified three new unrelated MRD57 families. Two were sporadic and caused by a missense change (c.1652A>G; p.(Asp551Gly)) or a 39 kb deletion encompassing TLK2, and one was familial with three affected siblings who inherited a nonsense change from an affected mother (c.1423G>T; p.(Glu475Ter)). The clinical phenotypes were consistent with those of previously reported cases. The tested mutations strongly impaired TLK2 kinase activity. Proximal interactions between TLK2 and other factors implicated in neurological disorders, including CHD7, CHD8, BRD4 and NACC1, were identified. Finally, we demonstrated a more relaxed chromatin state in lymphoblastoid cells harbouring the p.(Asp551Gly) variant compared with control cells, conferring susceptibility to DNA damage. Conclusion Our study identified novel TLK2 pathogenic variants, confirming and further expanding the MRD57-related phenotype. The molecular characterisation of missense variants increases our knowledge about TLK2 function and provides new insights into its rol

Published
2022

45. Developmental and Behavioral Phenotypes in a Mouse Model of DDX3X Syndrome

Author

Boitnott, Andrea, primary, Garcia-Forn, Marta, additional, Ung, Dévina C., additional, Niblo, Kristi, additional, Mendonca, Danielle, additional, Park, Yeaji, additional, Flores, Michael, additional, Maxwell, Sylvia, additional, Ellegood, Jacob, additional, Qiu, Lily R., additional, Grice, Dorothy E., additional, Lerch, Jason P., additional, Rasin, Mladen-Roko, additional, Buxbaum, Joseph D., additional, Drapeau, Elodie, additional, and De Rubeis, Silvia, additional

Published
2021
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46. Two knockdown models of the autism genes SYNGAP1 and SHANK3 in zebrafish produce similar behavioral phenotypes associated with embryonic disruptions of brain morphogenesis

Author

Kozol, Robert A., Cukier, Holly N., Zou, Bing, Mayo, Vera, De Rubeis, Silvia, Cai, Guiqing, Griswold, Anthony J., Whitehead, Patrice L., Haines, Jonathan L., Gilbert, John R., Cuccaro, Michael L., Martin, Eden R., Baker, James D., Buxbaum, Joseph D., Pericak-Vance, Margaret A., and Dallman, Julia E.

Published
2015
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47. Additional file 1 of How rare and common risk variation jointly affect liability for autism spectrum disorder

Author

Klei, Lambertus, McClain, Lora Lee, Mahjani, Behrang, Panayidou, Klea, De Rubeis, Silvia, Grahnat, Anna-Carin Säll, Karlsson, Gun, Lu, Yangyi, Melhem, Nadine, Xu, Xinyi, Reichenberg, Abraham, Sandin, Sven, Hultman, Christina M., Buxbaum, Joseph D., Roeder, Kathryn, and Devlin, Bernie

Subjects
musculoskeletal diseases
Abstract

Additional file 1. Supplementary information for joint effects of rare and common variation.

Published
2021
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48. Additional file 2 of Prevalence and phenotypic impact of rare potentially damaging variants in autism spectrum disorder

Author

Mahjani, Behrang, De Rubeis, Silvia, Gustavsson Mahjani, Christina, Mulhern, Maureen, Xu, Xinyi, Klei, Lambertus, Satterstrom, F. Kyle, Fu, Jack, Talkowski, Michael E., Reichenberg, Abraham, Sandin, Sven, Hultman, Christina M., Grice, Dorothy E., Roeder, Kathryn, Devlin, Bernie, and Buxbaum, Joseph D.

Subjects
viruses, mental disorders
Abstract

Additional file 2: Table S3. ICD codes used in this study. Table S4. Comorbidities and birth characteristics of the probands that were not genotyped or sequenced. Table S7. Odds ratios for comorbidities and birth characteristics probands with potentially damaging SNV, DGR list. Table S8. Odds ratios for comorbidities and birth characteristics of probands with potentially damaging CNV or SNV as defined for the additional analysis (see text).

Published
2021
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49. KCNK18 Biallelic Variants Associated with Intellectual Disability and Neurodevelopmental Disorders Alter TRESK Channel Activity

Author

Pavinato, Lisa, Nematian-Ardestani, Ehsan, Zonta, Andrea, De Rubeis, Silvia, Buxbaum, Joseph, Mancini, Cecilia, Bruselles, Alessandro, Tartaglia, Marco, Pessia, Mauro, Tucker, Stephen J., D'Adamo, Maria Cristina, Brusco, Alfredo, Pavinato, Lisa, Nematian-Ardestani, Ehsan, Zonta, Andrea, De Rubeis, Silvia, Buxbaum, Joseph, Mancini, Cecilia, Bruselles, Alessandro, Tartaglia, Marco, Pessia, Mauro, Tucker, Stephen J., D'Adamo, Maria Cristina, and Brusco, Alfredo

Abstract

The TWIK-related spinal cord potassium channel (TRESK) is encoded by KCNK18, and variants in this gene have previously been associated with susceptibility to familial migraine with aura (MIM #613656). A single amino acid substitution in the same protein, p.Trp101Arg, has also been associated with intellectual disability (ID), opening the possibility that variants in this gene might be involved in different disorders. Here, we report the identification of KCNK18 biallelic missense variants (p.Tyr163Asp and p.Ser252Leu) in a family characterized by three siblings affected by mild-to-moderate ID, autism spectrum disorder (ASD) and other neurodevelopment-related features. Functional characterization of the variants alone or in combination showed impaired channel activity. Interestingly, Ser252 is an important regulatory site of TRESK, suggesting that alteration of this residue could lead to additive downstream effects. The functional relevance of these mutations and the observed co-segregation in all the affected members of the family expand the clinical variability associated with altered TRESK function and provide further insight into the relationship between altered function of this ion channel and human disease.

Published
2021

50. Expanding the clinical phenotype of the ultra-rare Skraban-Deardorff syndrome: Two novel individuals with WDR26 loss-of-function variants and a literature review

Author

Pavinato, Lisa, Trajkova, Slavica, Grosso, Enrico, Giorgio, Elisa, Bruselles, Alessandro, Radio, Francesca Clementina, Pippucci, Tommaso, Dimartino, Paola, Tartaglia, Marco, Petlichkovski, Aleksandar, De Rubeis, Silvia, Buxbaum, Joseph, Ferrero, Giovanni Battista, Keller, Roberto, Brusco, Alfredo, Pavinato, Lisa, Trajkova, Slavica, Grosso, Enrico, Giorgio, Elisa, Bruselles, Alessandro, Radio, Francesca Clementina, Pippucci, Tommaso, Dimartino, Paola, Tartaglia, Marco, Petlichkovski, Aleksandar, De Rubeis, Silvia, Buxbaum, Joseph, Ferrero, Giovanni Battista, Keller, Roberto, and Brusco, Alfredo

Abstract

De novo variants in the WDR26 gene leading to haploinsufficiency have recently been associated with Skraban-Deardorff syndrome. This condition is an ultra-rare autosomal dominant neurodevelopmental disorder characterized by a broad range of clinical signs, including intellectual disability (ID), developmental delay (DD), seizures, abnormal facial features, feeding difficulties, and minor skeletal anomalies. Currently, 18 cases have been reported in the literature and for only 15 of them a clinical description is available. Here, we describe a child with Skraban-Deardorff syndrome associated with the WDR26 pathogenic de novo variant NM_025160.6:c.69dupC, p.(Gly24ArgfsTer48), and an adult associated with the pathogenic de novo variant c.1076G > A, p.(Trp359Ter). The adult patient was a 29-year-old female with detailed information on clinical history and pharmacological treatments since birth, providing an opportunity to map disease progression and patient management. By comparing our cases with published reports of Skraban-Deardorff syndrome, we provide a genetic and clinical summary of this ultrarare condition, describe the clinical management from childhood to adult age, and further expand on the clinical phenotype.

Published
2021

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