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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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3. Genomic architecture of autism from comprehensive whole-genome sequence annotation.

Author

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

Subjects
autism spectrum disorder, copy-number variation, neurodevelopmental disorders, phenotype measures, polygenic risk scores, rare variants, structural variation, whole-genome sequencing, Humans, Autism Spectrum Disorder, Autistic Disorder, Genetic Predisposition to Disease, DNA Copy Number Variations, Genomics
Abstract

Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.

Published
2022

4. Genome-wide enhancer-associated tandem repeats are expanded in cardiomyopathy

Author

Mitina, Aleksandra, Khan, Mahreen, Lesurf, Robert, Yin, Yue, Engchuan, Worrawat, Hamdan, Omar, Pellecchia, Giovanna, Trost, Brett, Backstrom, Ian, Guo, Keyi, Pallotto, Linda M., Lam Doong, Phoenix Hoi, Wang, Zhuozhi, Nalpathamkalam, Thomas, Thiruvahindrapuram, Bhooma, Papaz, Tanya, Pearson, Christopher E., Ragoussis, Jiannis, Subbarao, Padmaja, Azad, Meghan B., Turvey, Stuart E., Mandhane, Piushkumar, Moraes, Theo J., Simons, Elinor, Scherer, Stephen W., Lougheed, Jane, Mondal, Tapas, Smythe, John, Altamirano-Diaz, Luis, Oechslin, Erwin, Mital, Seema, and Yuen, Ryan K.C.

Published
2024
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5. 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. Leveraging cancer mutation data to predict the pathogenicity of germline missense variants

Author

Haque, Bushra, primary, Cheerie, David, additional, Pan, Amy, additional, Curtis, Meredith, additional, Nalpathamkalam, Thomas, additional, Nguyen, Jimmy, additional, Salhab, Celine, additional, Thiruvahindrapura, Bhooma, additional, Zhang, Jade, additional, Couse, Madeline, additional, Hartley, Taila, additional, Morrow, Michelle M, additional, Price, E Magda, additional, Walker, Susan, additional, Malkin, David, additional, Roth, Frederick P, additional, and Costain, Gregory, additional

Published
2024
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8. 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. Gene copy number variation and pediatric mental health/neurodevelopment in a general population

Author

Zarrei, Mehdi, primary, Burton, Christie L, additional, Engchuan, Worrawat, additional, Higginbotham, Edward J, additional, Wei, John, additional, Shaikh, Sabah, additional, Roslin, Nicole M, additional, MacDonald, Jeffrey R, additional, Pellecchia, Giovanna, additional, Nalpathamkalam, Thomas, additional, Lamoureux, Sylvia, additional, Manshaei, Roozbeh, additional, Howe, Jennifer, additional, Trost, Brett, additional, Thiruvahindrapuram, Bhooma, additional, Marshall, Christian R, additional, Yuen, Ryan K C, additional, Wintle, Richard F, additional, Strug, Lisa J, additional, Stavropoulos, Dimitri J, additional, Vorstman, Jacob A S, additional, Arnold, Paul, additional, Merico, Daniele, additional, Woodbury-Smith, Marc, additional, Crosbie, Jennifer, additional, Schachar, Russell, additional, and Scherer, Stephen W, additional

Published
2023
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12. Whole Genome Sequencing to Resolve the Genomic Architecture of Cerebral Palsy in a Canadian Cohort (P13-9.003)

Author

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

Published
2023
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13. The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants

Author

Reuter, Miriam S., Walker, Susan, Thiruvahindrapuram, Bhooma, Whitney, Joe, Cohn, Iris, Sondheimer, Neal, Yuen, Ryan K.C., Trost, Brett, Paton, Tara A., Pereira, Sergio L., Herbrick, Jo-Anne, Wintle, Richard F., Merico, Daniele, Howe, Jennifer, MacDonald, Jeffrey R., Lu, Chao, Nalpathamkalam, Thomas, Sung, Wilson W.L., Wang, Zhuozhi, Patel, Rohan V., Pellecchia, Giovanna, Wei, John, Strug, Lisa J., Bell, Sherilyn, Kellam, Barbara, Mahtani, Melanie M., Bassett, Anne S., Bombard, Yvonne, Weksberg, Rosanna, Shuman, Cheryl, Cohn, Ronald D., Stavropoulos, Dimitri J., Bowdin, Sarah, Hildebrandt, Matthew R., Wei, Wei, Romm, Asli, Pasceri, Peter, Ellis, James, Ray, Peter, Meyn, M. Stephen, Monfared, Nasim, Hosseini, S. Mohsen, Joseph-George, Ann M., Keeley, Fred W., Cook, Ryan A., Fiume, Marc, Lee, Hin C., Marshall, Christian R., Davies, Jill, Hazell, Allison, Buchanan, Janet A., Szego, Michael J., and Scherer, Stephen W.

Subjects
Health policy -- Analysis, DNA sequencing -- Analysis, Pharmacogenomics -- Analysis, Health
Abstract

BACKGROUND: The Personal Genome Project Canada is a comprehensive public data resource that integrates whole genome sequencing data and health information. We describe genomic variation identified in the initial recruitment cohort of 56 volunteers. METHODS: Volunteers were screened for eligibility and provided informed consent for open data sharing. Using blood DNA, we performed whole genome sequencing and identified all possible classes of DNA variants. A genetic counsellor explained the implication of the results to each participant. RESULTS: Whole genome sequencing of the first 56 participants identified 207662 805 sequence variants and 27494 copy number variations. We analyzed a prioritized disease-associated data set (n = 1606 variants) according to standardized guidelines, and interpreted 19 variants in 14 participants (25%) as having obvious health implications. Six of these variants (e.g., in BRCA1 or mosaic loss of an X chromosome) were pathogenic or likely pathogenic. Seven were risk factors for cancer, cardiovascular or neurobehavioural conditions. Four other variants--associated with cancer, cardiac or neurodegenerative phenotypes--remained of uncertain significance because of discrepancies among databases. We also identified a large structural chromosome aberration and a likely pathogenic mitochondrial variant. There were 172 recessive disease alleles (e.g., 5 individuals carried mutations for cystic fibrosis). Pharmacogenomics analyses revealed another 3.9 potentially relevant genotypes per individual. INTERPRETATION: Our analyses identified a spectrum of genetic variants with potential health impact in 25% of participants. When also considering recessive alleles and variants with potential pharmacologic relevance, all 56 participants had medically relevant findings. Although access is mostly limited to research, whole genome sequencing can provide specific and novel information with the potential of major impact for health care., Rapid technological advances are enabling a view of human genetic variation in ever-increasing detail and at plummeting costs. (1) Until recently, analysis has been targeted largely to defined genes, but [...]

Published
2018
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14. Gene copy number variation in pediatric mental illness in a general population

Author

Zarrei, Mehdi, primary, Burton, Christie L., additional, Engchuan, Worrawat, additional, Higginbotham, Edward J, additional, Wei, John, additional, Shaikh, Sabah, additional, Roslin, Nicole M., additional, MacDonald, Jeffrey R., additional, Pellecchia, Giovanna, additional, Nalpathamkalam, Thomas, additional, Lamoureux, Sylvia, additional, Manshaei, Roozbeh, additional, Howe, Jennifer, additional, Trost, Brett, additional, Thiruvahindrapuram, Bhooma, additional, Marshall, Christian R., additional, Yuen, Ryan K.C., additional, Wintle, Richard F., additional, Strug, Lisa J, additional, Stavropoulos, Dimitri J., additional, Vorstman, Jacob A.S., additional, Arnold, Paul, additional, Merico, Daniele, additional, Woodbury-Smith, Marc, additional, Crosbie, Jennifer, additional, Schachar, Russell, additional, and Scherer, Stephen W., additional

Published
2022
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15. 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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16. 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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19. 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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20. Clinical Genetic Risk Variants Inform a Functional Protein Interaction Network for Tetralogy of Fallot

Author

Reuter, Miriam S., primary, Chaturvedi, Rajiv R., additional, Jobling, Rebekah K., additional, Pellecchia, Giovanna, additional, Hamdan, Omar, additional, Sung, Wilson W.L., additional, Nalpathamkalam, Thomas, additional, Attaluri, Pratyusha, additional, Silversides, Candice K., additional, Wald, Rachel M., additional, Marshall, Christian R., additional, Williams, Simon G., additional, Keavney, Bernard D., additional, Thiruvahindrapuram, Bhooma, additional, Scherer, Stephen W., additional, and Bassett, Anne S., additional

Published
2021
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21. Genes and Pathways Implicated in Tetralogy of Fallot Revealed by Ultra-Rare Variant Burden Analysis in 231 Genome Sequences

Author

Manshaei, Roozbeh, primary, Merico, Daniele, additional, Reuter, Miriam S., additional, Engchuan, Worrawat, additional, Mojarad, Bahareh A., additional, Chaturvedi, Rajiv, additional, Heung, Tracy, additional, Pellecchia, Giovanna, additional, Zarrei, Mehdi, additional, Nalpathamkalam, Thomas, additional, Khan, Reem, additional, Okello, John B. A., additional, Liston, Eriskay, additional, Curtis, Meredith, additional, Yuen, Ryan K. C., additional, Marshall, Christian R., additional, Jobling, Rebekah K., additional, Oechslin, Erwin, additional, Wald, Rachel M., additional, Silversides, Candice K., additional, Scherer, Stephen W., additional, Kim, Raymond H., additional, and Bassett, Anne S., additional

Published
2020
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23. 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

24. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

Author

Lionel, Anath C., primary, Costain, Gregory, additional, Monfared, Nasim, additional, Walker, Susan, additional, Reuter, Miriam S., additional, Hosseini, S. Mohsen, additional, Thiruvahindrapuram, Bhooma, additional, Merico, Daniele, additional, Jobling, Rebekah, additional, Nalpathamkalam, Thomas, additional, Pellecchia, Giovanna, additional, Sung, Wilson W.L., additional, Wang, Zhuozhi, additional, Bikangaga, Peter, additional, Boelman, Cyrus, additional, Carter, Melissa T., additional, Cordeiro, Dawn, additional, Cytrynbaum, Cheryl, additional, Dell, Sharon D., additional, Dhir, Priya, additional, Dowling, James J., additional, Heon, Elise, additional, Hewson, Stacy, additional, Hiraki, Linda, additional, Inbar-Feigenberg, Michal, additional, Klatt, Regan, additional, Kronick, Jonathan, additional, Laxer, Ronald M., additional, Licht, Christoph, additional, MacDonald, Heather, additional, Mercimek-Andrews, Saadet, additional, Mendoza-Londono, Roberto, additional, Piscione, Tino, additional, Schneider, Rayfel, additional, Schulze, Andreas, additional, Silverman, Earl, additional, Siriwardena, Komudi, additional, Snead, O. Carter, additional, Sondheimer, Neal, additional, Sutherland, Joanne, additional, Vincent, Ajoy, additional, Wasserman, Jonathan D., additional, Weksberg, Rosanna, additional, Shuman, Cheryl, additional, Carew, Chris, additional, Szego, Michael J., additional, Hayeems, Robin Z., additional, Basran, Raveen, additional, Stavropoulos, Dimitri J., additional, Ray, Peter N., additional, Bowdin, Sarah, additional, Meyn, M. Stephen, additional, Cohn, Ronald D., additional, Scherer, Stephen W., additional, and Marshall, Christian R., additional

Published
2018
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25. OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3 Microdeletion Syndrome

Author

Uddin, Mohammed, primary, Unda, Brianna K., additional, Kwan, Vickie, additional, Holzapfel, Nicholas T., additional, White, Sean H., additional, Chalil, Leon, additional, Woodbury-Smith, Marc, additional, Ho, Karen S., additional, Harward, Erin, additional, Murtaza, Nadeem, additional, Dave, Biren, additional, Pellecchia, Giovanna, additional, D’Abate, Lia, additional, Nalpathamkalam, Thomas, additional, Lamoureux, Sylvia, additional, Wei, John, additional, Speevak, Marsha, additional, Stavropoulos, James, additional, Hope, Kristin J., additional, Doble, Brad W., additional, Nielsen, Jacob, additional, Wassman, E. Robert, additional, Scherer, Stephen W., additional, and Singh, Karun K., additional

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

Author

Onderzoek, Brain, 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., Scherer, Stephen W., Onderzoek, Brain, 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.

Published
2017

27. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder

Author

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

Published
2017
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28. 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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29. Indexing Effects of Copy Number Variation on Genes Involved in Developmental Delay

Author

Uddin, Mohammed, primary, Pellecchia, Giovanna, additional, Thiruvahindrapuram, Bhooma, additional, D’Abate, Lia, additional, Merico, Daniele, additional, Chan, Ada, additional, Zarrei, Mehdi, additional, Tammimies, Kristiina, additional, Walker, Susan, additional, Gazzellone, Matthew J., additional, Nalpathamkalam, Thomas, additional, Yuen, Ryan K. C., additional, Devriendt, Koenraad, additional, Mathonnet, Géraldine, additional, Lemyre, Emmanuelle, additional, Nizard, Sonia, additional, Shago, Mary, additional, Joseph-George, Ann M., additional, Noor, Abdul, additional, Carter, Melissa T., additional, Yoon, Grace, additional, Kannu, Peter, additional, Tihy, Frédérique, additional, Thorland, Erik C., additional, Marshall, Christian R., additional, Buchanan, Janet A., additional, Speevak, Marsha, additional, Stavropoulos, Dimitri J., additional, and Scherer, Stephen W., additional

Published
2016
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31. Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine

Author

Stavropoulos, Dimitri J, primary, Merico, Daniele, additional, Jobling, Rebekah, additional, Bowdin, Sarah, additional, Monfared, Nasim, additional, Thiruvahindrapuram, Bhooma, additional, Nalpathamkalam, Thomas, additional, Pellecchia, Giovanna, additional, Yuen, Ryan K C, additional, Szego, Michael J, additional, Hayeems, Robin Z, additional, Shaul, Randi Zlotnik, additional, Brudno, Michael, additional, Girdea, Marta, additional, Frey, Brendan, additional, Alipanahi, Babak, additional, Ahmed, Sohnee, additional, Babul-Hirji, Riyana, additional, Porras, Ramses Badilla, additional, Carter, Melissa T, additional, Chad, Lauren, additional, Chaudhry, Ayeshah, additional, Chitayat, David, additional, Doust, Soghra Jougheh, additional, Cytrynbaum, Cheryl, additional, Dupuis, Lucie, additional, Ejaz, Resham, additional, Fishman, Leona, additional, Guerin, Andrea, additional, Hashemi, Bita, additional, Helal, Mayada, additional, Hewson, Stacy, additional, Inbar-Feigenberg, Michal, additional, Kannu, Peter, additional, Karp, Natalya, additional, Kim, Raymond H, additional, Kronick, Jonathan, additional, Liston, Eriskay, additional, MacDonald, Heather, additional, Mercimek-Mahmutoglu, Saadet, additional, Mendoza-Londono, Roberto, additional, Nasr, Enas, additional, Nimmo, Graeme, additional, Parkinson, Nicole, additional, Quercia, Nada, additional, Raiman, Julian, additional, Roifman, Maian, additional, Schulze, Andreas, additional, Shugar, Andrea, additional, Shuman, Cheryl, additional, Sinajon, Pierre, additional, Siriwardena, Komudi, additional, Weksberg, Rosanna, additional, Yoon, Grace, additional, Carew, Chris, additional, Erickson, Raith, additional, Leach, Richard A, additional, Klein, Robert, additional, Ray, Peter N, additional, Meyn, M Stephen, additional, Scherer, Stephen W, additional, Cohn, Ronald D, additional, and Marshall, Christian R, additional

Published
2016
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32. 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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33. The genetic diversity of Epstein-Barr virus in the setting of transplantation relative to non-transplant settings: A feasibility study

Author

Allen, Upton D., primary, Hu, Pingzhao, additional, Pereira, Sergio L., additional, Robinson, Joan L., additional, Paton, Tara A., additional, Beyene, Joseph, additional, Khodai-Booran, Nasser, additional, Dipchand, Anne, additional, Hébert, Diane, additional, Ng, Vicky, additional, Nalpathamkalam, Thomas, additional, and Read, Stanley, additional

Published
2015
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34. Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing

Author

Merico, Daniele, primary, Roifman, Maian, additional, Braunschweig, Ulrich, additional, Yuen, Ryan K. C., additional, Alexandrova, Roumiana, additional, Bates, Andrea, additional, Reid, Brenda, additional, Nalpathamkalam, Thomas, additional, Wang, Zhuozhi, additional, Thiruvahindrapuram, Bhooma, additional, Gray, Paul, additional, Kakakios, Alyson, additional, Peake, Jane, additional, Hogarth, Stephanie, additional, Manson, David, additional, Buncic, Raymond, additional, Pereira, Sergio L., additional, Herbrick, Jo-Anne, additional, Blencowe, Benjamin J., additional, Roifman, Chaim M., additional, and Scherer, Stephen W., additional

Published
2015
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35. MG-132 Diagnostic utility of whole genome sequencing in paediatric medicine

Author

Marshall, Christian R, primary, Stavropoulos, Dimitri J, additional, Jobling, Rebekah, additional, Merico, Daniele, additional, Bowdin, Sarah, additional, Monfared, Nasim, additional, Meyn, MStephen, additional, Szego, Michael, additional, Shaul, Randi Zlotnik, additional, Thiruvahindrapuram, Bhooma, additional, Pellecchia, Giovanna, additional, Nalpathamkalam, Thomas, additional, Brudno, Michael, additional, Girdea, Marta, additional, Hayeems, Robin Z, additional, Carew, Chris, additional, Erickson, Raith, additional, Leach, Richard A, additional, Shuman, Cheryl, additional, Ray, Peter N, additional, Cohn, Ronald D, additional, and Scherer, Stephen W, additional

Published
2015
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36. Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome

Author

Merico, Daniele, primary, Zarrei, Mehdi, additional, Costain, Gregory, additional, Ogura, Lucas, additional, Alipanahi, Babak, additional, Gazzellone, Matthew J, additional, Butcher, Nancy J, additional, Thiruvahindrapuram, Bhooma, additional, Nalpathamkalam, Thomas, additional, Chow, Eva W C, additional, Andrade, Danielle M, additional, Frey, Brendan J, additional, Marshall, Christian R, additional, Scherer, Stephen W, additional, and Bassett, Anne S, additional

Published
2015
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37. Mutations in tetratricopeptide repeat domain 7A (TTC7A) are associated with combined immunodeficiency with dendriform lung ossification but no intestinal atresia

Author

Ngan, Bo, primary, Merico, Daniele, additional, Marcus, Nufar, additional, Kim, Vy H.D., additional, Upton, Julia, additional, Bates, Andrea, additional, Herbrick, Joanne, additional, Nalpathamkalam, Thomas, additional, Thiruvahindrapuram, Bhooma, additional, Cox, Peter, additional, and Roifman, Chaim M., additional

Published
2014
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39. Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing

Author

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

Published
2013

40. 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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42. 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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43. Using Next-Generation Sequencing Transcriptomics To Determine Markers of Post-traumatic Symptoms: Preliminary Findings from a Post-deployment Cohort of Soldiers.

Author

Boscarino C, Nalpathamkalam T, Pellecchia G, Li W, Thiruvahindrapuram B, and Merico D

Subjects
Adult, Biomarkers blood, Gene Expression Profiling methods, Humans, LDL-Receptor Related Proteins genetics, LDL-Receptor Related Proteins metabolism, Male, Membrane Proteins genetics, Membrane Proteins metabolism, RNA, Messenger blood, RNA, Messenger genetics, RNA, Messenger metabolism, Stress Disorders, Post-Traumatic blood, Military Personnel, Stress Disorders, Post-Traumatic genetics, Transcriptome
Abstract

Post-traumatic stress disorder is a concerning psychobehavioral disorder thought to emerge from the complex interaction between genetic and environmental factors. For soldiers exposed to combat, the risk of developing this disorder is twofold and diagnosis is often late, when much sequela has set in. To be able to identify and diagnose in advance those at "risk" of developing post-traumatic stress disorder, would greatly taper the gap between late sequelae and treatment. Therefore, this study sought to determine whether the transcriptome can be used to track the development of post-traumatic stress disorder in this unique and susceptible cohort of individuals. Gene expression levels in peripheral blood samples from 85 Canadian infantry soldiers (n = 58 participants negative for symptoms of post-traumatic stress disorder and n = 27 participants with symptoms of post-traumatic stress disorder) following return from deployment to Afghanistan were determined using RNA sequencing technology. Count-based gene expression quantification, normalization and differential analysis (with thorough correction for confounders) revealed genes associated to PTSD; LRP8 and GOLM1 These preliminary results provide a proof-of-principle for the diagnostic utility of blood-based gene expression profiles for tracking symptoms of post-traumatic stress disorder in soldiers returning from tour. It is also the first to report transcriptome-wide expression profiles alongside a post-traumatic symptom checklist., (Copyright © 2019 Boscarino et al.)

Published
2019
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44. Whole-Genome Sequencing Suggests Schizophrenia Risk Mechanisms in Humans with 22q11.2 Deletion Syndrome.

Author

Merico D, Zarrei M, Costain G, Ogura L, Alipanahi B, Gazzellone MJ, Butcher NJ, Thiruvahindrapuram B, Nalpathamkalam T, Chow EW, Andrade DM, Frey BJ, Marshall CR, Scherer SW, and Bassett AS

Subjects
Adolescent, Adult, Case-Control Studies, DiGeorge Syndrome genetics, Female, Humans, Male, Middle Aged, RNA, Long Noncoding genetics, RNA-Binding Proteins genetics, Schizophrenia epidemiology, DiGeorge Syndrome complications, Genome, Human, Schizophrenia genetics
Abstract

Chromosome 22q11.2 microdeletions impart a high but incomplete risk for schizophrenia. Possible mechanisms include genome-wide effects of DGCR8 haploinsufficiency. In a proof-of-principle study to assess the power of this model, we used high-quality, whole-genome sequencing of nine individuals with 22q11.2 deletions and extreme phenotypes (schizophrenia, or no psychotic disorder at age >50 years). The schizophrenia group had a greater burden of rare, damaging variants impacting protein-coding neurofunctional genes, including genes involved in neuron projection (nominal P = 0.02, joint burden of three variant types). Variants in the intact 22q11.2 region were not major contributors. Restricting to genes affected by a DGCR8 mechanism tended to amplify between-group differences. Damaging variants in highly conserved long intergenic noncoding RNA genes also were enriched in the schizophrenia group (nominal P = 0.04). The findings support the 22q11.2 deletion model as a threshold-lowering first hit for schizophrenia risk. If applied to a larger and thus better-powered cohort, this appears to be a promising approach to identify genome-wide rare variants in coding and noncoding sequence that perturb gene networks relevant to idiopathic schizophrenia. Similarly designed studies exploiting genetic models may prove useful to help delineate the genetic architecture of other complex phenotypes., (Copyright © 2015 Merico et al.)

Published
2015
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