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1. Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy

Author

Fehlings, Darcy L., Zarrei, Mehdi, Engchuan, Worrawat, Sondheimer, Neal, Thiruvahindrapuram, Bhooma, MacDonald, Jeffrey R., Higginbotham, Edward J., Thapa, Ritesh, Behlim, Tarannum, Aimola, Sabrina, Switzer, Lauren, Ng, Pamela, Wei, John, Danthi, Prakroothi S., Pellecchia, Giovanna, Lamoureux, Sylvia, Ho, Karen, Pereira, Sergio L., de Rijke, Jill, Sung, Wilson W. L., Mowjoodi, Alireza, Howe, Jennifer L., Nalpathamkalam, Thomas, Manshaei, Roozbeh, Ghaffari, Siavash, Whitney, Joseph, Patel, Rohan V., Hamdan, Omar, Shaath, Rulan, Trost, Brett, Knights, Shannon, Samdup, Dawa, McCormick, Anna, Hunt, Carolyn, Kirton, Adam, Kawamura, Anne, Mesterman, Ronit, Gorter, Jan Willem, Dlamini, Nomazulu, Merico, Daniele, Hilali, Murto, Hirschfeld, Kyle, Grover, Kritika, Bautista, Nelson X., Han, Kara, Marshall, Christian R., Yuen, Ryan K. C., Subbarao, Padmaja, Azad, Meghan B., Turvey, Stuart E., Mandhane, Piush, Moraes, Theo J., Simons, Elinor, Maxwell, George, Shevell, Michael, Costain, Gregory, Michaud, Jacques L., Hamdan, Fadi F., Gauthier, Julie, Uguen, Kevin, Stavropoulos, Dimitri J., Wintle, Richard F., Oskoui, Maryam, and Scherer, Stephen W.

Published
2024
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4. Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder

Author

Chan, Ada J. S., Engchuan, Worrawat, Reuter, Miriam S., Wang, Zhuozhi, Thiruvahindrapuram, Bhooma, Trost, Brett, Nalpathamkalam, Thomas, Negrijn, Carol, Lamoureux, Sylvia, Pellecchia, Giovanna, Patel, Rohan V., Sung, Wilson W. L., MacDonald, Jeffrey R., Howe, Jennifer L., Vorstman, Jacob, Sondheimer, Neal, Takahashi, Nicole, Miles, Judith H., Anagnostou, Evdokia, Tammimies, Kristiina, Zarrei, Mehdi, Merico, Daniele, Stavropoulos, Dimitri J., Yuen, Ryan K. C., Fernandez, Bridget A., and Scherer, Stephen W.

Published
2022
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6. Genetic variants inDDX53contribute to Autism Spectrum Disorder associated with the Xp22.11 locus

Author

Scala, Marcello, primary, Bradley, Clarrisa A., additional, Howe, Jennifer L., additional, Trost, Brett, additional, Bautista Salazar, Nelson, additional, Shum, Carole, additional, Reuter, Miriam S., additional, MacDonald, Jeffrey R., additional, Ko, Sangyoon Y., additional, Frankland, Paul W., additional, Granger, Leslie, additional, Anadiotis, George, additional, Pullano, Verdiana, additional, Brusco, Alfredo, additional, Keller, Roberto, additional, Parisotto, Sarah, additional, Pedro, Helio F., additional, Lusk, Laina, additional, Pojomovsky McDonnell, Pamela, additional, Helbig, Ingo, additional, Mullegama, Sureni V., additional, Douine, Emilie D., additional, Russell, Bianca E., additional, Nelson, Stanley F., additional, Zara, Federico, additional, and Scherer, Stephen W., additional

Published
2023
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7. Genome-wide detection of tandem DNA repeats that are expanded in autism

Author

Trost, Brett, Engchuan, Worrawat, Nguyen, Charlotte M., Thiruvahindrapuram, Bhooma, Dolzhenko, Egor, Backstrom, Ian, Mirceta, Mila, Mojarad, Bahareh A., Yin, Yue, Dov, Alona, Chandrakumar, Induja, Prasolava, Tanya, Shum, Natalie, Hamdan, Omar, Pellecchia, Giovanna, Howe, Jennifer L., Whitney, Joseph, Klee, Eric W., Baheti, Saurabh, Amaral, David G., Anagnostou, Evdokia, Elsabbagh, Mayada, Fernandez, Bridget A., Hoang, Ny, Lewis, M. E. Suzanne, Liu, Xudong, Sjaarda, Calvin, Smith, Isabel M., Szatmari, Peter, Zwaigenbaum, Lonnie, Glazer, David, Hartley, Dean, Stewart, A. Keith, Eberle, Michael A., Sato, Nozomu, Pearson, Christopher E., Scherer, Stephen W., and Yuen, Ryan K. C.

Published
2020
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8. A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder

Author

Loureiro, Livia O., Howe, Jennifer L., Reuter, Miriam S., Iaboni, Alana, Calli, Kristina, Roshandel, Delnaz, Pritišanac, Iva, Moses, Alan, Forman-Kay, Julie D., Trost, Brett, Zarrei, Mehdi, Rennie, Olivia, Lau, Lynette Y. S., Marshall, Christian R., Srivastava, Siddharth, Godlewski, Brianna, Buttermore, Elizabeth D., Sahin, Mustafa, Hartley, Dean, Frazier, Thomas, Vorstman, Jacob, Georgiades, Stelios, Lewis, Suzanne M. E., Szatmari, Peter, Bradley, Clarrisa A. (Lisa), Tabet, Anne-Claude, Willems, Marjolaine, Lumbroso, Serge, Piton, Amélie, Lespinasse, James, Delorme, Richard, Bourgeron, Thomas, Anagnostou, Evdokia, and Scherer, Stephen W.

Published
2021
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10. Disruption of the ASTN2/TRIM32 locus at 9q33.1 is a risk factor in males for autism spectrum disorders, ADHD and other neurodevelopmental phenotypes

Author

Lionel, Anath C, Tammimies, Kristiina, Vaags, Andrea K, Rosenfeld, Jill A, Ahn, Joo Wook, Merico, Daniele, Noor, Abdul, Runke, Cassandra K, Pillalamarri, Vamsee K, Carter, Melissa T, Gazzellone, Matthew J, Thiruvahindrapuram, Bhooma, Fagerberg, Christina, Laulund, Lone W, Pellecchia, Giovanna, Lamoureux, Sylvia, Deshpande, Charu, Clayton-Smith, Jill, White, Ann C, Leather, Susan, Trounce, John, Bedford, H Melanie, Hatchwell, Eli, Eis, Peggy S, Yuen, Ryan KC, Walker, Susan, Uddin, Mohammed, Geraghty, Michael T, Nikkel, Sarah M, Tomiak, Eva M, Fernandez, Bridget A, Soreni, Noam, Crosbie, Jennifer, Arnold, Paul D, Schachar, Russell J, Roberts, Wendy, Paterson, Andrew D, So, Joyce, Szatmari, Peter, Chrysler, Christina, Woodbury-Smith, Marc, Lowry, R Brian, Zwaigenbaum, Lonnie, Mandyam, Divya, Wei, John, MacDonald, Jeffrey R, Howe, Jennifer L, Nalpathamkalam, Thomas, Wang, Zhuozhi, Tolson, Daniel, Cobb, David S, Wilks, Timothy M, Sorensen, Mark J, Bader, Patricia I, An, Yu, Wu, Bai-Lin, Musumeci, Sebastiano Antonino, Romano, Corrado, Postorivo, Diana, Nardone, Anna M, Della Monica, Matteo, Scarano, Gioacchino, Zoccante, Leonardo, Novara, Francesca, Zuffardi, Orsetta, Ciccone, Roberto, Antona, Vincenzo, Carella, Massimo, Zelante, Leopoldo, Cavalli, Pietro, Poggiani, Carlo, Cavallari, Ugo, Argiropoulos, Bob, Chernos, Judy, Brasch-Andersen, Charlotte, Speevak, Marsha, Fichera, Marco, Ogilvie, Caroline Mackie, Shen, Yiping, Hodge, Jennelle C, Talkowski, Michael E, Stavropoulos, Dimitri J, Marshall, Christian R, and Scherer, Stephen W

Subjects
Pediatric Research Initiative, Pediatric, Intellectual and Developmental Disabilities (IDD), Mental Health, Brain Disorders, Human Genome, Neurosciences, Autism, Clinical Research, Behavioral and Social Science, Genetics, 2.1 Biological and endogenous factors, Aetiology, Mental health, Adolescent, Adult, Attention Deficit Disorder with Hyperactivity, Case-Control Studies, Child, Child Development Disorders, Pervasive, Child, Preschool, Chromosomes, Human, Pair 9, DNA Copy Number Variations, Exons, Female, Gene Expression, Genetic Association Studies, Genetic Predisposition to Disease, Glycoproteins, Humans, Infant, Infant, Newborn, Male, Nerve Tissue Proteins, Organ Specificity, Phenotype, Polymorphism, Single Nucleotide, Protein Isoforms, Receptors, Cell Surface, Risk Factors, Sequence Deletion, Transcription Factors, Transcription Initiation Site, Tripartite Motif Proteins, Ubiquitin-Protein Ligases, Young Adult, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders (NDDs). The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89 985 individuals across 10 sites, including 64 114 NDD subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the NDD subjects (P = 0.002) compared with 44 085 population-based controls. Frequent phenotypes observed in individuals with such deletions include autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), speech delay, anxiety and obsessive compulsive disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with NDDs, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.

Published
2014

11. Convergence of Genes and Cellular Pathways Dysregulated in Autism Spectrum Disorders

Author

Pinto, Dalila, Delaby, Elsa, Merico, Daniele, Barbosa, Mafalda, Merikangas, Alison, Klei, Lambertus, Thiruvahindrapuram, Bhooma, Xu, Xiao, Ziman, Robert, Wang, Zhuozhi, Vorstman, Jacob AS, Thompson, Ann, Regan, Regina, Pilorge, Marion, Pellecchia, Giovanna, Pagnamenta, Alistair T, Oliveira, Bárbara, Marshall, Christian R, Magalhaes, Tiago R, Lowe, Jennifer K, Howe, Jennifer L, Griswold, Anthony J, Gilbert, John, Duketis, Eftichia, Dombroski, Beth A, De Jonge, Maretha V, Cuccaro, Michael, Crawford, Emily L, Correia, Catarina T, Conroy, Judith, Conceição, Inês C, Chiocchetti, Andreas G, Casey, Jillian P, Cai, Guiqing, Cabrol, Christelle, Bolshakova, Nadia, Bacchelli, Elena, Anney, Richard, Gallinger, Steven, Cotterchio, Michelle, Casey, Graham, Zwaigenbaum, Lonnie, Wittemeyer, Kerstin, Wing, Kirsty, Wallace, Simon, van Engeland, Herman, Tryfon, Ana, Thomson, Susanne, Soorya, Latha, Rogé, Bernadette, Roberts, Wendy, Poustka, Fritz, Mouga, Susana, Minshew, Nancy, McInnes, L Alison, McGrew, Susan G, Lord, Catherine, Leboyer, Marion, Le Couteur, Ann S, Kolevzon, Alexander, González, Patricia Jiménez, Jacob, Suma, Holt, Richard, Guter, Stephen, Green, Jonathan, Green, Andrew, Gillberg, Christopher, Fernandez, Bridget A, Duque, Frederico, Delorme, Richard, Dawson, Geraldine, Chaste, Pauline, Café, Cátia, Brennan, Sean, Bourgeron, Thomas, Bolton, Patrick F, Bölte, Sven, Bernier, Raphael, Baird, Gillian, Bailey, Anthony J, Anagnostou, Evdokia, Almeida, Joana, Wijsman, Ellen M, Vieland, Veronica J, Vicente, Astrid M, Schellenberg, Gerard D, Pericak-Vance, Margaret, Paterson, Andrew D, Parr, Jeremy R, Oliveira, Guiomar, Nurnberger, John I, Monaco, Anthony P, Maestrini, Elena, Klauck, Sabine M, Hakonarson, Hakon, Haines, Jonathan L, Geschwind, Daniel H, Freitag, Christine M, Folstein, Susan E, and Ennis, Sean

Subjects
Genetics, Brain Disorders, Pediatric, Mental Health, Intellectual and Developmental Disabilities (IDD), Neurosciences, Autism, 2.1 Biological and endogenous factors, Aetiology, Child, Child Development Disorders, Pervasive, DNA Copy Number Variations, Female, Gene Regulatory Networks, Humans, Male, Metabolic Networks and Pathways, Multigene Family, Pedigree, Sequence Deletion, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Published
2014

12. Individual common variants exert weak effects on the risk for autism spectrum disorders

Author

Anney, Richard, Klei, Lambertus, Pinto, Dalila, Almeida, Joana, Bacchelli, Elena, Baird, Gillian, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Casey, Jillian, Conroy, Judith, Correia, Catarina, Corsello, Christina, Crawford, Emily L, de Jonge, Maretha, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Green, Andrew, Green, Jonathan, Guter, Stephen J, Heron, Elizabeth A, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Jacob, Suma, Kenny, Graham P, Kim, Cecilia, Kolevzon, Alexander, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Law-Smith, Miriam, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Liu, Xiao-Qing, Lombard, Frances, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Magalhaes, Tiago R, Mantoulan, Carine, McDougle, Christopher J, Melhem, Nadine M, Merikangas, Alison, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Noakes, Carolyn, Nygren, Gudrun, Papanikolaou, Katerina, Pagnamenta, Alistair T, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Posey, David J, Poustka, Fritz, Ragoussis, Jiannis, Regan, Regina, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L, Schlitt, Sabine, Shah, Naisha, Sheffield, Val C, Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Sykes, Nuala, Tancredi, Raffaella, Thompson, Ann P, Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Van Engeland, Herman, Vincent, John B, Volkmar, Fred, Vorstman, JAS, Wallace, Simon, Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Zurawiecki, Danielle, Zwaigenbaum, Lonnie, and Bailey, Anthony J

Subjects
Behavioral and Social Science, Clinical Research, Human Genome, Mental Health, Genetics, Brain Disorders, Pediatric, Intellectual and Developmental Disabilities (IDD), Autism, Prevention, Aetiology, 2.1 Biological and endogenous factors, Alleles, Child, Child Development Disorders, Pervasive, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Language Development, Male, Membrane Proteins, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Risk Factors, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Published
2012

13. A genome-wide scan for common alleles affecting risk for autism

Author

Anney, Richard, Klei, Lambertus, Pinto, Dalila, Regan, Regina, Conroy, Judith, Magalhaes, Tiago R, Correia, Catarina, Abrahams, Brett S, Sykes, Nuala, Pagnamenta, Alistair T, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Carson, Andrew R, Casallo, Guillermo, Casey, Jillian, Chu, Su H, Cochrane, Lynne, Corsello, Christina, Crawford, Emily L, Crossett, Andrew, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Goldberg, Jeremy, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Heron, Elizabeth A, Hill, Matthew, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lionel, Anath C, Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Melhem, Nadine M, Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Piven, Joseph, Posey, David J, Poustka, Annemarie, and Poustka, Fritz

Subjects
Clinical Research, Human Genome, Mental Health, Genetics, Brain Disorders, Pediatric, Biotechnology, Intellectual and Developmental Disabilities (IDD), Autism, Prevention, Aetiology, 2.1 Biological and endogenous factors, Alleles, Autistic Disorder, DNA Copy Number Variations, Databases, Genetic, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Risk Factors, White People, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

Published
2010

14. ANK2 loss-of-function variants are associated with epilepsy, and lead to impaired axon initial segment plasticity and hyperactive network activity in hiPSC-derived neuronal networks

Author

Teunissen, Maria W A, primary, Lewerissa, Elly, additional, van Hugte, Eline J H, additional, Wang, Shan, additional, Ockeloen, Charlotte W, additional, Koolen, David A, additional, Pfundt, Rolph, additional, Marcelis, Carlo L M, additional, Brilstra, Eva, additional, Howe, Jennifer L, additional, Scherer, Stephen W, additional, Le Guillou, Xavier, additional, Bilan, Frédéric, additional, Primiano, Michelle, additional, Roohi, Jasmin, additional, Piton, Amelie, additional, de Saint Martin, Anne, additional, Baer, Sarah, additional, Seiffert, Simone, additional, Platzer, Konrad, additional, Jamra, Rami Abou, additional, Syrbe, Steffen, additional, Doering, Jan H, additional, Lakhani, Shenela, additional, Nangia, Srishti, additional, Gilissen, Christian, additional, Vermeulen, R Jeroen, additional, Rouhl, Rob P W, additional, Brunner, Han G, additional, Willemsen, Marjolein H, additional, and Nadif Kasri, Nael, additional

Published
2023
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15. A large data resource of genomic copy number variation across neurodevelopmental disorders

Author

Zarrei, Mehdi, Burton, Christie L., Engchuan, Worrawat, Young, Edwin J., Higginbotham, Edward J., MacDonald, Jeffrey R., Trost, Brett, Chan, Ada J. S., Walker, Susan, Lamoureux, Sylvia, Heung, Tracy, Mojarad, Bahareh A., Kellam, Barbara, Paton, Tara, Faheem, Muhammad, Miron, Karin, Lu, Chao, Wang, Ting, Samler, Kozue, Wang, Xiaolin, Costain, Gregory, Hoang, Ny, Pellecchia, Giovanna, Wei, John, Patel, Rohan V., Thiruvahindrapuram, Bhooma, Roifman, Maian, Merico, Daniele, Goodale, Tara, Drmic, Irene, Speevak, Marsha, Howe, Jennifer L., Yuen, Ryan K. C., Buchanan, Janet A., Vorstman, Jacob A. S., Marshall, Christian R., Wintle, Richard F., Rosenberg, David R., Hanna, Gregory L., Woodbury-Smith, Marc, Cytrynbaum, Cheryl, Zwaigenbaum, Lonnie, Elsabbagh, Mayada, Flanagan, Janine, Fernandez, Bridget A., Carter, Melissa T., Szatmari, Peter, Roberts, Wendy, Lerch, Jason, Liu, Xudong, Nicolson, Rob, Georgiades, Stelios, Weksberg, Rosanna, Arnold, Paul D., Bassett, Anne S., Crosbie, Jennifer, Schachar, Russell, Stavropoulos, Dimitri J., Anagnostou, Evdokia, and Scherer, Stephen W.

Published
2019
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16. Additional file 2 of Disruption of DDX53 coding sequence has limited impact on iPSC-derived human NGN2 neurons

Author

Faheem, Muhammad, Deneault, Eric, Alexandrova, Roumiana, Rodrigues, Deivid C., Pellecchia, Giovanna, Shum, Carole, Zarrei, Mehdi, Piekna, Alina, Wei, Wei, Howe, Jennifer L., Thiruvahindrapuram, Bhooma, Lamoureux, Sylvia, Ross, P. Joel, Bradley, Clarrisa A., Ellis, James, and Scherer, Stephen W.

Abstract

Additional file 2. Supplementary figure.

Published
2023
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17. Genomic architecture of autism from comprehensive whole-genome sequence annotation

Author

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

Published
2022
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18. 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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20. Genomic architecture of Autism Spectrum Disorder from comprehensive whole-genome sequence annotation

Author

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

Published
2022
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21. Whole-genome sequencing of quartet families with autism spectrum disorder

Author

Yuen, Ryan K.C., Thiruvahindrapuram, Bhooma, Merico, Daniele, Walker, Susan, Tammimies, Kristiina, Hoang, Ny, Chrysler, Christina, Nalpathamkalam, Thomas, Pellecchia, Giovanna, Liu, Yi, Gazzellone, Matthew J., D'Abate, Lia, Deneault, Eric, Howe, Jennifer L., Liu, Richard S.C., Thompson, Ann, Zarrei, Mehdi, Uddin, Mohammed, Marshall, Christian R., Ring, Robert H., Zwaigenbaum, Lonnie, Ray, Peter N., Weksberg, Rosanna, Carter, Melissa T., Fernandez, Bridget A., Roberts, Wendy, Szatmari, Peter, and Scherer, Stephen W.

Subjects
Nucleotide sequencing -- Research, Pervasive developmental disorders -- Genetic aspects, Genetic research, DNA sequencing -- Research, Genomes -- Research, Biological sciences, Health
Abstract

Autism spectrum disorder (ASD) is genetically heterogeneous, with evidence for hundreds of susceptibility loci. Previous microarray and exome-sequencing studies have examined portions of the genome in simplex families (parents and one ASD-affected child) having presumed sporadic forms of the disorder. We used whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD, to generate a comprehensive data resource encompassing all classes of genetic variation (including noncoding variants) and accompanying phenotypes, in apparently familial forms of ASD. By examining de novo and rare inherited single-nucleotide and structural variations in genes previously reported to be associated with ASD or other neurodevelopmental disorders, we found that some (69.4%) of the affected siblings carried different ASD-relevant mutations. These siblings with discordant mutations tended to demonstrate more clinical variability than those who shared a risk variant. Our study emphasizes that substantial genetic heterogeneity exists in ASD, necessitating the use of WGS to delineate all genic and non-genic susceptibility variants in research and in clinical diagnostics., Evidence from twin and family studies suggests substantial heritability in ASD (1). Risk of recurrence in families is high, ranging from 12.9 (ref. 2) to 18.7% (ref. 3), suggesting that [...]

Published
2015
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22. CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD.

Author

Pavinato, Lisa, Vedove, Andrea Delle, Carli, Diana, Ferrero, Marta, Carestiato, Silvia, Howe, Jennifer L, Agolini, Emanuele, Coviello, Domenico A, van de Laar, Ingrid, Au, Ping Yee Billie, Gregorio, Eleonora Di, Fabbiani, Alessandra, Croci, Susanna, Mencarelli, Maria Antonietta, Bruno, Lucia P, Renieri, Alessandra, Veltra, Danai, Sofocleous, Christalena, Faivre, Laurence, and Mazel, Benoit

Subjects
LANGUAGE disorders, ATTENTION-deficit hyperactivity disorder, NEURAL development, PLURIPOTENT stem cells, NEURAL circuitry
Abstract

We describe an autosomal dominant disorder associated with loss-of-function variants in the Cell cycle associated protein 1 (CAPRIN1 ; MIM*601178). CAPRIN1 encodes a ubiquitous protein that regulates the transport and translation of neuronal mRNAs critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in multiple cell types. We identified 12 cases with loss-of-function CAPRIN1 variants, and a neurodevelopmental phenotype characterized by language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%). Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%). In patient-derived lymphoblasts and fibroblasts, we showed a monoallelic expression of the wild-type allele, and a reduction of the transcript and protein compatible with a half dose. To further study pathogenic mechanisms, we generated s CAPRIN1 +/− human induced pluripotent stem cells via CRISPR–Cas9 mutagenesis and differentiated them into neuronal progenitor cells and cortical neurons. CAPRIN1 loss caused reduced neuronal processes, overall disruption of the neuronal organization and an increased neuronal degeneration. We also observed an alteration of mRNA translation in CAPRIN1 +/− neurons, compatible with its suggested function as translational inhibitor. CAPRIN1 +/− neurons also showed an impaired calcium signalling and increased oxidative stress, two mechanisms that may directly affect neuronal networks development, maintenance and function. According to what was previously observed in the mouse model, measurements of activity in CAPRIN1 +/− neurons via micro-electrode arrays indicated lower spike rates and bursts, with an overall reduced activity. In conclusion, we demonstrate that CAPRIN1 haploinsufficiency causes a novel autosomal dominant neurodevelopmental disorder and identify morphological and functional alterations associated with this disorder in human neuronal models. [ABSTRACT FROM AUTHOR]

Published
2023
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23. Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

Author

Woodbury-Smith, Marc, Paterson, Andrew D., Thiruvahindrapduram, Bhooma, Lionel, Anath C., Marshall, Christian R., Merico, Daniele, Fernandez, Bridget A., Duku, Eric, Sutcliffe, James S., O’Conner, Irene, Chrysler, Christina, Thompson, Ann, Kellam, Barbara, Tammimies, Kristiina, Walker, Susan, Yuen, Ryan K. C., Uddin, Mohammed, Howe, Jennifer L., Parlier, Morgan, Whitten, Kathy, Szatmari, Peter, Vieland, Veronica J., Piven, Joseph, and Scherer, Stephen W.

Published
2015
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24. Delineation of a novel neurodevelopmental syndrome associated with PAX5 haploinsufficiency

Author

Gofin, Yoel, primary, Wang, Tianyun, additional, Gillentine, Madelyn A., additional, Scott, Tiana M., additional, Berry, Aliska M., additional, Azamian, Mahshid S., additional, Genetti, Casie, additional, Agrawal, Pankaj B., additional, Picker, Jonathan, additional, Wojcik, Monica H., additional, Delgado, Mauricio R., additional, Lynch, Sally A., additional, Scherer, Stephen W., additional, Howe, Jennifer L., additional, Bacino, Carlos A., additional, DiTroia, Stephanie, additional, VanNoy, Grace E., additional, O'Donnell‐Luria, Anne, additional, Lalani, Seema R., additional, Graf, William D., additional, Rosenfeld, Jill A., additional, Eichler, Evan E., additional, Earl, Rachel K., additional, and Scott, Daryl A., additional

Published
2022
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25. Genome-wide rare variant score associates with morphological subtypes of autism spectrum disorder

Author

Chan, Ada J.S, primary, Engchuan, Worrawat, additional, Reuter, Miriam S., additional, Wang, Zhuozhi, additional, Thiruvahindrapuram, Bhooma, additional, Trost, Brett, additional, Nalpathamkalam, Thomas, additional, Negrijn, Carol, additional, Lamoureux, Sylvia, additional, Pellecchia, Giovanna, additional, Patel, Rohan, additional, Sung, Wilson W.L., additional, MacDonald, Jeffrey R., additional, Howe, Jennifer L., additional, Vorstman, Jacob, additional, Sondheimer, Neal, additional, Takahashi, Nicole, additional, Miles, Judith H., additional, Anagnostou, Evdokia, additional, Tammimies, Kristiina, additional, Zarrei, Mehdi, additional, Merico, Daniele, additional, Stavropoulos, Dimitri J., additional, Yuen, Ryan K.C., additional, Fernandez, Bridget A., additional, and Scherer, Stephen W., additional

Published
2021
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26. Single cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss of function mutation genes regulating glial cells

Author

Nassir, Nasna, primary, Bankapur, Asma, additional, Samara, Bisan, additional, Ali, Abdulrahman, additional, Ahmed, Awab, additional, Inuwa, Ibrahim, additional, Zarrei, Mehdi, additional, Shabestari, Seyed Ali Safizadeh, additional, AlBanna, Ammar, additional, Howe, Jennifer L., additional, Berdiev, Bakhrom, additional, Scherer, Stephen W., additional, Woodbury-Smith, Marc, additional, and uddin, mohammed, additional

Published
2021
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27. Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder

Author

Tammimies, Kristiina, Marshall, Christian R., Walker, Susan, Kaur, Gaganjot, Thiruvahindrapuram, Bhooma, Lionel, Anath C., Yuen, Ryan K. C., Uddin, Mohammed, Roberts, Wendy, Weksberg, Rosanna, Woodbury-Smith, Marc, Zwaigenbaum, Lonnie, Anagnostou, Evdokia, Wang, Zhuozhi, Wei, John, Howe, Jennifer L., Gazzellone, Matthew J., Lau, Lynette, Sung, Wilson W. L., Whitten, Kathy, Vardy, Cathy, Crosbie, Victoria, Tsang, Brian, D’Abate, Lia, Tong, Winnie W. L., Luscombe, Sandra, Doyle, Tyna, Carter, Melissa T., Szatmari, Peter, Stuckless, Susan, Merico, Daniele, Stavropoulos, Dimitri J., Scherer, Stephen W., and Fernandez, Bridget A.

Published
2015
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28. Additional file 1 of Single-cell transcriptome identifies molecular subtype of autism spectrum disorder impacted by de novo loss-of-function variants regulating glial cells

Author

Nassir, Nasna, Bankapur, Asma, Samara, Bisan, Ali, Abdulrahman, Ahmed, Awab, Inuwa, Ibrahim M., Zarrei, Mehdi, Safizadeh Shabestari, Seyed Ali, AlBanna, Ammar, Howe, Jennifer L., Berdiev, Bakhrom K., Scherer, Stephen W., Woodbury-Smith, Marc, and Uddin, Mohammed

Abstract

Additional file 1. Additional methods, dataset availability, Supplementary Figures, 1-27.

Published
2021
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29. A recurrentSHANK3frameshift variant in Autism Spectrum Disorder

Author

Loureiro, Livia O, primary, Howe, Jennifer L, additional, Reuter, Miriam, additional, Iaboni, Alana, additional, Calli, Kristina, additional, Roshandel, Delnaz, additional, Pritisanac, Iva, additional, Moses, Alan, additional, Forman-Kay, Julie D., additional, Trost, Brett, additional, Zarrei, Mehdi, additional, Rennie, Olivia, additional, Lau, Lynette, additional, Marshall, Christian R, additional, Srivastava, Siddharth, additional, Godlewski, Brianna, additional, Buttermore, Elizabeth, additional, Sahin, Mustafa, additional, Hartley, Dean, additional, Frazier, Thomas, additional, Vorstman, Jacob, additional, Georgiades, Stelios, additional, Lewis, Suzanne ME, additional, Szatmari, Peter, additional, Bradley, Lisa, additional, Delorme, Richard, additional, Bourgeron, Thomas, additional, Anagnostou, Evdokia, additional, and Scherer, Stephen W., additional

Published
2021
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30. Mutations in trpγ, the homologue of TRPC6autism candidate gene, causes autism-like behavioral deficits in Drosophila

Author

Palacios-Muñoz, Angelina, de Paula Moreira, Danielle, Silva, Valeria, García, Isaac E., Aboitiz, Francisco, Zarrei, Mehdi, Campos, Gabriele, Rennie, Olivia, Howe, Jennifer L., Anagnostou, Evdokia, Ambrozewic, Patricia, Scherer, Stephen W., Passos-Bueno, Maria Rita, and Ewer, John

Abstract

Autism Spectrum Disorder (ASD) is characterized by impaired social communication, restricted interests, and repetitive and stereotyped behaviors. The TRPC6(transient receptor potential channel 6) represents an ASD candidate gene under an oligogenic/multifactorial model based on the initial description and cellular characterization of an individual with ASD bearing a de novo heterozygous mutation disrupting TRPC6, together with the enrichment of disruptive TRPC6variants in ASD cases as compared to controls. Here, we perform a clinical re-evaluation of the initial non-verbal patient, and also present eight newly reported individuals ascertained for ASD and bearing predicted loss-of-function mutations in TRPC6. In order to understand the consequences of mutations in TRPC6on nervous system function, we used the fruit fly, Drosophila melanogaster, to show that null mutations in transient receptor gamma(trpγ; the fly gene most similar to TRPC6), cause a number of behavioral defects that mirror features seen in ASD patients, including deficits in social interactions (based on courtship behavior), impaired sleep homeostasis (without affecting the circadian control of sleep), hyperactivity in both young and old flies, and defects in learning and memory. Some defects, most notably in sleep, differed in severity between males and females and became normal with age. Interestingly, hyperforin, a TRPC6agonist and the primary active component of the St. John’s wort antidepressant, attenuated many of the deficits expressed by trpγmutant flies. In summary, our results provide further evidence that the TRPC6gene is a risk factor for ASD. In addition, they show that the behavioral defects caused by mutations in TRPC6can be modeled in Drosophila, thereby establishing a paradigm to examine the impact of mutations in other candidate genes.

Published
2022
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31. Segregating patterns of copy number variations in extended autism spectrum disorder ( ASD ) pedigrees

Author

Woodbury‐Smith, Marc, primary, Zarrei, Mehdi, additional, Wei, John, additional, Thiruvahindrapuram, Bhooma, additional, O'Connor, Irene, additional, Paterson, Andrew D., additional, Yuen, Ryan K. C., additional, Dastan, Jila, additional, Stavropoulos, Dimitri J., additional, Howe, Jennifer L., additional, Thompson, Ann, additional, Parlier, Morgan, additional, Fernandez, Bridget, additional, Piven, Joseph, additional, Anagnostou, Evdokia, additional, Scherer, Stephen W., additional, Vieland, Veronica J., additional, and Szatmari, Peter, additional

Published
2020
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32. Functional impact of global rare copy number variation in autism spectrum disorders

Author

Pinto, Dalila, Pagnamenta, Alistair T., Klei, Lambertus, Anney, Richard, Merico, Daniele, Regan, Regina, Conroy, Judith, Magalhaes, Tiago R., Correia, Catarina, Abrahams, Brett S., Almeida, Joana, Bacchelli, Elena, Bader, Gary D., Bailey, Anthony J., Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F., Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Bryson, Susan E., Carson, Andrew R., Casallo, Guillermo, Casey, Jillian, Chung, Brian H.Y., Cochrane, Lynne, Corsello, Christina, Crawford, Emily L., Crossett, Andrew, Cytrynbaum, Cheryl, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A., Folstein, Susan E., Fombonne, Eric, Freitag, Christine M., Gilbert, John, Gillberg, Christopher, Glessner, Joseph T., Goldberg, Jeremy, Green, Andrew, Green, Jonathan, Guter, Stephen J., Hakonarson, Hakon, Heron, Elizabeth A., Hill, Matthew, Holt, Richard, Howe, Jennifer L., Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M., Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M., Lamb, Janine A., Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L., Lionel, Anath C., Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C., Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R., McConachie, Helen, McDougle, Christopher J., McGrath, Jane, McMahon, William M., Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J., Mirza, Ghazala K., Munson, Jeff, Nelson, Stanley F., Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R., Parrini, Barbara, Paton, Tara, Pickles, Andrew, Pilorge, Marion, Piven, Joseph, Ponting, Chris P., Posey, David J., Poustka, Annemarie, Poustka, Fritz, Prasad, Aparna, Ragoussis, Jiannis, Renshaw, Katy, Rickaby, Jessica, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L., Bierut, Laura J., Rice, John P., Salt, Jeff, Sansom, Katherine, Sato, Daisuke, Segurado, Ricardo, Sequeira, Ana F., Senman, Lili, Shah, Naisha, Sheffield, Val C., Soorya, Latha, Sousa, Inês, Stein, Olaf, Sykes, Nuala, Stoppioni, Vera, Strawbridge, Christina, Tancredi, Raffaella, Tansey, Katherine, Thiruvahindrapduram, Bhooma, Thompson, Ann P., Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Van Engeland, Herman, Vincent, John B., Volkmar, Fred, Wallace, Simon, Wang, Kai, Wang, Zhouzhi, Wassink, Thomas H., Webber, Caleb, Weksberg, Rosanna, Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Wu, Jing, Yaspan, Brian L., Zurawiecki, Danielle, Zwaigenbaum, Lonnie, Buxbaum, Joseph D., Cantor, Rita M., Cook, Edwin H., Coon, Hilary, Cuccaro, Michael L., Devlin, Bernie, Ennis, Sean, Gallagher, Louise, Geschwind, Daniel H., Gill, Michael, Haines, Jonathan L., Hallmayer, Joachim, Miller, Judith, Monaco, Anthony P., Nurnberger, John I., Jr, Paterson, Andrew D., Pericak-Vance, Margaret A., Schellenberg, Gerard D., Szatmari, Peter, Vicente, Astrid M., Vieland, Veronica J., Wijsman, Ellen M., Scherer, Stephen W., Sutcliffe, James S., and Betancur, Catalina

Published
2010
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33. CNTN5-/+or EHMT2-/+human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks

Author

Deneault, Eric, primary, Faheem, Muhammad, additional, White, Sean H, additional, Rodrigues, Deivid C, additional, Sun, Song, additional, Wei, Wei, additional, Piekna, Alina, additional, Thompson, Tadeo, additional, Howe, Jennifer L, additional, Chalil, Leon, additional, Kwan, Vickie, additional, Walker, Susan, additional, Pasceri, Peter, additional, Roth, Frederick P, additional, Yuen, Ryan KC, additional, Singh, Karun K, additional, Ellis, James, additional, and Scherer, Stephen W, additional

Published
2019
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34. Complete Disruption of Autism-Susceptibility Genes by Gene Editing Predominantly Reduces Functional Connectivity of Isogenic Human Neurons

Author

Deneault, Eric, primary, White, Sean H., additional, Rodrigues, Deivid C., additional, Ross, P. Joel, additional, Faheem, Muhammad, additional, Zaslavsky, Kirill, additional, Wang, Zhuozhi, additional, Alexandrova, Roumiana, additional, Pellecchia, Giovanna, additional, Wei, Wei, additional, Piekna, Alina, additional, Kaur, Gaganjot, additional, Howe, Jennifer L., additional, Kwan, Vickie, additional, Thiruvahindrapuram, Bhooma, additional, Walker, Susan, additional, Lionel, Anath C., additional, Pasceri, Peter, additional, Merico, Daniele, additional, Yuen, Ryan K.C., additional, Singh, Karun K., additional, Ellis, James, additional, and Scherer, Stephen W., additional

Published
2019
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35. Author response: CNTN5-/+or EHMT2-/+human iPSC-derived neurons from individuals with autism develop hyperactive neuronal networks

Author

Deneault, Eric, primary, Faheem, Muhammad, additional, White, Sean H, additional, Rodrigues, Deivid C, additional, Sun, Song, additional, Wei, Wei, additional, Piekna, Alina, additional, Thompson, Tadeo, additional, Howe, Jennifer L, additional, Chalil, Leon, additional, Kwan, Vickie, additional, Walker, Susan, additional, Pasceri, Peter, additional, Roth, Frederick P, additional, Yuen, Ryan KC, additional, Singh, Karun K, additional, Ellis, James, additional, and Scherer, Stephen W, additional

Published
2018
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36. Complete Disruption of Autism-Susceptibility Genes by Gene Editing Predominantly Reduces Functional Connectivity of Isogenic Human Neurons

Author

Deneault, Eric, primary, White, Sean H., additional, Rodrigues, Deivid C., additional, Ross, P. Joel, additional, Faheem, Muhammad, additional, Zaslavsky, Kirill, additional, Wang, Zhuozhi, additional, Alexandrova, Roumiana, additional, Pellecchia, Giovanna, additional, Wei, Wei, additional, Piekna, Alina, additional, Kaur, Gaganjot, additional, Howe, Jennifer L., additional, Kwan, Vickie, additional, Thiruvahindrapuram, Bhooma, additional, Walker, Susan, additional, Lionel, Anath C., additional, Pasceri, Peter, additional, Merico, Daniele, additional, Yuen, Ryan K.C., additional, Singh, Karun K., additional, Ellis, James, additional, and Scherer, Stephen W., additional

Published
2018
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37. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

Author

Yuen, Ryan K C, Merico, Daniele, Bookman, Matt, Howe, Jennifer L., Thiruvahindrapuram, Bhooma, Patel, Rohan V., Whitney, Joe, Deflaux, Nicole, Bingham, Jonathan, Wang, Zhuozhi, Pellecchia, Giovanna, Buchanan, Janet A., Walker, Susan, Marshall, Christian R., Uddin, Mohammed, Zarrei, Mehdi, Deneault, Eric, D'Abate, Lia, Chan, Ada J S, Koyanagi, Stephanie, Paton, Tara, Pereira, Sergio L., Hoang, Ny, Engchuan, Worrawat, Higginbotham, Edward J., Ho, Karen, Lamoureux, Sylvia, Li, Weili, MacDonald, Jeffrey R., Nalpathamkalam, Thomas, Sung, Wilson W L, Tsoi, Fiona J., Wei, John, Xu, Lizhen, Tasse, Anne Marie, Kirby, Emily, Van Etten, William, Twigger, Simon, Roberts, Wendy, Drmic, Irene, Jilderda, Sanne, Modi, Bonnie Mackinnon, Kellam, Barbara, Szego, Michael, Cytrynbaum, Cheryl, Weksberg, Rosanna, Zwaigenbaum, Lonnie, Woodbury-Smith, Marc, Brian, Jessica, Senman, Lili, Iaboni, Alana, Doyle-Thomas, Krissy, Thompson, Ann, Chrysler, Christina, Leef, Jonathan, Savion-Lemieux, Tal, Smith, Isabel M., Liu, Xudong, Nicolson, Rob, Seifer, Vicki, Fedele, Angie, Cook, Edwin H., Dager, Stephen, Estes, Annette, Gallagher, Louise, Malow, Beth A., Parr, Jeremy R., Spence, Sarah J., Vorstman, Jacob, Frey, Brendan J., Robinson, James T., Strug, Lisa J., Fernandez, Bridget A., Elsabbagh, Mayada, Carter, Melissa T., Hallmayer, Joachim, Knoppers, Bartha M., Anagnostou, Evdokia, Szatmari, Peter, Ring, Robert H., Glazer, David, Pletcher, Mathew T., and Scherer, Stephen W.

Subjects
Neuroscience(all), Next-generation sequencing, Journal Article, Autism spectrum disorders
Abstract

We are performing whole-genome sequencing of families with autism spectrum disorder (ASD) to build a resource (MSSNG) for subcategorizing the phenotypes and underlying genetic factors involved. Here we report sequencing of 5,205 samples from families with ASD, accompanied by clinical information, creating a database accessible on a cloud platform and through a controlled-access internet portal. We found an average of 73.8 de novo single nucleotide variants and 12.6 de novo insertions and deletions or copy number variations per ASD subject. We identified 18 new candidate ASD-risk genes and found that participants bearing mutations in susceptibility genes had significantly lower adaptive ability (P = 6 × 10-4). In 294 of 2,620 (11.2%) of ASD cases, a molecular basis could be determined and 7.2% of these carried copy number variations and/or chromosomal abnormalities, emphasizing the importance of detecting all forms of genetic variation as diagnostic and therapeutic targets in ASD.

Published
2017

38. CNTN5−/+orEHMT2−/+iPSC-Derived Neurons from Individuals with Autism Develop Hyperactive Neuronal Networks

Author

Deneault, Eric, primary, Faheem, Muhammad, additional, White, Sean H., additional, Rodrigues, Deivid C., additional, Sun, Song, additional, Wei, Wei, additional, Piekna, Alina, additional, Thompson, Tadeo, additional, Howe, Jennifer L., additional, Chalil, Leon, additional, Kwan, Vickie, additional, Walker, Susan, additional, Pasceri, Peter, additional, Roth, Frederick P., additional, Yuen, Ryan K.C., additional, Singh, Karun K., additional, Ellis, James, additional, and Scherer, Stephen W., additional

Published
2018
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39. Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly

Author

Woodbury-Smith, Marc, primary, Deneault, Eric, additional, Yuen, Ryan K. C., additional, Walker, Susan, additional, Zarrei, Mehdi, additional, Pellecchia, Giovanna, additional, Howe, Jennifer L., additional, Hoang, Ny, additional, Uddin, Mohammed, additional, Marshall, Christian R., additional, Chrysler, Christina, additional, Thompson, Ann, additional, Szatmari, Peter, additional, and Scherer, Stephen W., additional

Published
2017
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40. Genome-wide characteristics of de novo mutations in autism

Author

Yuen, Ryan KC, primary, Merico, Daniele, additional, Cao, Hongzhi, additional, Pellecchia, Giovanna, additional, Alipanahi, Babak, additional, Thiruvahindrapuram, Bhooma, additional, Tong, Xin, additional, Sun, Yuhui, additional, Cao, Dandan, additional, Zhang, Tao, additional, Wu, Xueli, additional, Jin, Xin, additional, Zhou, Ze, additional, Liu, Xiaomin, additional, Nalpathamkalam, Thomas, additional, Walker, Susan, additional, Howe, Jennifer L, additional, Wang, Zhuozhi, additional, MacDonald, Jeffrey R, additional, Chan, Ada JS, additional, D’Abate, Lia, additional, Deneault, Eric, additional, Siu, Michelle T, additional, Tammimies, Kristiina, additional, Uddin, Mohammed, additional, Zarrei, Mehdi, additional, Wang, Mingbang, additional, Li, Yingrui, additional, Wang, Jun, additional, Wang, Jian, additional, Yang, Huanming, additional, Bookman, Matt, additional, Bingham, Jonathan, additional, Gross, Samuel S, additional, Loy, Dion, additional, Pletcher, Mathew, additional, Marshall, Christian R, additional, Anagnostou, Evdokia, additional, Zwaigenbaum, Lonnie, additional, Weksberg, Rosanna, additional, Fernandez, Bridget A, additional, Roberts, Wendy, additional, Szatmari, Peter, additional, Glazer, David, additional, Frey, Brendan J, additional, Ring, Robert H, additional, Xu, Xun, additional, and Scherer, Stephen W, additional

Published
2016
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41. ISDN2014_0253: High resolution genomic analyses of a clinically defined autism spectrum disorder cohort

Author

Tammimies, Kristiina, primary, Fernandez, Bridget A., additional, Walker, Susan, additional, Thiruvahindrapuram, Bhooma, additional, Kaur, Gaganjot, additional, Lionel, Anath C., additional, Roberts, Wendy, additional, Weksberg, Rosanna, additional, Howe, Jennifer L., additional, Uddin, Mohammed, additional, Yuen, Ryan K.C., additional, Wang, Zhuozhi, additional, Szatmari, Peter, additional, Whitten, Kathy, additional, Vardy, Cathy, additional, Crosbie, Victoria, additional, Luscombe, Sandra, additional, Doyle, Tyna, additional, Stuckless, Susan, additional, Merico, Daniele, additional, Marshall, Christian R., additional, and Scherer, Stephen W., additional

Published
2015
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42. Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

Author

Anagnostou, Evdokia, Cao, Dandan, Drmic, Irene E., Jiang, Yong-hui, Marshall, Christian R., Luo, Jun, Chrysler, Christina, Wang, Mingbang, Yuen, Ryan K.C., Lau, Lynette, Howe, Jennifer L., Carter, Melissa T., Lajonchere, Clara, Walker, Susan, Ring, Robert H., Wang, Guangbiao, He, Mingze, Nalpathamkalam, Thomas, Shi, Yujian, Ju, Jia, Mei, Junpu, Uddin, Mohammed, Thiruvahindrapuram, Bhooma, Chen, Nong, Wang, Jian, Thompson, Ann, Liang, Jieqin, Jin, Xin, Wu, Xueli, Zwaigenbaum, Lonnie, Merico, Daniele, and Wang, Zhe

Subjects
mental disorders
Abstract

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.

Published
2013
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43. Individual common variants exert weak effects on the risk for autism spectrum disorderspi

Author

Anney, Richard Klei, Lambertus Pinto, Dalila Almeida, Joana and Bacchelli, Elena Baird, Gillian Bolshakova, Nadia and Boelte, Sven Bolton, Patrick F. Bourgeron, Thomas Brennan, Sean Brian, Jessica Casey, Jillian Conroy, Judith and Correia, Catarina Corsello, Christina Crawford, Emily L. de Jonge, Maretha Delorme, Richard Duketis, Eftichia Duque, Frederico Estes, Annette Farrar, Penny Fernandez, Bridget A. and Folstein, Susan E. Fombonne, Eric Gilbert, John and Gillberg, Christopher Glessner, Joseph T. Green, Andrew and Green, Jonathan Guter, Stephen J. Heron, Elizabeth A. Holt, Richard Howe, Jennifer L. Hughes, Gillian Hus, Vanessa and Igliozzi, Roberta Jacob, Suma Kenny, Graham P. Kim, Cecilia and Kolevzon, Alexander Kustanovich, Vlad Lajonchere, Clara M. and Lamb, Janine A. Law-Smith, Miriam Leboyer, Marion Le Couteur, Ann Leventhal, Bennett L. Liu, Xiao-Qing Lombard, Frances Lord, Catherine Lotspeich, Linda Lund, Sabata C. and Magalhaes, Tiago R. Mantoulan, Carine McDougle, Christopher J. and Melhem, Nadine M. Merikangas, Alison Minshew, Nancy J. and Mirza, Ghazala K. Munson, Jeff Noakes, Carolyn Nygren, Gudrun Papanikolaou, Katerina Pagnamenta, Alistair T. and Parrini, Barbara Paton, Tara Pickles, Andrew Posey, David J. and Poustka, Fritz Ragoussis, Jiannis Regan, Regina Roberts, Wendy Roeder, Kathryn Roge, Bernadette Rutter, Michael L. and Schlitt, Sabine Shah, Naisha Sheffield, Val C. Soorya, Latha Sousa, Ines Stoppioni, Vera Sykes, Nuala Tancredi, Raffaella Thompson, Ann P. Thomson, Susanne Tryfon, Ana and Tsiantis, John Van Engeland, Herman Vincent, John B. and Volkmar, Fred Vorstman, J. A. S. Wallace, Simon Wing, Kirsty and Wittemeyer, Kerstin Wood, Shawn Zurawiecki, Danielle and Zwaigenbaum, Lonnie Bailey, Anthony J. Battaglia, Agatino and Cantor, Rita M. Coon, Hilary Cuccaro, Michael L. Dawson, Geraldine Ennis, Sean Freitag, Christine M. Geschwind, Daniel H. Haines, Jonathan L. Klauck, Sabine M. McMahon, William M. Maestrini, Elena Miller, Judith Monaco, Anthony P. Nelson, Stanley F. Nurnberger, Jr., John I. Oliveira, Guiomar Parr, Jeremy R. Pericak-Vance, Margaret A. Piven, Joseph Schellenberg, Gerard D. Scherer, StephenW. Vicente, Astrid M. Wassink, Thomas H. Wijsman, Ellen M. Betancur, Catalina Buxbaum, Joseph D. Cook, Edwin H. Gallagher, Louise and Gill, Michael Hallmayer, Joachim Paterson, Andrew D. and Sutcliffe, James S. Szatmari, Peter Vieland, Veronica J. and Hakonarson, Hakon Devlin, Bernie

Subjects
mental disorders
Abstract

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm 1). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Published
2012

44. Using extended pedigrees to identify novel autism spectrum disorder (ASD) candidate genes

Author

Woodbury-Smith, Marc, primary, Paterson, Andrew D., additional, Thiruvahindrapduram, Bhooma, additional, Lionel, Anath C., additional, Marshall, Christian R., additional, Merico, Daniele, additional, Fernandez, Bridget A., additional, Duku, Eric, additional, Sutcliffe, James S., additional, O’Conner, Irene, additional, Chrysler, Christina, additional, Thompson, Ann, additional, Kellam, Barbara, additional, Tammimies, Kristiina, additional, Walker, Susan, additional, Yuen, Ryan K. C., additional, Uddin, Mohammed, additional, Howe, Jennifer L., additional, Parlier, Morgan, additional, Whitten, Kathy, additional, Szatmari, Peter, additional, Vieland, Veronica J., additional, Piven, Joseph, additional, and Scherer, Stephen W., additional

Published
2014
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45. Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

Author

Jiang, Yong-hui, primary, Yuen, Ryan K.C., additional, Jin, Xin, additional, Wang, Mingbang, additional, Chen, Nong, additional, Wu, Xueli, additional, Ju, Jia, additional, Mei, Junpu, additional, Shi, Yujian, additional, He, Mingze, additional, Wang, Guangbiao, additional, Liang, Jieqin, additional, Wang, Zhe, additional, Cao, Dandan, additional, Carter, Melissa T., additional, Chrysler, Christina, additional, Drmic, Irene E., additional, Howe, Jennifer L., additional, Lau, Lynette, additional, Marshall, Christian R., additional, Merico, Daniele, additional, Nalpathamkalam, Thomas, additional, Thiruvahindrapuram, Bhooma, additional, Thompson, Ann, additional, Uddin, Mohammed, additional, Walker, Susan, additional, Luo, Jun, additional, Anagnostou, Evdokia, additional, Zwaigenbaum, Lonnie, additional, Ring, Robert H., additional, Wang, Jian, additional, Lajonchere, Clara, additional, Wang, Jun, additional, Shih, Andy, additional, Szatmari, Peter, additional, Yang, Huanming, additional, Dawson, Geraldine, additional, Li, Yingrui, additional, and Scherer, Stephen W., additional

Published
2013
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46. Rare Copy Number Variation Discovery and Cross-Disorder Comparisons Identify Risk Genes for ADHD

Author

Lionel, Anath C., primary, Crosbie, Jennifer, additional, Barbosa, Nicole, additional, Goodale, Tara, additional, Thiruvahindrapuram, Bhooma, additional, Rickaby, Jessica, additional, Gazzellone, Matthew, additional, Carson, Andrew R., additional, Howe, Jennifer L., additional, Wang, Zhuozhi, additional, Wei, John, additional, Stewart, Alexandre F. R., additional, Roberts, Robert, additional, McPherson, Ruth, additional, Fiebig, Andreas, additional, Franke, Andre, additional, Schreiber, Stefan, additional, Zwaigenbaum, Lonnie, additional, Fernandez, Bridget A., additional, Roberts, Wendy, additional, Arnold, Paul D., additional, Szatmari, Peter, additional, Marshall, Christian R., additional, Schachar, Russell, additional, and Scherer, Stephen W., additional

Published
2011
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48. High resolution genomic analyses of a clinically defined autism spectrum disorder cohort.

Author

Tammimies, Kristiina, Fernandez, Bridget A., Walker, Susan, Thiruvahindrapuram, Bhooma, Kaur, Gaganjot, Lionel, Anath C., Roberts, Wendy, Weksberg, Rosanna, Howe, Jennifer L., Uddin, Mohammed, Yuen, Ryan K.C., Wang, Zhuozhi, Szatmari, Peter, Whitten, Kathy, Vardy, Cathy, Crosbie, Victoria, Luscombe, Sandra, Doyle, Tyna, Stuckless, Susan, and Merico, Daniele

Published
2015
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49. Chromosome X-Wide Common Variant Association Study (XWAS) in Autism Spectrum Disorder.

Author

Mendes M, Chen DZ, Engchuan W, Leal TP, Thiruvahindrapuram B, Trost B, Howe JL, Pellecchia G, Nalpathamkalam T, Alexandrova R, Salazar NB, McKee EA, Alfaro NR, Lai MC, Bandres-Ciga S, Roshandel D, Bradley CA, Anagnostou E, Sun L, and Scherer SW

Abstract

Autism Spectrum Disorder (ASD) displays a notable male bias in prevalence. Research into rare (<0.1) genetic variants on the X chromosome has implicated over 20 genes in ASD pathogenesis, such as MECP2 , DDX3X , and DMD . The "female protective effect" in ASD suggests that females may require a higher genetic burden to manifest similar symptoms as males, yet the mechanisms remain unclear. Despite technological advances in genomics, the complexity of the biological nature of sex chromosomes leave them underrepresented in genome-wide studies. Here, we conducted an X chromosome-wide association study (XWAS) using whole-genome sequencing data from 6,873 individuals with ASD (82% males) across Autism Speaks MSSNG, Simons Simplex Cohort SSC, and Simons Foundation Powering Autism Research SPARK, alongside 8,981 population controls (43% males). We analyzed 418,652 X-chromosome variants, identifying 59 associated with ASD (p-values 7.9×10 -6 to 1.51×10 -5 ), surpassing Bonferroni-corrected thresholds. Key findings include significant regions on chrXp22.2 (lead SNP=rs12687599, p=3.57×10 -7 ) harboring ASB9 / ASB11 , and another encompassing DDX53/PTCHD1-AS long non-coding RNA (lead SNP=rs5926125, p=9.47×10 -6 ). When mapping genes within 10kb of the 59 most significantly associated SNPs, 91 genes were found, 17 of which yielded association with ASD ( GRPR , AP1S2 , DDX53 , HDAC8 , PCDH19 , PTCHD1 , PCDH11X , PTCHD1-AS , DMD , SYAP1 , CNKSR2 , GLRA2 , OFD1 , CDKL5 , GPRASP2 , NXF5 , SH3KBP1 ). FGF13 emerged as a novel X-linked ASD candidate gene, highlighted by sex-specific differences in minor allele frequencies. These results reveal significant new insights into X chromosome biology in ASD, confirming and nominating genes and pathways for further investigation., Competing Interests: At the time of this study and its publication, S.W.S. served on the Scientific Advisory Committee of Population Bio. Intellectual property from aspects of his research held at The Hospital for Sick Children are licensed to Athena Diagnostics and Population Bio. These relationships did not influence data interpretation or presentation during this study but are disclosed for potential future considerations.

Published
2024
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50. Genetic variants in DDX53 contribute to Autism Spectrum Disorder associated with the Xp22.11 locus.

Author

Scala M, Bradley CA, Howe JL, Trost B, Salazar NB, Shum C, Reuter MS, MacDonald JR, Ko SY, Frankland PW, Granger L, Anadiotis G, Pullano V, Brusco A, Keller R, Parisotto S, Pedro HF, Lusk L, McDonnell PP, Helbig I, Mullegama SV, Douine ED, Russell BE, Nelson SF, Zara F, and Scherer SW

Abstract

Autism Spectrum Disorder (ASD) exhibits an ~4:1 male-to-female sex bias and is characterized by early-onset impairment of social/communication skills, restricted interests, and stereotyped behaviors. Disruption of the Xp22.11 locus has been associated with ASD in males. This locus includes the three-exon PTCHD1 gene, an adjacent multi-isoform long noncoding RNA (lncRNA) named PTCHD1-AS (spanning ~1Mb), and a poorly characterized single-exon RNA helicase named DDX53 that is intronic to PTCHD1-AS . While the relationship between PTCHD1/PTCHD1-AS and ASD is being studied, the role of DDX53 has not been examined, in part because there is no apparent functional murine orthologue. Through clinical testing, here, we identified 6 males and 1 female with ASD from 6 unrelated families carrying rare, predicted-damaging or loss-of-function variants in DDX53 . Then, we examined databases, including the Autism Speaks MSSNG and Simons Foundation Autism Research Initiative, as well as population controls. We identified 24 additional individuals with ASD harboring rare, damaging DDX53 variations, including the same variants detected in two families from the original clinical analysis. In this extended cohort of 31 participants with ASD (28 male, 3 female), we identified 25 mostly maternally-inherited variations in DDX53 , including 18 missense changes, 2 truncating variants, 2 in-frame variants, 2 deletions in the 3' UTR and 1 copy number deletion. Our findings in humans support a direct link between DDX53 and ASD, which will be important in clinical genetic testing. These same autism-related findings, coupled with the observation that a functional orthologous gene is not found in mouse, may also influence the design and interpretation of murine-modelling of ASD., Competing Interests: Competing interests At the time of this study and its publication, S.W.S. served on the Scientific Advisory Committee of Population Bio. Intellectual property from aspects of his research held at The Hospital for Sick Children are licensed to Athena Diagnostics and Population Bio. These relationships did not influence data interpretation or presentation during this study but are disclosed for potential future considerations. SVM is an employee of GeneDx, LLC. HFP is on the research advisory boards and speaker bureau for Takeda Pharmaceutical, AvroBio, Amicus Therapeutics, Sanofi, Alexion Therapeutics, Denali Therapeutics and Acer Therapeutics. All other authors declare no conflict of interest.

Published
2023
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