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1. Whole Genome Sequencing to Resolve the Genomic Architecture of Cerebral Palsy in a Canadian Cohort (P13-9.003)

Author

Maryam Oskoui, Mehdi Zarrei, Worrawat Engchuan, Neal Sondheimer, Bhooma Thiruv, Edward Higginbotham, Ritesh Thapa, Tarannum Behlim, Sabrina Aimola, John Wei, Prakroothi Danthi, Giovanna Pellecchia, Karen Ho, Jill de Rijke, Jennifer Howe, Thomas Nalpathamkalam, Roozbeh Manshaei, Joseph Whitney, Rohan Patel, Omar Hamdan, Rulan Shaath, Shannon Knights, Brett Trost, Dawa Samdup, ANNA MCCORMICK, Carolyn Hunt, Adam Kirton, Anne Kawamura, Ronit Mesterman, Jan Willem Gorter, Nomazulu Dlamini, Daniele Merico, Ryan Yuen, Michael Shevell, Dimitri Stavropoulos, Richard Wintle, Darcy Fehlings, and Stephen Scherer

Published
2023
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4. Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism

Author

Gail E. Herman, Jennifer Reichert, Camilla Stoltenberg, Stephen Sanders, Menachem Fromer, Branko Aleksic, Julian Maller, Rachel Nguyen, Utku Norman, J. Jay Gargus, Donna M. Werling, David J. Cutler, Silvia De Rubeis, Kathryn Roeder, Ryan N. Doan, Sherif Gerges, Joseph D. Buxbaum, Per Magnus, Patrick Turley, Moyra Smith, Isaac N. Pessah, Rebecca J. Schmidt, Chiara Fallerini, Michael E. Talkowski, Carla Lintas, Pål Surén, Paige M. Siper, Duncan S. Palmer, Timothy W. Yu, Michael S. Breen, Sven Sandin, Esben Agerbo, Rich Belliveau, Antonio M. Persico, Elaine Cristina Zachi, Matthew W. State, Karoline Teufel, Margaret A. Pericak-Vance, Caitlin E. Carey, Ryan Collins, Lambertus Klei, Lara Tang, Mads V. Hollegaard, Ole Mors, Iuliana Ionita-Laza, Elisa Giorgio, Astanand Jugessur, Gerry Schellenberg, Christopher A. Walsh, A. Ercument Cicek, Caroline Dias, Gun Peggy Knudsen, Louise Gallagher, Elise B. Robinson, Abraham Reichenberg, Judith Miller, Ashley Dumont, Flora Tassone, Grace Schwartz, Peter Szatmari, Jacqueline I. Goldstein, Evelise Riberi, Brian H.Y. Chung, Stephen W. Scherer, Fátima Lopes, Jesslyn Jamison, Thomas Werge, Mara Parellada, Gabriela Soares, Hilary Coon, Shan Dong, Terho Lehtimäki, Norio Ozaki, Lauren A. Weiss, Susan L. Santangelo, F. Kyle Satterstrom, Daniel P. Howrigan, Emily Hansen-Kiss, Anders D. Børglum, Vivek Appadurai, Maria Rita Passos-Bueno, Hailiang Huang, Marcus C.Y. Chan, Eric M. Morrow, Stephen J. Guter, Catalina Betancur, Ditte Demontis, Matthew W. Mosconi, Pierandrea Muglia, Joanna Martin, Jack A. Kosmicki, Christine M. Freitag, Suma Jacob, W. Ian Lipkin, Angel Carracedo, Mark J. Daly, Andreas G. Chiocchetti, Eduarda Montenegro M. de Souza, Carsten Bøcker Pedersen, Isabela Maya Wahys Silva, Elizabeth E. Guerrero, Mafalda Barbosa, A. Jeremy Willsey, Maureen Mulhern, Claire Churchhouse, Raymond K. Walters, Timothy Poterba, Alessandra Renieri, Emilie M. Wigdor, Lauren M. Schmitt, Jennifer L. Moran, Mullin H.C. Yu, Edwin H. Cook, Jiebiao Wang, Behrang Mahjani, Kaitlin E. Samocha, Kaija Puura, Xin He, Ezra Susser, Aarno Palotie, Bernardo Dalla Bernardina, Montserrat Fernández-Prieto, Thomas Damm Als, Mykyta Artomov, Emma Wilkinson, Mads E. Hauberg, Enrico Domenici, Joon Yong An, Christine Søholm Hansen, Somer L. Bishop, Idan Menashe, So Lun Lee, Marianne Giørtz Pedersen, Alfredo Brusco, Nancy J. Minshew, Michael E. Zwick, Jesper Buchhave Poulsen, Elaine T. Lim, Benjamin M. Neale, Harrison Brand, Danielle Halpern, Elisabetta Trabetti, Alexander Kolevzon, Christine Stevens, Aurora Currò, Miia Kaartinen, Gal Meiri, Richard Anney, Søren Dalsgaard, Minshi Peng, Kimberly Chambert, Brooke Sheppard, Yunin Ludena, James S. Sutcliffe, Marie Bækvad-Hansen, Xinyi Xu, Audrey Thurm, Itaru Kushima, Michael Gill, Irva Hertz-Picciotto, Jonatan Pallesen, Stephan Ripke, Dara S. Manoach, Giovanni Battista Ferrero, Nell Maltman, Michael L. Cuccaro, David M. Hougaard, Javier González-Peñas, Wesley K. Thompson, Felecia Cerrato, Danielle de Paula Moreira, Jonas Bybjerg-Grauholm, Alicia R. Martin, Merete Nordentoft, John A. Sweeney, Alfonso Buil, Tarjinder Singh, Bernie Devlin, Jakob Grove, Daniel H. Geschwind, Manuel Mattheisen, Patrícia Maciel, Preben Bo Mortensen, Andrew J. Schork, Ryan Yuen, Christina M. Hultman, Maria del Pilar Trelles, Aparna Bhaduri, Sabine Schlitt, Diego Lopergolo, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Carnegie Mellon University [Pittsburgh] (CMU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of California [San Francisco] (UCSF), University of California, Korea University [Seoul], The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus University [Aarhus], Center for Genomics and Personalized Medicine [Aarhus, Denmark] (CGPM), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research [San Francisco, CA, USA], Bilkent University [Ankara], University of California [Irvine] (UCI), Medical Investigation of Neurodevelopmental Disorders Institute [Davis, CA, USA] (MIND), University of California [Davis] (UC Davis), University of California-University of California, Boston Children's Hospital, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of Illinois [Chicago] (UIC), University of Illinois System, Trinity College Dublin, Vanderbilt University School of Medicine [Nashville], National Institute of Mental Health (NIMH), Emory University School of Medicine, Emory University [Atlanta, GA], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), University of Helsinki-University of Helsinki, Autism Sequencing Consortium : Branko Aleksic, Richard Anney, Mafalda Barbosa, Somer Bishop, Alfredo Brusco, Jonas Bybjerg-Grauholm, Angel Carracedo, Marcus C.Y. Chan, Andreas G. Chiocchetti, Brian H.Y. Chung, Hilary Coon, Michael L. Cuccaro, Aurora Curro´ , Bernardo Dalla Bernardina, Ryan Doan, Enrico Domenici, Shan Dong, Chiara Fallerini, Montserrat Ferna´ ndez-Prieto, Giovanni Battista Ferrero, Christine M. Freitag, Menachem Fromer, J. Jay Gargus, Daniel Geschwind, Elisa Giorgio, Javier Gonza´ lez-Pen˜ as, Stephen Guter, Danielle Halpern, Emily HansenKiss, Xin He, Gail E. Herman, Irva Hertz-Picciotto, David M. Hougaard, Christina M. Hultman, Iuliana Ionita-Laza, Suma Jacob, Jesslyn Jamison, Astanand Jugessur, Miia Kaartinen, Gun Peggy Knudsen, Alexander Kolevzon, Itaru Kushima, So Lun Lee, Terho Lehtima¨ ki, Elaine T. Lim, Carla Lintas, W. Ian Lipkin, Diego Lopergolo, Fa´ tima Lopes, Yunin Ludena, Patricia Maciel, Per Magnus, Behrang Mahjani, Nell Maltman, Dara S. Manoach, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Eduarda M.S. Montenegro, Danielle Moreira, Eric M. Morrow, Ole Mors, Preben Bo Mortensen, Matthew Mosconi, Pierandrea Muglia, Benjamin M. Neale, Merete Nordentoft, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio M. Persico, Isaac Pessah, Kaija Puura, Abraham Reichenberg, Alessandra Renieri, Evelise Riberi, Elise B. Robinson, Kaitlin E. Samocha, Sven Sandin, Susan L. Santangelo, Gerry Schellenberg, Stephen W. Scherer, Sabine Schlitt, Rebecca Schmidt, Lauren Schmitt, Isabela M.W. Silva, Tarjinder Singh, Paige M. Siper, Moyra Smith, Gabriela Soares, Camilla Stoltenberg, Pa˚ l Suren, Ezra Susser, John Sweeney, Peter Szatmari, Lara Tang, Flora Tassone, Karoline Teufel, Elisabetta Trabetti, Maria del Pilar Trelles, Christopher A. Walsh, Lauren A. Weiss, Thomas Werge, Donna M. Werling, Emilie M. Wigdor, Emma Wilkinson, A. Jeremy Willsey, Timothy W. Yu, Mullin H.C. Yu, Ryan Yuen, and Elaine Zachi. and iPSYCH-Broad Consortium : e Esben Agerbo, Thomas Damm Als, Vivek Appadurai, Marie Bækvad-Hansen, Rich Belliveau, Alfonso Buil, Caitlin E. Carey, Felecia Cerrato, Kimberly Chambert, Claire Churchhouse, Søren Dalsgaard, Ditte Demontis, Ashley Dumont, Jacqueline Goldstein, Christine S. Hansen, Mads Engel Hauberg, Mads V. Hollegaard, Daniel P. Howrigan, Hailiang Huang, Julian Maller, Alicia R. Martin, Joanna Martin, Manuel Mattheisen, Jennifer Moran, Jonatan Pallesen, Duncan S. Palmer, Carsten Bøcker Pedersen, Marianne Giørtz Pedersen, Timothy Poterba, Jesper Buchhave Poulsen, Stephan Ripke, Andrew J. Schork, Wesley K. Thompson, Patrick Turley, and Raymond K. Walters., Norman, Utku, Çicek, A. Ercüment, Betancur, Catalina, University of California [San Francisco] (UC San Francisco), University of California (UC), University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki

Subjects
Male, INTELLECTUAL DISABILITY, genetic structures, MESH: Neurons, Genome-wide association study, [SDV.GEN] Life Sciences [q-bio]/Genetics, Whole Exome Sequencing, Cohort Studies, 0302 clinical medicine, Gene Frequency, Neurobiology, MESH: Gene Expression Regulation, Developmental, Spectrum disorder, Exome, Developmental, genetics, Copy-number variation, excitatory-inhibitory balance, MESH: Cohort Studies, Exome sequencing, Genetics, Cerebral Cortex, Neurons, 0303 health sciences, MESH: Exome, autism spectrum disorder, cell type, cytoskeleton, excitatory neurons, exome sequencing, inhibitory neurons, liability, neurodevelopment, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, Phenotype, Autism spectrum disorder, Female, Single-Cell Analysis, AGED 8 YEARS, MESH: Autistic Disorder, UNITED-STATES, GENETIC RISK, Biology, MESH: Phenotype, behavioral disciplines and activities, SAND DOMAIN, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Sex Factors, MESH: Sex Factors, MESH: Whole Exome Sequencing, MESH: Neurobiology, mental disorders, medicine, MESH: Gene Frequency, Humans, Cell Lineage, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Autistic Disorder, Allele frequency, Case-Control Studies, Mutation, Missense, Gene Expression Regulation, Developmental, SPECTRUM DISORDER, COPY NUMBER VARIATION, 030304 developmental biology, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Cell Lineage, medicine.disease, MESH: Male, MESH: Cerebral Cortex, DISABILITIES MONITORING NETWORK, Gene Expression Regulation, DE-NOVO MUTATIONS, Mutation, Autism, Missense, MESH: Female, 030217 neurology & neurosurgery, MESH: Single-Cell Analysis
Abstract

International audience; 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
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5. Genome-wide repeat expansions in complex disorders: beyond the coding sequence

Author

Ryan Yuen

Subjects
Tandem repeat, Autism spectrum disorder, Missing heritability problem, medicine, Coding region, Identification (biology), Human genome, Computational biology, Heritability, Biology, medicine.disease, Genome
Abstract

Identification of underlying genetic factors has provided important information on the functional pathways involved in many of complex disorders. However, the casual genetic factors identified in many complex disorders so far generally confer less risk than expected from the empirical estimates of their heritability. Tandem DNA repeats make up around 6% of the human genome and have been associated with more than 40 monogenic disorders, but their involvement in complex disorders is largely unknown. I will present our novel approach to detect genome-wide tandem repeat expansions. This approach has led to the identification of rare tandem repeat expansions contributing to autism spectrum disorder and other related conditions. It provides a model to search for missing heritability in other complex disorders.

Published
2020
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6. 82. INCREASED BURDEN OF RARE TANDEM REPEAT EXPANSIONS IN SCHIZOPHRENIA

Author

NaEshia Ancalade, Patrick F. Sullivan, Martilias S. Farrell, Paola Giusti, Jia Wen, Christina M. Hultman, Brett Trost, Ryan Yuen, Worrawat Engchuan, Patrik K. E. Magnusson, Ulf Gyllensten, and Jin P. Szatkiewicz

Subjects
Pharmacology, Psychiatry and Mental health, Neurology, Tandem repeat, business.industry, Schizophrenia (object-oriented programming), Medicine, Pharmacology (medical), Neurology (clinical), business, Bioinformatics, Biological Psychiatry
Published
2021
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7. Gestational Age-Dependent Variations in Effects of Prophylactic Indomethacin on Brain Injury and Intestinal Injury

Author

Mosarrat Qureshi, Prakesh S. Shah, Dalal Abdelgadir, Xiang Y. Ye, Jehier Afifi, Ryan Yuen, Sara Calderon Crossman, Barbara Taylor, Khorshid Mohammad, Bruno Piedboeuf, Khalid Aziz, Marc Beltempo, Jaideep Kanungo, Joseph Ting, Zenon Cieslak, Rebecca Sherlock, Ayman Abou Mehrem, Jennifer Toye, Carlos Fajardo, Zarin Kalapesi, Jaya Bodani, Koravangattu Sankaran, Lannae Strueby, Mary Seshia, Deepak Louis, Ruben Alvaro, Amit Mukerji, Orlando Da Silva, Mohammad Adie, Kyong-Soon Lee, Eugene Ng, Brigitte Lemyre, Faiza Khurshid, Ermelinda Pelausa, Keith Barrington, Anie Lapoint, Guillaume Ethier, Christine Drolet, Martine Claveau, Valerie Bertelle, Edith Masse, Roderick Canning, Hala Makary, Cecil Ojah, Luis Monterrosa, Julie Emberley, Andrzej Kajetanowicz, and Shoo K. Lee

Subjects
Pediatrics, medicine.medical_specialty, business.industry, Birth weight, Confounding, Gestational age, Retrospective cohort study, medicine.disease, 3. Good health, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, 030225 pediatrics, Intensive care, Pediatrics, Perinatology and Child Health, Necrotizing enterocolitis, Severity of illness, Medicine, 030212 general & internal medicine, business
Abstract

Objective To evaluate the impact of prophylactic indomethacin on early death ( Study design This was a multicenter, retrospective cohort study of neonates (n = 12 515) born at 236/7 weeks of gestational age, admitted to neonatal intensive care units participating in the Canadian Neonatal Network who received prophylactic indomethacin started within the first 12 hours after birth. Univariate and multivariate analysis compared the composite outcomes of early death or severe neurologic injury and early death or spontaneous intestinal perforation. Results Of 12 515 eligible neonates, 1435 (11.5%) were exposed to prophylactic indomethacin; recipients were of lower gestational age and birth weight and had greater severity of illness (Score of Neonatal Acute Physiology with Perinatal Extension) on admission compared with nonrecipients. After we adjusted for confounders, prophylactic indomethacin was associated with reduced odds of early death or severe neurologic injury and early death or spontaneous intestinal perforation in neonates born at 23-24 weeks of gestational age. However, prophylactic indomethacin was associated with increased odds of early mortality or spontaneous intestinal perforation for neonates born at 26-28 weeks of gestational age. Conclusions Prophylactic indomethacin use was associated with benefit in neonates born at 23-24 weeks of gestational age, but with harm at 26-28 weeks of gestational age. Given the observation of significantly improved survival, a randomized controlled trial is needed to investigate the effect of prophylactic indomethacin in babies born at 23-25 weeks of gestational age.

Published
2021
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8. Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size (vol 142, pg 2617, 2019)

Author

Le Duc, Diana, Giulivi, Cecilia, Hiatt, Susan M., Napoli, Eleonora, Panoutsopoulos, Alexios, Crescenzo, Angelo Harlan, Kotzaeridou, Urania, Syrbe, Steffen, Anagnostou, Evdokia, Azage, Meron, Bend, Renee, Begtrup, Amber, Brown, Natasha J., Buttner, Benjamin, Cho, Megan T., Cooper, Gregory M., Doering, Jan H., Dubourg, Christele, Everman, David B., Hildebrand, Michael S., Santos, Francis Jeshira Reynoso, Kellam, Barbara, Keller-Ramey, Jennifer, Lemke, Johannes R., Liu, Shuxi, Niyazov, Dmitriy, Payne, Katelyn, Person, Richard, Quelin, Chloe, Schnur, Rhonda E., Smith, Brooke T., Strober, Jonathan, Walker, Susan, Wallis, Mathew, Walsh, Laurence, Yang, Sandra, Ryan Yuen, Ziegler, Andreas, Sticht, Heinrich, Pride, Michael C., Orosco, Lori, Martinez-Cerdeno, Veronica, Silverman, Jill L., Crawley, Jacqueline N., Scherer, Stephen W., Zarbalis, Konstantinos S., and Jamra, Rami

Subjects
Neurology & Neurosurgery, Psychology and Cognitive Sciences, Medical and Health Sciences
Published
2019

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

Author

Evelise Riber, Suma Jacob, Isabela Maya Wahys Silva, Edwin H. Cook, Jennifer Reichert, Merete Nordentoft, Jiebiao Wang, Kaitlin E. Samocha, John A. Sweeney, Elaine Cristina Zachi, Brooke Sheppard, Yunin Ludena, Maureen Mulhern, Lambertus Klei, Christina M. Hultman, Branko Aleksic, Paige M. Siper, Nell Maltman, Fátima Lopes, Jesslyn Jamison, Astanand Jugessur, Timothy W. Yu, F. Kyle Satterstrom, Tarjinder Singh, Bernie Devlin, Per Magnus, Mara Parellada, Louise Gallagher, Christine Stevens, Susan L. Santangelo, David J. Cutler, Shan Dong, Margaret A. Pericak-Vance, Norio Ozaki, Camilla Stoltenberg, Matthew W. State, Emma Wilkinson, Lauren A. Weiss, Michael L. Cuccaro, Stephen Sanders, Aparna Bhaduri, Brian H.Y. Chung, Maria del Pilar Trelles, Ezra Susser, Somer L. Bishop, Catalina Betancur, Donna M. Werling, Sabine Schlitt, Diego Lopergolo, Abraham Reichenberg, Judith Miller, Gabriela Soares, Karoline Teufel, David M. Hougaard, Enrico Domenici, Thomas Werge, Terho Lehtimäki, Sherif Gerges, Audrey Thurm, Emily Hansen-Kiss, Christopher T. Walsh, Michael Gill, Maria Rita Passos-Bueno, Aurora Currò, Utku Norman, Nancy J. Minshew, Harrison Brand, Elisa Giorgio, A. Ercument Cicek, Elaine T. Lim, Joseph D. Buxbaum, Chiara Fallerini, Caroline Dias, Miia Kaartinen, Gal Meiri, Rachel Nguyen, Isaac N. Pessah, J. Jay Gargus, Ryan N. Doan, Minshi Peng, Matthew W. Mosconi, Elizabeth E. Guerrero, Michael E. Talkowski, Iuliana Ionita-Laza, Carla Lintas, Gerry Schellenberg, Alessandra Renieri, Marcus C.Y. Chan, Stephen J. Guter, Danielle Halpern, Javier González-Peñas, Flora Tassone, So Lun Lee, Elise B. Robinson, Alfredo Brusco, Danielle de Paula Moreira, Bernardo Dalla Bernardina, Benjamin M. Neale, Gun Peggy Knudsen, Behrang Mahjani, Peter Szatmari, Elisabetta Trabetti, Lauren M. Schmitt, Kaija Puura, Mykyta Artomov, Rebecca J. Schmidt, Michael S. Breen, Mark J. Daly, Joon Yong An, Dara S. Manoach, Grace Schwartz, Hilary Coon, Christine M. Freitag, Andreas G. Chiocchetti, Eduarda Montenegro M. de Souza, Ryan L. Collins, Mafalda Barbosa, Emilie M. Wigdor, Montserrat Fernández-Prieto, Stephen W. Scherer, Anders D. Børglum, Jack A. Kosmicki, W. Ian Lipkin, Mullin H.C. Yu, Michael E. Zwick, Irva Hertz-Picciotto, Kathryn Roeder, Moyra Smith, Gail E. Herman, James S. Sutcliffe, Xinyi Xu, A. Jeremy Willsey, Alexander Kolevzon, Itaru Kushima, Menachem Fromer, Jakob Grove, Patrícia Maciel, Preben Bo Mortensen, Xin He, Aarno Palotie, Silvia De Rubeis, Idan Menashe, Jonas Bybjerg-Grauholm, Pål Surén, Antonio M. Persico, Ole Mors, Sven Sandin, Lara Tang, Eric M. Morrow, Pierandrea Muglia, Angel Carracedo, Ryan Yuen, and Giovanni Battista Ferrero

Subjects
False discovery rate, Regulation of gene expression, Genetics, 0303 health sciences, Biology, medicine.disease, Phenotype, 03 medical and health sciences, 0302 clinical medicine, Autism spectrum disorder, mental disorders, medicine, Autism, Copy-number variation, Gene, 030217 neurology & neurosurgery, Exome sequencing, 030304 developmental biology
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 Bayesian framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate ≤ 0.1. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained for severe neurodevelopmental delay, while 53 show higher frequencies in individuals ascertained for ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most of the 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 human cortex single-cell gene expression data, expression of risk genes is enriched in both excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory/inhibitory imbalance underlying ASD.

Published
2019
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10. The Autism Sequencing Consortium: Large-Scale, High-Throughput Sequencing in Autism Spectrum Disorders

Author

Joseph Buxbaum, Stephen W. Scherer, Kyriacos Markianos, Jay Shendure, Stephan Sanders, Maria Chahrour, Kathryn Roeder, Jeffrey Barrett, and Ryan Yuen

Subjects
Genetics, Neuroscience(all), General Neuroscience, Scale (chemistry), High-Throughput Nucleotide Sequencing, Computational biology, Biology, medicine.disease, Article, DNA sequencing, Genetic architecture, Child Development Disorders, Pervasive, Child, Preschool, Consensus Sequence, mental disorders, medicine, Humans, Autism, Child, Genetic Association Studies, Gene Discovery
Abstract

Research during the past decade has seen significant progress in the understanding of the genetic architecture of autism spectrum disorders (ASDs), with gene discovery accelerating as the characterization of genomic variation has become increasingly comprehensive. At the same time, this research has highlighted ongoing challenges. Here we address the enormous impact of high-throughput sequencing (HTS) on ASD gene discovery, outline a consensus view for leveraging this technology, and describe a large multisite collaboration developed to accomplish these goals. Similar approaches could prove effective for severe neurodevelopmental disorders more broadly.

Published
2012
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14. Widespread DNA hypomethylation at gene enhancer and low CpG density regions in placentas associated with early-onset preeclampsia

Author

Brendan Lim, Peter von Dadelszen, Wendy P. Robinson, Deborah E. McFadden, John D. Blair, and Ryan Yuen

Subjects
Genetics, Microarray, Obstetrics and Gynecology, Methylation, Biology, medicine.disease, Preeclampsia, Andrology, Reproductive Medicine, CpG site, DNA methylation, medicine, Epigenetics, Gene, Developmental Biology, DNA hypomethylation
Abstract

s / Placenta 34 (2013) A1–A99 A86 P2.88. WIDESPREAD DNA HYPOMETHYLATION AT GENE ENHANCER AND LOW CPG DENSITY REGIONS IN PLACENTAS ASSOCIATEDWITH EARLY-ONSET PREECLAMPSIA John Blair , Ryan Yuen , Brendan Lim , Deborah McFadden , Peter von Dadelszen , Wendy Robinson 1 University of British Columbia, Vancouver, BC, Canada; University of Toronto, Toronto, ON, Canada Preeclampsia is a serious complication of pregnancy that can affect both maternal and fetal outcomes. Early-onset preeclampsia (EOPET) is a severe form of preeclampsia that is associated with altered physiological characteristics and gene expression in the placenta. DNA methylation is a relatively stable epigenetic modification to DNA that can reflect gene expression, and can provide insight into the mechanisms underlying such expression changes. Objectives: We sought to profile DNA methylation changes in EOPET to better characterize the pathology underlying this condition and the relationship to clinical features. Methods: DNA methylation was profiled in placentas from 20 EOPET and 20-gestational age matched control pregnancies using the Infinium HumanMethylation450 Beadchip. This analysis was followed up using the HT-12v4 Expression BeadChip microarray, bisulfite pyrosequencing and bioinformatic analysis. Results: We identified 38,840 CpG sites with significant (FDR 12.5% methylation difference compared to the gestational age-matched normotensive controls. Significant sites were enriched at the enhancers and low CpG density regions of the associated genes and the majority (74.5%) of these sites were hypomethylated in EOPET. No stratification of the EOPET DNA methylation profile was apparent based on presence/absence of intrauterine growth restriction (IUGR) or severe proteinuria. CpG sites from four genes relevant to preeclampsia (INHBA, BHLHE40, SLC2A1, and ADAM12) were followed up using bisulfite pyrosequencing in a larger cohort, and they showed different extent of changes in related pregnancy disorders (late-onset preeclampsia (LOPET) and normotensive IUGR (nIUGR)). Genome-wide expression in a subset of samples showed that some of the gene expression changes were negatively correlated with DNA methylation changes, particularly for genes that are responsible for angiogenesis (such as EPAS1 and FLT1). Conclusion: Based on DNA methylation profiling, we conclude that there are widespread DNA methylation alterations in EOPET that may be associated with changes in placental function. This property may provide a useful tool for early screening of such placentas. http://dx.doi.org/10.1016/j.placenta.2013.06.254 P2.89. MORPHOLOGY OF THE MOUSE MESOMETRIAL DECIDUA DURING EARLY PREGNANCY Alex Kors Vidsiunas , Sergio Ferreira de Oliveira 2 Nove de Julho University, Sao Paulo-SP, Brazil; University of Sao Paulo, Sao

Published
2013
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16. On the Drinfeld double of a semi-simple Hopf algebra

Author

Tsang, Ryan Yuen Fan and Tsang, Ryan Yuen Fan

Abstract

Given a finite dimensional Hopf algebra H, Drinfeld constructed a new Hopf algebra D(H) called Drinfeld double of H. In this thesis, we prove under the condition that H is a semi-simple Hopf algebra over a field of characteristic 0, D(D(H)) is isomorphic to D(H) ⊕ D(H) as an associative algebra.

Published
1998

19. Genome-Wide Mutation Landscape in Autism Spectrum Disorder

Author

Ryan Yuen, Merico, D., Cao, H., Alipanahi, B., Thiruvahindrapuram, B., Pellecchia, G., Tong, X., Cao, D., Sun, Y., Li, M., Chen, W., Jin, X., Nalpathamkalam, T., Bookman, M., Bingham, J., Gross, S., Loy, D., Walker, S., Howe, J. L., Pletcher, M., Marshall, C. R., Szatmari, P., Glazer, D., Frey, B. J., Ring, R. H., and Scherer, S. W.

21. Rare coding variation provides insight into the genetic architecture and phenotypic context of autism

Author

J. M., Fu, Satterstrom, F. K., Peng, M., Brand, H., Collins, R. L., Dong, S., Wamsley, B., Klei, L., Wang, L., Hao, S. P., Stevens, C. R., Cusick, C., Babadi, M., Banks, E., Collins, B., Dodge, S., Gabriel, S. B., Gauthier, L., Lee, S. K., Liang, L., Ljungdahl, A., Mahjani, B., Sloofman, L., Smirnov, A. N., Barbosa, M., Betancur, C., Brusco, A., Chung, B. H. Y., Cook, E. H., Cuccaro, M. L., Domenici, E., Ferrero, G. B., Gargus, J. J., Herman, G. E., Hertz-Picciotto, I., Maciel, P., Manoach, D. S., Passos-Bueno, M. R., Persico, A., Renieri, A., Sutcliffe, J. S., Tassone, F., Trabetti, E., Campos, G., Cardaropoli, S., Carli, D., Chan, M. C. Y., Fallerini, C., Giorgio, E., Girardi, A. C., Hansen-Kiss, E., Lee, S. L., Lintas, C., Ludena, Y., Nguyen, R., Pavinato, L., Pericak-Vance, M., Pessah, I. N., Schmidt, R. J., Smith, M., Costa, C. I. S., Trajkova, S., Wang, J. Y. T., M. H. C., Yu, Aleksic, B., Artomov, M., Benetti, E., Biscaldi-Schafer, M., Borglum, A. D., Carracedo, A., Chiocchetti, A. G., Coon, H., Doan, R. N., Fernandez-Prieto, M., Freitag, C. M., Gerges, S., Guter, S., Hougaard, D. M., Hultman, C. M., Jacob, S., Kaartinen, M., Kolevzon, A., Kushima, I., Lehtimaki, T., Rizzo, C. L., Maltman, N., Manara, M., Meiri, G., Menashe, I., Miller, J., Minshew, N., Mosconi, M., Ozaki, N., Palotie, A., Parellada, M., Puura, K., Reichenberg, A., Sandin, S., Scherer, S. W., Schlitt, S., Schmitt, L., Schneider-Momm, K., Siper, P. M., Suren, P., Sweeney, J. A., Teufel, K., del Pilar Trelles, M., Weiss, L. A., Yuen, R., Cutler, D. J., De Rubeis, S., Buxbaum, J. D., Daly, M. J., Devlin, B., Roeder, K., Sanders, S. J., Talkowski, M. E., Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Carnegie Mellon University [Pittsburgh] (CMU), Harvard Medical School [Boston] (HMS), University of California [San Francisco] (UC San Francisco), University of California (UC), University of California [Los Angeles] (UCLA), University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Azienda Ospedalerio - Universitaria Città della Salute e della Scienza di Torino = University Hospital Città della Salute e della Scienza di Torino, The University of Hong Kong (HKU), University of Illinois [Chicago] (UIC), University of Illinois System, University of Miami Leonard M. Miller School of Medicine (UMMSM), University of Trento [Trento], University of California [Irvine] (UC Irvine), Nationwide Children's Hospital, University of California [Davis] (UC Davis), Universidade do Minho = University of Minho [Braga], Massachusetts General Hospital [Boston, MA, USA], Escola Politecnica da Universidade de Sao Paulo [Sao Paulo], Università degli Studi di Messina = University of Messina (UniMe), Università degli Studi di Siena = University of Siena (UNISI), Azienda Ospedaliera Universitaria Senese, Vanderbilt University [Nashville], Vanderbilt University School of Medicine [Nashville], Università degli studi di Verona = University of Verona (UNIVR), University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome ( UCBM), Emory University School of Medicine, Emory University [Atlanta, GA], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Autism Sequencing Consortium (ASC), Broad Institute Center for Common Disease Genomics (Broad-CCDG), iPSYCH-BROAD Consortium : Branko Aleksic, Mykyta Artomov, Elisa Benetti, Monica Biscaldi-Schafer, Anders D Børglum, Angel Carracedo, Andreas G Chiocchetti, Hilary Coon, Ryan N Doan, Montserrat Fernández-Prieto, Christine M Freitag, Sherif Gerges, Stephen Guter, David M Hougaard, Christina M Hultman, Suma Jacob, Miia Kaartinen, Alexander Kolevzon, Itaru Kushima, Terho Lehtimäki, Caterina Lo Rizzo, Nell Maltman, Marianna Manara, Gal Meiri, Idan Menashe, Judith Miller, Nancy Minshew, Matthew Mosconi, Norio Ozaki, Aarno Palotie, Mara Parellada, Kaija Puura, Abraham Reichenberg, Sven Sandin, Stephen W Scherer, Sabine Schlitt, Lauren Schmitt, Katja Schneider-Momm, Paige M Siper, Pål Suren, John A Sweeney, Karoline Teufel, Maria Del Pilar Trelles, Lauren A Weiss, Ryan Yuen., and Betancur, Catalina

Subjects
Broad Institute Center for Common Disease Genomics, Autism Sequencing Consortium, DNA Copy Number Variations, Autism Spectrum Disorder, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Autism, Intellectual and Developmental Disabilities (IDD), iPSYCH-BROAD Consortium, autism spectrum disorders, disease gene, copy number variants, neuropsychiatric disorders, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, GENOMAS, Medical and Health Sciences, Article, Clinical Research, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Autistic Disorder, Aetiology, Genetic association study, Pediatric, Human Genome, Neurodevelopmental disorders, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biological Sciences, Autism spectrum disorders, Brain Disorders, Mental Health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Gene expression, Biotechnology, Developmental Biology
Abstract

International audience; 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
Full Text
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22. 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., Walsh, Christopher A, Aleksic, B, Anney, R, Barbosa, M, Barrett, J, Betancur, C, Bishop, S, Brusco, A, Buxbaum, Jd, Carracedo, A, Chiocchetti, Ag, Chung, Bhy, Cook, E, Coon, H, Cutler, Dj, Daly, M, De Rubeis, S, Doan, R, Fernández-Prieto, M, Ferrero, Gb, Freitag, Cm, Fromer, M, Gargus, J, Geschwind, D, Gill, M, Gómez-Guerrero, L, Hansen-Kiss, E, He, X, Herman, G, Hertz-Picciotto, I, Hultman, C, Iliadou, B, Ionita-Laza, I, Jugessur, A, Knudsen, Gp, Kolevzon, A, Kosmicki, J, Kushima, I, Lee, Sl, Lehner, T, Lennertz, S, Lim, E, Maciel, P, Magnus, P, Manoach, D, Minshew, N, Morrow, E, Mulle, J, Neale, B, Ozaki, N, Palotie, A, Parellada, M, Passos-Bueno, Mr, Pericak-Vance, M, Persico, A, Pessah, I, Reichenberg, A, Reichert, J, Renieri, A, Robinson, E, Samocha, K, Sanders, S, Sandin, S, Santangelo, Sl, Satterstrom, K, Schafer, C, Schellenberg, G, Scherer, S, Senthil, G, Silva, M, Singh, T, Siper, Pm, Soares, G, Stevens, C, Stoltenberg, C, Surén, P, Sutcliffe, Js, Szatmari, P, Tassone, F, Thurm, A, Walsh, C, Weiss, L, Werling, D, Willsey, J, Xu, X, Yu, Tw, Yuen, R, Zwick, Me., Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard University [Cambridge], Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU), Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Nagoya University, Hospital General Universitario 'Gregorio Marañón' [Madrid], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Universidade de Santiago de Compostela [Spain] (USC ), CIBER de Enfermedades Raras (CIBERER), Fundación Pública Galega Medicina Xenómica - SERGAS [Santiago de Compostela, Spain] (Grupo de Medicina Xenómica), CIBER de Enfermedades Raras (CIBERER)-Universidade de Santiago de Compostela [Spain] (USC ), King Abdulaziz University, Karolinska Institutet [Stockholm], University of California [San Francisco] (UCSF), University of California, Goethe-University Frankfurt am Main, Génétique de l'autisme = Genetics of Autism (NPS-01), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Hospital for sick children [Toronto] (SickKids), University of Toronto, McLaughlin Centre for Population Health Risk Assessment, University of Ottawa [Ottawa], Autism Sequencing Consortium: Branko Aleksic, Richard Anney, Mafalda Barbosa, Jeffrey Barrett, Catalina Betancur, Somer Bishop, Alfredo Brusco, Joseph D Buxbaum, Angel Carracedo, Andreas G Chiocchetti, Brian H Y Chung, Edwin Cook, Hilary Coon, David J Cutler, Mark Daly, Silvia De Rubeis, Ryan Doan, Montserrat Fernández-Prieto, Giovanni Battista Ferrero, Christine M Freitag, Menachem Fromer, Jay Gargus, Dan Geschwind, Michael Gill, Lorena Gómez-Guerrero, Emily Hansen-Kiss, Xin He, Gail Herman, Irva Hertz-Picciotto, Christina Hultman, Bozenna Iliadou, Iuliana Ionita-Laza, Anil Jugessur, Gun Peggy Knudsen, Alexander Kolevzon, Jack Kosmicki, Itaru Kushima, S L Lee, Thomas Lehner, Savannah Lennertz, Elaine Lim, Patricia Maciel, Per Magnus, Dara Manoach, Nancy Minshew, Eric Morrow, Jennifer Mulle, Benjamin Neale, Norio Ozaki, Aarno Palotie, Mara Parellada, Maria Rita Passos-Bueno, Margaret Pericak-Vance, Antonio Persico, Isaac Pessah, Avi Reichenberg, Jennifer Reichert, Alessandra Renieri, Elise Robinson, Kaitlin Samocha, Stephan Sanders, Sven Sandin, Susan L Santangelo, Kyle Satterstrom, Chad Schafer, Gerry Schellenberg, Stephen Scherer, Geetha Senthil, Marisol Silva, Tarjinder Singh, Paige M Siper, Gabriela Soares, Christine Stevens, Camilla Stoltenberg, Pål Surén, James S Sutcliffe, Peter Szatmari, Flora Tassone, Audrey Thurm, Christopher Walsh, Lauren Weiss, Donna Werling, Jeremy Willsey, Xinyi Xu, Timothy W Yu, Ryan Yuen, Michael E Zwick., University of California [San Francisco] (UC San Francisco), University of California (UC), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Betancur, Catalina

Subjects
0301 basic medicine, Proband, Nonsynonymous substitution, Autism Spectrum Disorder, Databases, Genetic, Genetic Predisposition to Disease, Genetic Variation, Humans, Mosaicism, Mutation, Missense, Zygote, Neuroscience (all), Mutation, Missense, Epigenetics of autism, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, medicine.disease_cause, Article, 03 medical and health sciences, Genetic variation, mental disorders, Databases, Genetic, medicine, Missense mutation, Heritability of autism, MESH: Genetic Variation, MESH: Databases, Genetic, Genetics, MESH: Autism Spectrum Disorder, MESH: Mutation, Missense, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, General Neuroscience, MESH: Genetic Predisposition to Disease, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, MESH: Zygote, MESH: Mosaicism
Abstract

International audience; 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
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