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203. Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate

Author

Jayaraman, Divya, primary, Kodani, Andrew, additional, Gonzalez, Dilenny M., additional, Mancias, Joseph D., additional, Mochida, Ganeshwaran H., additional, Vagnoni, Cristiana, additional, Johnson, Jeffrey, additional, Krogan, Nevan, additional, Harper, J. Wade, additional, Reiter, Jeremy F., additional, Yu, Timothy W., additional, Bae, Byoung-il, additional, and Walsh, Christopher A., additional

Published
2016
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204. The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States

Author

Reddy, Hemakumar M, primary, Cho, Kyung-Ah, additional, Lek, Monkol, additional, Estrella, Elicia, additional, Valkanas, Elise, additional, Jones, Michael D, additional, Mitsuhashi, Satomi, additional, Darras, Basil T, additional, Amato, Anthony A, additional, Lidov, Hart GW, additional, Brownstein, Catherine A, additional, Margulies, David M, additional, Yu, Timothy W, additional, Salih, Mustafa A, additional, Kunkel, Louis M, additional, MacArthur, Daniel G, additional, and Kang, Peter B, additional

Published
2016
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206. A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia

Author

Smedemark-Margulies, Niklas, primary, Brownstein, Catherine A., additional, Vargas, Sigella, additional, Tembulkar, Sahil K., additional, Towne, Meghan C., additional, Shi, Jiahai, additional, Gonzalez-Cuevas, Elisa, additional, Liu, Kevin X., additional, Bilguvar, Kaya, additional, Kleiman, Robin J., additional, Han, Min-Joon, additional, Torres, Alcy, additional, Berry, Gerard T., additional, Yu, Timothy W., additional, Beggs, Alan H., additional, Agrawal, Pankaj B., additional, and Gonzalez-Heydrich, Joseph, additional

Published
2016
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207. The TRPA1 ion channel is expressed in CD4+ T cells and restrains T-cell-mediated colitis through inhibition of TRPV1

Author

Bertin, Samuel, primary, Aoki-Nonaka, Yukari, additional, Lee, Jihyung, additional, de Jong, Petrus R, additional, Kim, Peter, additional, Han, Tiffany, additional, Yu, Timothy, additional, To, Keith, additional, Takahashi, Naoki, additional, Boland, Brigid S, additional, Chang, John T, additional, Ho, Samuel B, additional, Herdman, Scott, additional, Corr, Maripat, additional, Franco, Alessandra, additional, Sharma, Sonia, additional, Dong, Hui, additional, Akopian, Armen N, additional, and Raz, Eyal, additional

Published
2016
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208. BRAT1mutations present with a spectrum of clinical severity

Author

Srivastava, Siddharth, primary, Olson, Heather E., additional, Cohen, Julie S., additional, Gubbels, Cynthia S., additional, Lincoln, Sharyn, additional, Davis, Brigette Tippin, additional, Shahmirzadi, Layla, additional, Gupta, Siddharth, additional, Picker, Jonathan, additional, Yu, Timothy W., additional, Miller, David T., additional, Soul, Janet S., additional, Poretti, Andrea, additional, and Naidu, SakkuBai, additional

Published
2016
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209. Orthogonal NGS for High Throughput Clinical Diagnostics

Author

Chennagiri, Niru, primary, White, Eric J., additional, Frieden, Alexander, additional, Lopez, Edgardo, additional, Lieber, Daniel S., additional, Nikiforov, Anastasia, additional, Ross, Tristen, additional, Batorsky, Rebecca, additional, Hansen, Sherry, additional, Lip, Va, additional, Luquette, Lovelace J., additional, Mauceli, Evan, additional, Margulies, David, additional, Milos, Patrice M., additional, Napolitano, Nichole, additional, Nizzari, Marcia M., additional, Yu, Timothy, additional, and Thompson, John F., additional

Published
2016
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213. A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

Author

Chaste, Pauline, Chaste, Pauline, Klei, Lambertus, Sanders, Stephan J, Hus, Vanessa, Murtha, Michael T, Lowe, Jennifer K, Willsey, A Jeremy, Moreno-De-Luca, Daniel, Yu, Timothy W, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy E, Ledbetter, David H, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Walsh, Christopher A, Sutcliffe, James S, Lese Martin, Christa, Beaudet, Arthur L, Lord, Catherine, State, Matthew W, Cook, Edwin H, Devlin, Bernie, Chaste, Pauline, Chaste, Pauline, Klei, Lambertus, Sanders, Stephan J, Hus, Vanessa, Murtha, Michael T, Lowe, Jennifer K, Willsey, A Jeremy, Moreno-De-Luca, Daniel, Yu, Timothy W, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy E, Ledbetter, David H, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Walsh, Christopher A, Sutcliffe, James S, Lese Martin, Christa, Beaudet, Arthur L, Lord, Catherine, State, Matthew W, Cook, Edwin H, and Devlin, Bernie

Abstract

BackgroundPhenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD.MethodsGenome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup.ResultsAssociation analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups.ConclusionsIn genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.

Published
2015

214. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.

Author

Sanders, Stephan J, Sanders, Stephan J, He, Xin, Willsey, A Jeremy, Ercan-Sencicek, A Gulhan, Samocha, Kaitlin E, Cicek, A Ercument, Murtha, Michael T, Bal, Vanessa H, Bishop, Somer L, Dong, Shan, Goldberg, Arthur P, Jinlu, Cai, Keaney, John F, Klei, Lambertus, Mandell, Jeffrey D, Moreno-De-Luca, Daniel, Poultney, Christopher S, Robinson, Elise B, Smith, Louw, Solli-Nowlan, Tor, Su, Mack Y, Teran, Nicole A, Walker, Michael F, Werling, Donna M, Beaudet, Arthur L, Cantor, Rita M, Fombonne, Eric, Geschwind, Daniel H, Grice, Dorothy E, Lord, Catherine, Lowe, Jennifer K, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Talkowski, Michael E, Sutcliffe, James S, Walsh, Christopher A, Yu, Timothy W, Autism Sequencing Consortium, Ledbetter, David H, Martin, Christa Lese, Cook, Edwin H, Buxbaum, Joseph D, Daly, Mark J, Devlin, Bernie, Roeder, Kathryn, State, Matthew W, Sanders, Stephan J, Sanders, Stephan J, He, Xin, Willsey, A Jeremy, Ercan-Sencicek, A Gulhan, Samocha, Kaitlin E, Cicek, A Ercument, Murtha, Michael T, Bal, Vanessa H, Bishop, Somer L, Dong, Shan, Goldberg, Arthur P, Jinlu, Cai, Keaney, John F, Klei, Lambertus, Mandell, Jeffrey D, Moreno-De-Luca, Daniel, Poultney, Christopher S, Robinson, Elise B, Smith, Louw, Solli-Nowlan, Tor, Su, Mack Y, Teran, Nicole A, Walker, Michael F, Werling, Donna M, Beaudet, Arthur L, Cantor, Rita M, Fombonne, Eric, Geschwind, Daniel H, Grice, Dorothy E, Lord, Catherine, Lowe, Jennifer K, Mane, Shrikant M, Martin, Donna M, Morrow, Eric M, Talkowski, Michael E, Sutcliffe, James S, Walsh, Christopher A, Yu, Timothy W, Autism Sequencing Consortium, Ledbetter, David H, Martin, Christa Lese, Cook, Edwin H, Buxbaum, Joseph D, Daly, Mark J, Devlin, Bernie, Roeder, Kathryn, and State, Matthew W

Abstract

Analysis of de novo CNVs (dnCNVs) from the full Simons Simplex Collection (SSC) (N = 2,591 families) replicates prior findings of strong association with autism spectrum disorders (ASDs) and confirms six risk loci (1q21.1, 3q29, 7q11.23, 16p11.2, 15q11.2-13, and 22q11.2). The addition of published CNV data from the Autism Genome Project (AGP) and exome sequencing data from the SSC and the Autism Sequencing Consortium (ASC) shows that genes within small de novo deletions, but not within large dnCNVs, significantly overlap the high-effect risk genes identified by sequencing. Alternatively, large dnCNVs are found likely to contain multiple modest-effect risk genes. Overall, we find strong evidence that de novo mutations are associated with ASD apart from the risk for intellectual disability. Extending the transmission and de novo association test (TADA) to include small de novo deletions reveals 71 ASD risk loci, including 6 CNV regions (noted above) and 65 risk genes (FDR ≤ 0.1).

Published
2015

215. 20151119 Equinox Nov 19 2015

Author

Perez, Melanie; Arathoon, Katelyn; Levanti, Larry; Levine, Sandy; Clarke, Daniel; Holt, Molly; King, Terry; Yu, Timothy; Butera, Armand; Kennedy, Bill; Alami, Khadija; Madden, Chris; Martinez, Christina; Carlosn, Chris; Ashby, Natasha; Miles, David; White, Elizabeth; Goweh, Tyonna; Gaitan, Jeremy and Perez, Melanie; Arathoon, Katelyn; Levanti, Larry; Levine, Sandy; Clarke, Daniel; Holt, Molly; King, Terry; Yu, Timothy; Butera, Armand; Kennedy, Bill; Alami, Khadija; Madden, Chris; Martinez, Christina; Carlosn, Chris; Ashby, Natasha; Miles, David; White, Elizabeth; Goweh, Tyonna; Gaitan, Jeremy

Abstract

Teaneck edition; Volume 27, Issue 6; Frequency varies

Published
2015

216. DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome.

Author

Marsh, Ashley P. L., Edwards, Timothy J., Galea, Charles, Cooper, Helen M., Engle, Elizabeth C., Jamuar, Saumya S., Méneret, Aurélie, Moutard, Marie‐Laure, Nava, Caroline, Rastetter, Agnès, Robinson, Gail, Rouleau, Guy, Roze, Emmanuel, Spencer‐Smith, Megan, Trouillard, Oriane, Billette de Villemeur, Thierry, Walsh, Christopher A., Yu, Timothy W., IRC5 Consortium, and Heron, Delphine

Abstract

The deleted in colorectal cancer ( DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (). [ABSTRACT FROM AUTHOR]

Published
2018
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217. Unique bioinformatic approach and comprehensive reanalysis improve diagnostic yield of clinical exomes

Author

Schmitz-Abe, Klaus, Li, Qifei, Rosen, Samantha M., Nori, Neeharika, Madden, Jill A., Genetti, Casie A., Wojcik, Monica H., Ponnaluri, Sadhana, Gubbels, Cynthia S., Picker, Jonathan D., O’Donnell-Luria, Anne H., Yu, Timothy W., Bodamer, Olaf, Brownstein, Catherine A., Beggs, Alan H., and Agrawal, Pankaj B.

Abstract

Clinical exome sequencing (CES) is increasingly being utilized; however, a large proportion of patients remain undiagnosed, creating a need for a systematic approach to increase the diagnostic yield. We have reanalyzed CES data for a clinically heterogeneous cohort of 102 probands with likely Mendelian conditions, including 74 negative cases and 28 cases with candidate variants, but reanalysis requested by clinicians. Reanalysis was performed by an interdisciplinary team using a validated custom-built pipeline, “Variant Explorer Pipeline” (VExP). This reanalysis approach and results were compared with existing literature. Reanalysis of candidate variants from CES in 28 cases revealed 1 interpretation that needed to be reclassified. A confirmed or potential genetic diagnosis was identified in 24 of 75 CES-negative/reclassified cases (32.0%), including variants in known disease-causing genes (n= 6) or candidate genes (n= 18). This yield was higher compared with similar studies demonstrating the utility of this approach. In summary, reanalysis of negative CES in a research setting enhances diagnostic yield by about a third. This study suggests the need for comprehensive, continued reanalysis of exome data when molecular diagnosis is elusive.

Published
2019
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218. Recessive gene disruptions in autism spectrum disorder

Author

Doan, Ryan, Lim, Elaine, Rubeis, Silvia, Betancur, Catalina, Cutler, David, Chiocchetti, Andreas, Overman, Lynne, Soucy, Aubrie, Goetze, Susanne, Freitag, Christine, Daly, Mark, Walsh, Christopher, Buxbaum, Joseph, and Yu, Timothy

Abstract

Autism spectrum disorder (ASD) affects up to 1 in 59 individuals1. Genome-wide association and large-scale sequencing studies strongly implicate both common variants2–4and rare de novo variants5–10in ASD. Recessive mutations have also been implicated11–14but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to approximately 5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes (CA2,DDHD1,NSUN2,PAH,RARB,ROGDI,SLC1A1,USH2A) as well as other genes not previously implicated in ASD including FEV(FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition. Analysis of whole-exome sequencing data from 2,343 individuals with autism spectrum disorder compared to 5,852 unaffected individuals demonstrates an excess of biallelic, autosomal mutations for both loss-of-function and damaging missense variants.

Published
2019
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220. Chinese Silence, Asian American Critique

Author

Yu, Timothy

Abstract

Abstract:Timothy Yu uses as his jumping off point the imaginary cultural metaphor of Chinese 'Silences,' a trope that he mocks in his poetry book 100 Chinese Silences. Moving from this imagined idea to the reality of silencing Asian voices, Yu makes a compelling argument for the necessity of speaking up.

Published
2018

222. Mapping the neutralizing specificity of human anti-HIV serum by deep mutational scanning.

Author

Radford, Caelan E., Schommers, Philipp, Gieselmann, Lutz, Crawford, Katharine H.D., Dadonaite, Bernadeta, Yu, Timothy C., Dingens, Adam S., Overbaugh, Julie, Klein, Florian, and Bloom, Jesse D.

Abstract

Understanding the specificities of human serum antibodies that broadly neutralize HIV can inform prevention and treatment strategies. Here, we describe a deep mutational scanning system that can measure the effects of combinations of mutations to HIV envelope (Env) on neutralization by antibodies and polyclonal serum. We first show that this system can accurately map how all functionally tolerated mutations to Env affect neutralization by monoclonal antibodies. We then comprehensively map Env mutations that affect neutralization by a set of human polyclonal sera that neutralize diverse strains of HIV and target the site engaging the host receptor CD4. The neutralizing activities of these sera target different epitopes, with most sera having specificities reminiscent of individual characterized monoclonal antibodies, but one serum targeting two epitopes within the CD4-binding site. Mapping the specificity of the neutralizing activity in polyclonal human serum will aid in assessing anti-HIV immune responses to inform prevention strategies. [Display omitted] • Non-replicative lentiviral deep mutational scanning of HIV envelope • Accurate mapping of how thousands of mutations affect antibody neutralization • Comprehensive mapping of neutralizing activity of anti-HIV polyclonal sera • Multi-epitope neutralizing activity detected using deep mutational scanning Radford et al. use a non-replicative lentiviral system to measure how thousands of mutations to the HIV envelope affect viral entry and neutralizing antibody escape. They show that this system can map the neutralizing activity of polyclonal sera, including activity targeting two epitopes on the HIV envelope protein. [ABSTRACT FROM AUTHOR]

Published
2023
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223. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci

Author

Sanders, Stephan J., primary, He, Xin, additional, Willsey, A. Jeremy, additional, Ercan-Sencicek, A. Gulhan, additional, Samocha, Kaitlin E., additional, Cicek, A. Ercument, additional, Murtha, Michael T., additional, Bal, Vanessa H., additional, Bishop, Somer L., additional, Dong, Shan, additional, Goldberg, Arthur P., additional, Jinlu, Cai, additional, Keaney, John F., additional, Klei, Lambertus, additional, Mandell, Jeffrey D., additional, Moreno-De-Luca, Daniel, additional, Poultney, Christopher S., additional, Robinson, Elise B., additional, Smith, Louw, additional, Solli-Nowlan, Tor, additional, Su, Mack Y., additional, Teran, Nicole A., additional, Walker, Michael F., additional, Werling, Donna M., additional, Beaudet, Arthur L., additional, Cantor, Rita M., additional, Fombonne, Eric, additional, Geschwind, Daniel H., additional, Grice, Dorothy E., additional, Lord, Catherine, additional, Lowe, Jennifer K., additional, Mane, Shrikant M., additional, Martin, Donna M., additional, Morrow, Eric M., additional, Talkowski, Michael E., additional, Sutcliffe, James S., additional, Walsh, Christopher A., additional, Yu, Timothy W., additional, Ledbetter, David H., additional, Martin, Christa Lese, additional, Cook, Edwin H., additional, Buxbaum, Joseph D., additional, Daly, Mark J., additional, Devlin, Bernie, additional, Roeder, Kathryn, additional, and State, Matthew W., additional

Published
2015
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224. Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication

Author

Kodani, Andrew, primary, Yu, Timothy W, additional, Johnson, Jeffrey R, additional, Jayaraman, Divya, additional, Johnson, Tasha L, additional, Al-Gazali, Lihadh, additional, Sztriha, Lāszló, additional, Partlow, Jennifer N, additional, Kim, Hanjun, additional, Krup, Alexis L, additional, Dammermann, Alexander, additional, Krogan, Nevan J, additional, Walsh, Christopher A, additional, and Reiter, Jeremy F, additional

Published
2015
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225. Author response: Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication

Author

Kodani, Andrew, primary, Yu, Timothy W, additional, Johnson, Jeffrey R, additional, Jayaraman, Divya, additional, Johnson, Tasha L, additional, Al-Gazali, Lihadh, additional, Sztriha, Lāszló, additional, Partlow, Jennifer N, additional, Kim, Hanjun, additional, Krup, Alexis L, additional, Dammermann, Alexander, additional, Krogan, Nevan J, additional, Walsh, Christopher A, additional, and Reiter, Jeremy F, additional

Published
2015
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226. A Genome-wide Association Study of Autism Using the Simons Simplex Collection: Does Reducing Phenotypic Heterogeneity in Autism Increase Genetic Homogeneity?

Author

Chaste, Pauline, primary, Klei, Lambertus, additional, Sanders, Stephan J., additional, Hus, Vanessa, additional, Murtha, Michael T., additional, Lowe, Jennifer K., additional, Willsey, A. Jeremy, additional, Moreno-De-Luca, Daniel, additional, Yu, Timothy W., additional, Fombonne, Eric, additional, Geschwind, Daniel, additional, Grice, Dorothy E., additional, Ledbetter, David H., additional, Mane, Shrikant M., additional, Martin, Donna M., additional, Morrow, Eric M., additional, Walsh, Christopher A., additional, Sutcliffe, James S., additional, Lese Martin, Christa, additional, Beaudet, Arthur L., additional, Lord, Catherine, additional, State, Matthew W., additional, Cook, Edwin H., additional, and Devlin, Bernie, additional

Published
2015
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227. Joint Analysis of Psychiatric Disorders Increases Accuracy of Risk Prediction for Schizophrenia, Bipolar Disorder, and Major Depressive Disorder

Author

Maier, Robert, primary, Moser, Gerhard, additional, Chen, Guo-Bo, additional, Ripke, Stephan, additional, Coryell, William, additional, Potash, James B., additional, Scheftner, William A., additional, Shi, Jianxin, additional, Weissman, Myrna M., additional, Hultman, Christina M., additional, Landén, Mikael, additional, Levinson, Douglas F., additional, Kendler, Kenneth S., additional, Smoller, Jordan W., additional, Wray, Naomi R., additional, Lee, S. Hong, additional, Absher, Devin, additional, Agartz, Ingrid, additional, Akil, Huda, additional, Amin, Farooq, additional, Andreassen, Ole A., additional, Anjorin, Adebayo, additional, Anney, Richard, additional, Arking, Dan E., additional, Asherson, Philip, additional, Azevedo, Maria H., additional, Backlund, Lena, additional, Badner, Judith A., additional, Bailey, Anthony J., additional, Banaschewski, Tobias, additional, Barchas, Jack D., additional, Barnes, Michael R., additional, Barrett, Thomas B., additional, Bass, Nicholas, additional, Battaglia, Agatino, additional, Bauer, Michael, additional, Bayés, Mònica, additional, Bellivier, Frank, additional, Bergen, Sarah E., additional, Berrettini, Wade, additional, Betancur, Catalina, additional, Bettecken, Thomas, additional, Biederman, Joseph, additional, Binder, Elisabeth B., additional, Black, Donald W., additional, Blackwood, Douglas H.R., additional, Bloss, Cinnamon S., additional, Boehnke, Michael, additional, Boomsma, Dorret I., additional, Breen, Gerome, additional, Breuer, René, additional, Bruggeman, Richard, additional, Buccola, Nancy G., additional, Buitelaar, Jan K., additional, Bunney, William E., additional, Buxbaum, Joseph D., additional, Byerley, William F., additional, Caesar, Sian, additional, Cahn, Wiepke, additional, Cantor, Rita M., additional, Casas, Miguel, additional, Chakravarti, Aravinda, additional, Chambert, Kimberly, additional, Choudhury, Khalid, additional, Cichon, Sven, additional, Cloninger, C. Robert, additional, Collier, David A., additional, Cook, Edwin H., additional, Coon, Hilary, additional, Cormand, Bru, additional, Cormican, Paul, additional, Corvin, Aiden, additional, Coryell, William H., additional, Craddock, Nicholas, additional, Craig, David W., additional, Craig, Ian W., additional, Crosbie, Jennifer, additional, Cuccaro, Michael L., additional, Curtis, David, additional, Czamara, Darina, additional, Daly, Mark J., additional, Datta, Susmita, additional, Dawson, Geraldine, additional, Day, Richard, additional, De Geus, Eco J., additional, Degenhardt, Franziska, additional, Devlin, Bernie, additional, Djurovic, Srdjan, additional, Donohoe, Gary J., additional, Doyle, Alysa E., additional, Duan, Jubao, additional, Dudbridge, Frank, additional, Duketis, Eftichia, additional, Ebstein, Richard P., additional, Edenberg, Howard J., additional, Elia, Josephine, additional, Ennis, Sean, additional, Etain, Bruno, additional, Fanous, Ayman, additional, Faraone, Stephen V., additional, Farmer, Anne E., additional, Ferrier, I. Nicol, additional, Flickinger, Matthew, additional, Fombonne, Eric, additional, Foroud, Tatiana, additional, Frank, Josef, additional, Franke, Barbara, additional, Fraser, Christine, additional, Freedman, Robert, additional, Freimer, Nelson B., additional, Freitag, Christine M., additional, Friedl, Marion, additional, Frisén, Louise, additional, Gallagher, Louise, additional, Gejman, Pablo V., additional, Georgieva, Lyudmila, additional, Gershon, Elliot S., additional, Geschwind, Daniel H., additional, Giegling, Ina, additional, Gill, Michael, additional, Gordon, Scott D., additional, Gordon-Smith, Katherine, additional, Green, Elaine K., additional, Greenwood, Tiffany A., additional, Grice, Dorothy E., additional, Gross, Magdalena, additional, Grozeva, Detelina, additional, Guan, Weihua, additional, Gurling, Hugh, additional, De Haan, Lieuwe, additional, Haines, Jonathan L., additional, Hakonarson, Hakon, additional, Hallmayer, Joachim, additional, Hamilton, Steven P., additional, Hamshere, Marian L., additional, Hansen, Thomas F., additional, Hartmann, Annette M., additional, Hautzinger, Martin, additional, Heath, Andrew C., additional, Henders, Anjali K., additional, Herms, Stefan, additional, Hickie, Ian B., additional, Hipolito, Maria, additional, Hoefels, Susanne, additional, Holmans, Peter A., additional, Holsboer, Florian, additional, Hoogendijk, Witte J., additional, Hottenga, Jouke-Jan, additional, Hultman, Christina M., additional, Hus, Vanessa, additional, Ingason, Andrés, additional, Ising, Marcus, additional, Jamain, Stéphane, additional, Jones, Ian, additional, Jones, Lisa, additional, Kähler, Anna K., additional, Kahn, René S., additional, Kandaswamy, Radhika, additional, Keller, Matthew C., additional, Kelsoe, John R., additional, Kendler, Kenneth S., additional, Kennedy, James L., additional, Kenny, Elaine, additional, Kent, Lindsey, additional, Kim, Yunjung, additional, Kirov, George K., additional, Klauck, Sabine M., additional, Klei, Lambertus, additional, Knowles, James A., additional, Kohli, Martin A., additional, Koller, Daniel L., additional, Konte, Bettina, additional, Korszun, Ania, additional, Krabbendam, Lydia, additional, Krasucki, Robert, additional, Kuntsi, Jonna, additional, Kwan, Phoenix, additional, Långström, Niklas, additional, Lathrop, Mark, additional, Lawrence, Jacob, additional, Lawson, William B., additional, Leboyer, Marion, additional, Ledbetter, David H., additional, Lee, Phil H., additional, Lencz, Todd, additional, Lesch, Klaus-Peter, additional, Levinson, Douglas F., additional, Lewis, Cathryn M., additional, Li, Jun, additional, Lichtenstein, Paul, additional, Lieberman, Jeffrey A., additional, Lin, Dan-Yu, additional, Linszen, Don H., additional, Liu, Chunyu, additional, Lohoff, Falk W., additional, Loo, Sandra K., additional, Lord, Catherine, additional, Lowe, Jennifer K., additional, Lucae, Susanne, additional, MacIntyre, Donald J., additional, Madden, Pamela A.F., additional, Maestrini, Elena, additional, Magnusson, Patrik K.E., additional, Mahon, Pamela B., additional, Maier, Wolfgang, additional, Malhotra, Anil K., additional, Mane, Shrikant M., additional, Martin, Christa L., additional, Martin, Nicholas G., additional, Mattheisen, Manuel, additional, Matthews, Keith, additional, Mattingsdal, Morten, additional, McCarroll, Steven A., additional, McGhee, Kevin A., additional, McGough, James J., additional, McGrath, Patrick J., additional, McGuffin, Peter, additional, McInnis, Melvin G., additional, McIntosh, Andrew, additional, McKinney, Rebecca, additional, McLean, Alan W., additional, McMahon, Francis J., additional, McMahon, William M., additional, McQuillin, Andrew, additional, Medeiros, Helena, additional, Medland, Sarah E., additional, Meier, Sandra, additional, Melle, Ingrid, additional, Meng, Fan, additional, Meyer, Jobst, additional, Middeldorp, Christel M., additional, Middleton, Lefkos, additional, Milanova, Vihra, additional, Miranda, Ana, additional, Monaco, Anthony P., additional, Montgomery, Grant W., additional, Moran, Jennifer L., additional, Moreno-De-Luca, Daniel, additional, Morken, Gunnar, additional, Morris, Derek W., additional, Morrow, Eric M., additional, Moskvina, Valentina, additional, Mowry, Bryan J., additional, Muglia, Pierandrea, additional, Mühleisen, Thomas W., additional, Müller-Myhsok, Bertram, additional, Murtha, Michael, additional, Myers, Richard M., additional, Myin-Germeys, Inez, additional, Neale, Benjamin M., additional, Nelson, Stan F., additional, Nievergelt, Caroline M., additional, Nikolov, Ivan, additional, Nimgaonkar, Vishwajit, additional, Nolen, Willem A., additional, Nöthen, Markus M., additional, Nurnberger, John I., additional, Nwulia, Evaristus A., additional, Nyholt, Dale R., additional, O’Donovan, Michael C., additional, O’Dushlaine, Colm, additional, Oades, Robert D., additional, Olincy, Ann, additional, Oliveira, Guiomar, additional, Olsen, Line, additional, Ophoff, Roel A., additional, Osby, Urban, additional, Owen, Michael J., additional, Palotie, Aarno, additional, Parr, Jeremy R., additional, Paterson, Andrew D., additional, Pato, Carlos N., additional, Pato, Michele T., additional, Penninx, Brenda W., additional, Pergadia, Michele L., additional, Pericak-Vance, Margaret A., additional, Perlis, Roy H., additional, Pickard, Benjamin S., additional, Pimm, Jonathan, additional, Piven, Joseph, additional, Posthuma, Danielle, additional, Potash, James B., additional, Poustka, Fritz, additional, Propping, Peter, additional, Purcell, Shaun M., additional, Puri, Vinay, additional, Quested, Digby J., additional, Quinn, Emma M., additional, Ramos-Quiroga, Josep Antoni, additional, Rasmussen, Henrik B., additional, Raychaudhuri, Soumya, additional, Rehnström, Karola, additional, Reif, Andreas, additional, Ribasés, Marta, additional, Rice, John P., additional, Rietschel, Marcella, additional, Roeder, Kathryn, additional, Roeyers, Herbert, additional, Rossin, Lizzy, additional, Rothenberger, Aribert, additional, Rouleau, Guy, additional, Ruderfer, Douglas, additional, Rujescu, Dan, additional, Sanders, Alan R., additional, Sanders, Stephan J., additional, Santangelo, Susan L., additional, Schachar, Russell, additional, Schalling, Martin, additional, Schatzberg, Alan F., additional, Scheftner, William A., additional, Schellenberg, Gerard D., additional, Scherer, Stephen W., additional, Schork, Nicholas J., additional, Schulze, Thomas G., additional, Schumacher, Johannes, additional, Schwarz, Markus, additional, Scolnick, Edward, additional, Scott, Laura J., additional, Sergeant, Joseph A., additional, Shilling, Paul D., additional, Shyn, Stanley I., additional, Silverman, Jeremy M., additional, Sklar, Pamela, additional, Slager, Susan L., additional, Smalley, Susan L., additional, Smit, Johannes H., additional, Smith, Erin N., additional, Smoller, Jordan W., additional, Sonuga-Barke, Edmund J.S., additional, St Clair, David, additional, State, Matthew, additional, Steffens, Michael, additional, Steinhausen, Hans-Christoph, additional, Strauss, John S., additional, Strohmaier, Jana, additional, Stroup, T. Scott, additional, Sullivan, Patrick F., additional, Sutcliffe, James, additional, Szatmari, Peter, additional, Szelinger, Szabocls, additional, Thapar, Anita, additional, Thirumalai, Srinivasa, additional, Thompson, Robert C., additional, Todorov, Alexandre A., additional, Tozzi, Federica, additional, Treutlein, Jens, additional, Tzeng, Jung-Ying, additional, Uhr, Manfred, additional, van den Oord, Edwin J.C.G., additional, Van Grootheest, Gerard, additional, Van Os, Jim, additional, Vicente, Astrid M., additional, Vieland, Veronica J., additional, Vincent, John B., additional, Visscher, Peter M., additional, Walsh, Christopher A., additional, Wassink, Thomas H., additional, Watson, Stanley J., additional, Weiss, Lauren A., additional, Weissman, Myrna M., additional, Werge, Thomas, additional, Wienker, Thomas F., additional, Wiersma, Durk, additional, Wijsman, Ellen M., additional, Willemsen, Gonneke, additional, Williams, Nigel, additional, Willsey, A. Jeremy, additional, Witt, Stephanie H., additional, Wray, Naomi R., additional, Xu, Wei, additional, Young, Allan H., additional, Yu, Timothy W., additional, Zammit, Stanley, additional, Zandi, Peter P., additional, Zhang, Peng, additional, Zitman, Frans G., additional, and Zöllner, Sebastian, additional

Published
2015
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228. Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2.

Author

Chaste, Pauline, Chaste, Pauline, Sanders, Stephan, Mohan, Kommu, Klei, Lambertus, Song, Youeun, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Martin, Donna, Morrow, Eric, Walsh, Christopher, Sutcliffe, James, State, Matthew, Martin, Christa, Devlin, Bernie, Beaudet, Arthur, Cook, Edwin, Kim, Soo-Jeong, Chaste, Pauline, Chaste, Pauline, Sanders, Stephan, Mohan, Kommu, Klei, Lambertus, Song, Youeun, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Martin, Donna, Morrow, Eric, Walsh, Christopher, Sutcliffe, James, State, Matthew, Martin, Christa, Devlin, Bernie, Beaudet, Arthur, Cook, Edwin, and Kim, Soo-Jeong

Abstract

The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.

Published
2014

229. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

Author

Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie, David, Jr., Szolovits, Peter, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzynski, Piotr, Fairbrother, William, Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. Ann, Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrecic, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., San Lucas, F. Anthony, Gonzalez-Garay, Manuel L., Caskey, C. Thomas, Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., Gonzalez-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De la Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. Micheil, Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac S., Margulies, David M., Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie, David, Jr., Szolovits, Peter, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzynski, Piotr, Fairbrother, William, Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. Ann, Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrecic, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., San Lucas, F. Anthony, Gonzalez-Garay, Manuel L., Caskey, C. Thomas, Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., Gonzalez-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De la Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. Micheil, Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac S., and Margulies, David M.

Abstract

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups., QC 20140819

Published
2014
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230. Somatic mutations in cerebral cortical malformations.

Author

Jamuar, Saumya S, Jamuar, Saumya S, Lam, Anh-Thu N, Kircher, Martin, D'Gama, Alissa M, Wang, Jian, Barry, Brenda J, Zhang, Xiaochang, Hill, Robert Sean, Partlow, Jennifer N, Rozzo, Aldo, Servattalab, Sarah, Mehta, Bhaven K, Topcu, Meral, Amrom, Dina, Andermann, Eva, Dan, Bernard, Parrini, Elena, Guerrini, Renzo, Scheffer, Ingrid E, Berkovic, Samuel F, Leventer, Richard J, Shen, Yiping, Wu, Bai Lin, Barkovich, A James, Sahin, Mustafa, Chang, Bernard S, Bamshad, Michael, Nickerson, Deborah A, Shendure, Jay, Poduri, Annapurna, Yu, Timothy W, Walsh, Christopher A, Jamuar, Saumya S, Jamuar, Saumya S, Lam, Anh-Thu N, Kircher, Martin, D'Gama, Alissa M, Wang, Jian, Barry, Brenda J, Zhang, Xiaochang, Hill, Robert Sean, Partlow, Jennifer N, Rozzo, Aldo, Servattalab, Sarah, Mehta, Bhaven K, Topcu, Meral, Amrom, Dina, Andermann, Eva, Dan, Bernard, Parrini, Elena, Guerrini, Renzo, Scheffer, Ingrid E, Berkovic, Samuel F, Leventer, Richard J, Shen, Yiping, Wu, Bai Lin, Barkovich, A James, Sahin, Mustafa, Chang, Bernard S, Bamshad, Michael, Nickerson, Deborah A, Shendure, Jay, Poduri, Annapurna, Yu, Timothy W, and Walsh, Christopher A

Abstract

BackgroundAlthough there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated.MethodsUsing a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing.ResultsValidated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria.ConclusionsTargeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).

Published
2014

231. Katanin p80 regulates human cortical development by limiting centriole and cilia number.

Author

Hu, Wen F, Hu, Wen F, Pomp, Oz, Ben-Omran, Tawfeg, Kodani, Andrew, Henke, Katrin, Mochida, Ganeshwaran H, Yu, Timothy W, Woodworth, Mollie B, Bonnard, Carine, Raj, Grace Selva, Tan, Thong Teck, Hamamy, Hanan, Masri, Amira, Shboul, Mohammad, Al Saffar, Muna, Partlow, Jennifer N, Al-Dosari, Mohammed, Alazami, Anas, Alowain, Mohammed, Alkuraya, Fowzan S, Reiter, Jeremy F, Harris, Matthew P, Reversade, Bruno, Walsh, Christopher A, Hu, Wen F, Hu, Wen F, Pomp, Oz, Ben-Omran, Tawfeg, Kodani, Andrew, Henke, Katrin, Mochida, Ganeshwaran H, Yu, Timothy W, Woodworth, Mollie B, Bonnard, Carine, Raj, Grace Selva, Tan, Thong Teck, Hamamy, Hanan, Masri, Amira, Shboul, Mohammad, Al Saffar, Muna, Partlow, Jennifer N, Al-Dosari, Mohammed, Alazami, Anas, Alowain, Mohammed, Alkuraya, Fowzan S, Reiter, Jeremy F, Harris, Matthew P, Reversade, Bruno, and Walsh, Christopher A

Abstract

Katanin is a microtubule-severing complex whose catalytic activities are well characterized, but whose in vivo functions are incompletely understood. Human mutations in KATNB1, which encodes the noncatalytic regulatory p80 subunit of katanin, cause severe microlissencephaly. Loss of Katnb1 in mice confirms essential roles in neurogenesis and cell survival, while loss of zebrafish katnb1 reveals specific roles for katnin p80 in early and late developmental stages. Surprisingly, Katnb1 null mutant mouse embryos display hallmarks of aberrant Sonic hedgehog signaling, including holoprosencephaly. KATNB1-deficient human cells show defective proliferation and spindle structure, while Katnb1 null fibroblasts also demonstrate a remarkable excess of centrioles, with supernumerary cilia but deficient Hedgehog signaling. Our results reveal unexpected functions for KATNB1 in regulating overall centriole, mother centriole, and cilia number, and as an essential gene for normal Hedgehog signaling during neocortical development.

Published
2014

232. The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4⁺ T cells.

Author

Bertin, Samuel, Bertin, Samuel, Aoki-Nonaka, Yukari, de Jong, Petrus Rudolf, Nohara, Lilian L, Xu, Hongjian, Stanwood, Shawna R, Srikanth, Sonal, Lee, Jihyung, To, Keith, Abramson, Lior, Yu, Timothy, Han, Tiffany, Touma, Ranim, Li, Xiangli, González-Navajas, José M, Herdman, Scott, Corr, Maripat, Fu, Guo, Dong, Hui, Gwack, Yousang, Franco, Alessandra, Jefferies, Wilfred A, Raz, Eyal, Bertin, Samuel, Bertin, Samuel, Aoki-Nonaka, Yukari, de Jong, Petrus Rudolf, Nohara, Lilian L, Xu, Hongjian, Stanwood, Shawna R, Srikanth, Sonal, Lee, Jihyung, To, Keith, Abramson, Lior, Yu, Timothy, Han, Tiffany, Touma, Ranim, Li, Xiangli, González-Navajas, José M, Herdman, Scott, Corr, Maripat, Fu, Guo, Dong, Hui, Gwack, Yousang, Franco, Alessandra, Jefferies, Wilfred A, and Raz, Eyal

Abstract

TRPV1 is a Ca(2+)-permeable channel studied mostly as a pain receptor in sensory neurons. However, its role in other cell types is poorly understood. Here we found that TRPV1 was functionally expressed in CD4(+) T cells, where it acted as a non-store-operated Ca(2+) channel and contributed to T cell antigen receptor (TCR)-induced Ca(2+) influx, TCR signaling and T cell activation. In models of T cell-mediated colitis, TRPV1 promoted colitogenic T cell responses and intestinal inflammation. Furthermore, genetic and pharmacological inhibition of TRPV1 in human CD4(+) T cells recapitulated the phenotype of mouse Trpv1(-/-) CD4(+) T cells. Our findings suggest that inhibition of TRPV1 could represent a new therapeutic strategy for restraining proinflammatory T cell responses.

Published
2014

233. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

Author

Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Szolovits, Peter, Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie Jr., David, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzyński, Piotr, Fairbrother, William G., Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. A., Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrečić, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., Lucas, F Anthony S., Gonzalez-Garay, Manuel L., Caskey, C. T., Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., González-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De La Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. M., Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac, Margulies, David M., Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Szolovits, Peter, Brownstein, Catherine A., Beggs, Alan H., Homer, Nils, Merriman, Barry, Yu, Timothy W., Flannery, Katherine C., DeChene, Elizabeth T., Towne, Meghan C., Savage, Sarah K., Price, Emily N., Holm, Ingrid A., Luquette, Lovelace J., Lyon, Elaine, Majzoub, Joseph, Neupert, Peter, McCallie Jr., David, Willard, Huntington F., Mendelsohn, Nancy J., Temme, Renee, Finkel, Richard S., Yum, Sabrina W., Medne, Livija, Sunyaev, Shamil R., Adzhubey, Ivan, Cassa, Christopher A., de Bakker, Paul I. W., Duzkale, Hatice, Dworzyński, Piotr, Fairbrother, William G., Francioli, Laurent, Funke, Birgit H., Giovanni, Monica A., Handsaker, Robert E., Lage, Kasper, Lebo, Matthew S., Lek, Monkol, Leshchiner, Ignaty, MacArthur, Daniel G., McLaughlin, Heather M., Murray, Michael F., Pers, Tune H., Polak, Paz P., Raychaudhuri, Soumya, Rehm, Heidi L., Soemedi, Rachel, Stitziel, Nathan O., Vestecka, Sara, Supper, Jochen, Gugenmus, Claudia, Klocke, Bernward, Hahn, Alexander, Schubach, Max, Menzel, Mortiz, Biskup, Saskia, Freisinger, Peter, Deng, Mario, Braun, Martin, Perner, Sven, Smith, Richard J. H., Andorf, Janeen L., Huang, Jian, Ryckman, Kelli, Sheffield, Val C., Stone, Edwin M., Bair, Thomas, Black-Ziegelbein, E. A., Braun, Terry A., Darbro, Benjamin, DeLuca, Adam P., Kolbe, Diana L., Scheetz, Todd E., Shearer, Aiden E., Sompallae, Rama, Wang, Kai, Bassuk, Alexander G., Edens, Erik, Mathews, Katherine, Moore, Steven A., Shchelochkov, Oleg A., Trapane, Pamela, Bossler, Aaron, Campbell, Colleen A., Heusel, Jonathan W., Kwitek, Anne, Maga, Tara, Panzer, Karin, Wassink, Thomas, Van Daele, Douglas, Azaiez, Hela, Booth, Kevin, Meyer, Nic, Segal, Michael M., Williams, Marc S., Tromp, Gerard, White, Peter, Corsmeier, Donald, Fitzgerald-Butt, Sara, Herman, Gail, Lamb-Thrush, Devon, McBride, Kim L., Newsom, David, Pierson, Christopher R., Rakowsky, Alexander T., Maver, Ales, Lovrečić, Luca, Palandacic, Anja, Peterlin, Borut, Torkamani, Ali, Wedell, Anna, Huss, Mikael, Alexeyenko, Andrey, Lindvall, Jessica M., Magnusson, Mans, Nilsson, Daniel, Stranneheim, Henrik, Taylan, Fulya, Gilissen, Christian, Hoischen, Alexander, van Bon, Bregje, Yntema, Helger, Nelen, Marcel, Zhang, Weidong, Sager, Jason, Zhang, Lu, Blair, Kathryn, Kural, Deniz, Cariaso, Michael, Lennon, Greg G., Javed, Asif, Agrawal, Saloni, Ng, Pauline C., Sandhu, Komal S., Krishna, Shuba, Veeramachaneni, Vamsi, Isakov, Ofer, Halperin, Eran, Friedman, Eitan, Shomron, Noam, Glusman, Gustavo, Roach, Jared C., Caballero, Juan, Cox, Hannah C., Mauldin, Denise, Ament, Seth A., Rowen, Lee, Richards, Daniel R., Lucas, F Anthony S., Gonzalez-Garay, Manuel L., Caskey, C. T., Bai, Yu, Huang, Ying, Fang, Fang, Zhang, Yan, Wang, Zhengyuan, Barrera, Jorge, Garcia-Lobo, Juan M., González-Lamuno, Domingo, Llorca, Javier, Rodriguez, Maria C., Varela, Ignacio, Reese, Martin G., De La Vega, Francisco M., Kiruluta, Edward, Cargill, Michele, Hart, Reece K., Sorenson, Jon M., Lyon, Gholson J., Stevenson, David A., Bray, Bruce E., Moore, Barry M., Eilbeck, Karen, Yandell, Mark, Zhao, Hongyu, Hou, Lin, Chen, Xiaowei, Yan, Xiting, Chen, Mengjie, Li, Cong, Yang, Can, Gunel, Murat, Li, Peining, Kong, Yong, Alexander, Austin C., Albertyn, Zayed I., Boycott, Kym M., Bulman, Dennis E., Gordon, Paul M. K., Innes, A. M., Knoppers, Bartha M., Majewski, Jacek, Marshall, Christian R., Parboosingh, Jillian S., Sawyer, Sarah L., Samuels, Mark E., Schwartzentruber, Jeremy, Kohane, Isaac, and Margulies, David M.

Abstract

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups., Boston Children's Hospital (Manton Center for Orphan Disease Research), Harvard Medical School (Center for Biomedical Infomatics)

Published
2014

234. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

Author

Brownstein, Catherine A, Beggs, Alan H, Homer, Nils, Merriman, Barry, Yu, Timothy W, Flannery, Katherine C, DeChene, Elizabeth T, Towne, Meghan C, Savage, Sarah K, Price, Emily N, Dworzynski, Piotr, Brownstein, Catherine A, Beggs, Alan H, Homer, Nils, Merriman, Barry, Yu, Timothy W, Flannery, Katherine C, DeChene, Elizabeth T, Towne, Meghan C, Savage, Sarah K, Price, Emily N, and Dworzynski, Piotr

Abstract

Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.

Published
2014

235. Katanin p80 Regulates Human Cortical Development by Limiting Centriole and Cilia Number

Author

Hu, Wen F., primary, Pomp, Oz, additional, Ben-Omran, Tawfeg, additional, Kodani, Andrew, additional, Henke, Katrin, additional, Mochida, Ganeshwaran H., additional, Yu, Timothy W., additional, Woodworth, Mollie B., additional, Bonnard, Carine, additional, Raj, Grace Selva, additional, Tan, Thong Teck, additional, Hamamy, Hanan, additional, Masri, Amira, additional, Shboul, Mohammad, additional, Al Saffar, Muna, additional, Partlow, Jennifer N., additional, Al-Dosari, Mohammed, additional, Alazami, Anas, additional, Alowain, Mohammed, additional, Alkuraya, Fowzan S., additional, Reiter, Jeremy F., additional, Harris, Matthew P., additional, Reversade, Bruno, additional, and Walsh, Christopher A., additional

Published
2014
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236. Rare variant association test in family-based sequencing studies.

Author

Xuefeng Wang, Yu, Timothy W., Walsh, Christopher A., Xihong Lin, Zhenyu Zhang, Morris, Nathan, Tianxi Cai, Seunggeun Lee, and Chaolong Wang

Subjects
*ASSOCIATION (Chemistry), *PERTURBATION theory, *NUCLEOTIDE sequencing, *GENETIC polymorphisms, *SIMULATION methods & models
Abstract

The objective of this article is to introduce valid and robust methods for the analysis of rare variants for family-based exome chips, whole-exome sequencing or whole-genome sequencing data. Family-based designs provide unique opportunities to detect genetic variants that complement studies of unrelated individuals. Currently, limited methods and software tools have been developed to assist family-based association studies with rare variants, especially for analyzing binary traits. In this article, we address this gap by extending existing burden and kernel-based gene set association tests for population data to related samples, with a particular emphasis on binary phenotypes. The proposed approach blends the strengths of kernel machine methods and generalized estimating equations. Importantly, the efficient generalized kernel score test can be applied as a mega-analysis framework to combine studies with different designs. We illustrate the application of the pro- posed method using data from an exome sequencing study of autism. Methods discussed in this article are implemented in an R package 'gskat', which is available on CRAN and GitHub. [ABSTRACT FROM AUTHOR]

Published
2017
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240. The ion channel TRPV1 regulates the activation and proinflammatory properties of CD4+ T cells

Author

Bertin, Samuel, primary, Aoki-Nonaka, Yukari, additional, de Jong, Petrus Rudolf, additional, Nohara, Lilian L, additional, Xu, Hongjian, additional, Stanwood, Shawna R, additional, Srikanth, Sonal, additional, Lee, Jihyung, additional, To, Keith, additional, Abramson, Lior, additional, Yu, Timothy, additional, Han, Tiffany, additional, Touma, Ranim, additional, Li, Xiangli, additional, González-Navajas, José M, additional, Herdman, Scott, additional, Corr, Maripat, additional, Fu, Guo, additional, Dong, Hui, additional, Gwack, Yousang, additional, Franco, Alessandra, additional, Jefferies, Wilfred A, additional, and Raz, Eyal, additional

Published
2014
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241. Somatic Mutations in Cerebral Cortical Malformations

Author

Jamuar, Saumya S., primary, Lam, Anh-Thu N., additional, Kircher, Martin, additional, D’Gama, Alissa M., additional, Wang, Jian, additional, Barry, Brenda J., additional, Zhang, Xiaochang, additional, Hill, Robert Sean, additional, Partlow, Jennifer N., additional, Rozzo, Aldo, additional, Servattalab, Sarah, additional, Mehta, Bhaven K., additional, Topcu, Meral, additional, Amrom, Dina, additional, Andermann, Eva, additional, Dan, Bernard, additional, Parrini, Elena, additional, Guerrini, Renzo, additional, Scheffer, Ingrid E., additional, Berkovic, Samuel F., additional, Leventer, Richard J., additional, Shen, Yiping, additional, Wu, Bai Lin, additional, Barkovich, A. James, additional, Sahin, Mustafa, additional, Chang, Bernard S., additional, Bamshad, Michael, additional, Nickerson, Deborah A., additional, Shendure, Jay, additional, Poduri, Annapurna, additional, Yu, Timothy W., additional, and Walsh, Christopher A., additional

Published
2014
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242. Modest Impact on Risk for Autism Spectrum Disorder of Rare Copy Number Variants at 15q11.2, Specifically Breakpoints 1 to 2

Author

Chaste, Pauline, primary, Sanders, Stephan J., additional, Mohan, Kommu N., additional, Klei, Lambertus, additional, Song, Youeun, additional, Murtha, Michael T., additional, Hus, Vanessa, additional, Lowe, Jennifer K., additional, Willsey, A. Jeremy, additional, Moreno‐De‐Luca, Daniel, additional, Yu, Timothy W., additional, Fombonne, Eric, additional, Geschwind, Daniel, additional, Grice, Dorothy E., additional, Ledbetter, David H., additional, Lord, Catherine, additional, Mane, Shrikant M., additional, Martin, Donna M., additional, Morrow, Eric M., additional, Walsh, Christopher A., additional, Sutcliffe, James S., additional, State, Matthew W., additional, Martin, Christa Lese, additional, Devlin, Bernie, additional, Beaudet, Arthur L., additional, Cook, Edwin H., additional, and Kim, Soo‐Jeong, additional

Published
2014
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243. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

Author

Brownstein, Catherine A, primary, Beggs, Alan H, additional, Homer, Nils, additional, Merriman, Barry, additional, Yu, Timothy W, additional, Flannery, Katherine C, additional, DeChene, Elizabeth T, additional, Towne, Meghan C, additional, Savage, Sarah K, additional, Price, Emily N, additional, Holm, Ingrid A, additional, Luquette, Lovelace J, additional, Lyon, Elaine, additional, Majzoub, Joseph, additional, Neupert, Peter, additional, McCallie Jr, David, additional, Szolovits, Peter, additional, Willard, Huntington F, additional, Mendelsohn, Nancy J, additional, Temme, Renee, additional, Finkel, Richard S, additional, Yum, Sabrina W, additional, Medne, Livija, additional, Sunyaev, Shamil R, additional, Adzhubey, Ivan, additional, Cassa, Christopher A, additional, de Bakker, Paul IW, additional, Duzkale, Hatice, additional, Dworzyński, Piotr, additional, Fairbrother, William, additional, Francioli, Laurent, additional, Funke, Birgit H, additional, Giovanni, Monica A, additional, Handsaker, Robert E, additional, Lage, Kasper, additional, Lebo, Matthew S, additional, Lek, Monkol, additional, Leshchiner, Ignaty, additional, MacArthur, Daniel G, additional, McLaughlin, Heather M, additional, Murray, Michael F, additional, Pers, Tune H, additional, Polak, Paz P, additional, Raychaudhuri, Soumya, additional, Rehm, Heidi L, additional, Soemedi, Rachel, additional, Stitziel, Nathan O, additional, Vestecka, Sara, additional, Supper, Jochen, additional, Gugenmus, Claudia, additional, Klocke, Bernward, additional, Hahn, Alexander, additional, Schubach, Max, additional, Menzel, Mortiz, additional, Biskup, Saskia, additional, Freisinger, Peter, additional, Deng, Mario, additional, Braun, Martin, additional, Perner, Sven, additional, Smith, Richard JH, additional, Andorf, Janeen L, additional, Huang, Jian, additional, Ryckman, Kelli, additional, Sheffield, Val C, additional, Stone, Edwin M, additional, Bair, Thomas, additional, Black-Ziegelbein, E, additional, Braun, Terry A, additional, Darbro, Benjamin, additional, DeLuca, Adam P, additional, Kolbe, Diana L, additional, Scheetz, Todd E, additional, Shearer, Aiden E, additional, Sompallae, Rama, additional, Wang, Kai, additional, Bassuk, Alexander G, additional, Edens, Erik, additional, Mathews, Katherine, additional, Moore, Steven A, additional, Shchelochkov, Oleg A, additional, Trapane, Pamela, additional, Bossler, Aaron, additional, Campbell, Colleen A, additional, Heusel, Jonathan W, additional, Kwitek, Anne, additional, Maga, Tara, additional, Panzer, Karin, additional, Wassink, Thomas, additional, Van Daele, Douglas, additional, Azaiez, Hela, additional, Booth, Kevin, additional, Meyer, Nic, additional, Segal, Michael M, additional, Williams, Marc S, additional, Tromp, Gerard, additional, White, Peter, additional, Corsmeier, Donald, additional, Fitzgerald-Butt, Sara, additional, Herman, Gail, additional, Lamb-Thrush, Devon, additional, McBride, Kim L, additional, Newsom, David, additional, Pierson, Christopher R, additional, Rakowsky, Alexander T, additional, Maver, Aleš, additional, Lovrečić, Luca, additional, Palandačić, Anja, additional, Peterlin, Borut, additional, Torkamani, Ali, additional, Wedell, Anna, additional, Huss, Mikael, additional, Alexeyenko, Andrey, additional, Lindvall, Jessica M, additional, Magnusson, Måns, additional, Nilsson, Daniel, additional, Stranneheim, Henrik, additional, Taylan, Fulya, additional, Gilissen, Christian, additional, Hoischen, Alexander, additional, van Bon, Bregje, additional, Yntema, Helger, additional, Nelen, Marcel, additional, Zhang, Weidong, additional, Sager, Jason, additional, Zhang, Lu, additional, Blair, Kathryn, additional, Kural, Deniz, additional, Cariaso, Michael, additional, Lennon, Greg G, additional, Javed, Asif, additional, Agrawal, Saloni, additional, Ng, Pauline C, additional, Sandhu, Komal S, additional, Krishna, Shuba, additional, Veeramachaneni, Vamsi, additional, Isakov, Ofer, additional, Halperin, Eran, additional, Friedman, Eitan, additional, Shomron, Noam, additional, Glusman, Gustavo, additional, Roach, Jared C, additional, Caballero, Juan, additional, Cox, Hannah C, additional, Mauldin, Denise, additional, Ament, Seth A, additional, Rowen, Lee, additional, Richards, Daniel R, additional, Lucas, F Anthony, additional, Gonzalez-Garay, Manuel L, additional, Caskey, C, additional, Bai, Yu, additional, Huang, Ying, additional, Fang, Fang, additional, Zhang, Yan, additional, Wang, Zhengyuan, additional, Barrera, Jorge, additional, Garcia-Lobo, Juan M, additional, González-Lamuño, Domingo, additional, Llorca, Javier, additional, Rodriguez, Maria C, additional, Varela, Ignacio, additional, Reese, Martin G, additional, De La Vega, Francisco M, additional, Kiruluta, Edward, additional, Cargill, Michele, additional, Hart, Reece K, additional, Sorenson, Jon M, additional, Lyon, Gholson J, additional, Stevenson, David A, additional, Bray, Bruce E, additional, Moore, Barry M, additional, Eilbeck, Karen, additional, Yandell, Mark, additional, Zhao, Hongyu, additional, Hou, Lin, additional, Chen, Xiaowei, additional, Yan, Xiting, additional, Chen, Mengjie, additional, Li, Cong, additional, Yang, Can, additional, Gunel, Murat, additional, Li, Peining, additional, Kong, Yong, additional, Alexander, Austin C, additional, Albertyn, Zayed I, additional, Boycott, Kym M, additional, Bulman, Dennis E, additional, Gordon, Paul MK, additional, Innes, A, additional, Knoppers, Bartha M, additional, Majewski, Jacek, additional, Marshall, Christian R, additional, Parboosingh, Jillian S, additional, Sawyer, Sarah L, additional, Samuels, Mark E, additional, Schwartzentruber, Jeremy, additional, Kohane, Isaac S, additional, and Margulies, David M, additional

Published
2014
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244. Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait.

Author

Chaste, Pauline, Chaste, Pauline, Klei, Lambertus, Sanders, Stephan, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Lese Martin, Christa, Martin, Donna, Morrow, Eric, Walsh, Christopher, Sutcliffe, James, State, Matthew, Devlin, Bernie, Cook, Edwin, Kim, Soo-Jeong, Chaste, Pauline, Chaste, Pauline, Klei, Lambertus, Sanders, Stephan, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Lese Martin, Christa, Martin, Donna, Morrow, Eric, Walsh, Christopher, Sutcliffe, James, State, Matthew, Devlin, Bernie, Cook, Edwin, and Kim, Soo-Jeong

Abstract

BACKGROUND: Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort. METHODS: We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters. RESULTS: Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC. CONCLUSIONS: Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.

Published
2013

245. Identification of KLHL41 Mutations Implicates BTB-Kelch-Mediated Ubiquitination as an Alternate Pathway to Myofibrillar Disruption in Nemaline Myopathy

Author

Gupta, Vandana A., primary, Ravenscroft, Gianina, additional, Shaheen, Ranad, additional, Todd, Emily J., additional, Swanson, Lindsay C., additional, Shiina, Masaaki, additional, Ogata, Kazuhiro, additional, Hsu, Cynthia, additional, Clarke, Nigel F., additional, Darras, Basil T., additional, Farrar, Michelle A., additional, Hashem, Amal, additional, Manton, Nicholas D., additional, Muntoni, Francesco, additional, North, Kathryn N., additional, Sandaradura, Sarah A., additional, Nishino, Ichizo, additional, Hayashi, Yukiko K., additional, Sewry, Caroline A., additional, Thompson, Elizabeth M., additional, Yau, Kyle S., additional, Brownstein, Catherine A., additional, Yu, Timothy W., additional, Allcock, Richard J.N., additional, Davis, Mark R., additional, Wallgren-Pettersson, Carina, additional, Matsumoto, Naomichi, additional, Alkuraya, Fowzan S., additional, Laing, Nigel G., additional, and Beggs, Alan H., additional

Published
2013
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246. Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2

Author

Mitsuhashi, Satomi, primary, Boyden, Steven E., additional, Estrella, Elicia A., additional, Jones, Takako I., additional, Rahimov, Fedik, additional, Yu, Timothy W., additional, Darras, Basil T., additional, Amato, Anthony A., additional, Folkerth, Rebecca D., additional, Jones, Peter L., additional, Kunkel, Louis M., additional, and Kang, Peter B., additional

Published
2013
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248. Targeting a Putative Intronic Splicing Silencer Salvages Expression from the Recurrent SBDS C.258+2T>C Mutant Allele in Shwachman-Diamond Syndrome Patient Cells and Mouse Model

Author

Peters, Michael J., Deck, Anna, Hu, April, Fujiwara, Yuko, Kim, Jinkuk, Soucy, Aubrie, Zhang, Kevin, Kenny, Julianna, Lin, Linda Y., Kennedy, Alyssa L., Bowers, Caitlin, Harris, Chad E., Zhang, Chi Yuan, Ponnienselvan, Karthik, Liu, Pengpeng, Luk, Kevin, Seruggia, Davide, Lindsley, R. Coleman, Manis, John P., Brendel, Christian, Wolfe, Scot A., Orkin, Stuart H., Yu, Timothy, Shimamura, Akiko, and Bauer, Daniel E.

Published
2022
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249. Targeting a Putative Intronic Splicing Silencer Salvages Expression from the Recurrent SBDSC.258+2T>C Mutant Allele in Shwachman-Diamond Syndrome Patient Cells and Mouse Model

Author

Peters, Michael J., Deck, Anna, Hu, April, Fujiwara, Yuko, Kim, Jinkuk, Soucy, Aubrie, Zhang, Kevin, Kenny, Julianna, Lin, Linda Y., Kennedy, Alyssa L., Bowers, Caitlin, Harris, Chad E., Zhang, Chi Yuan, Ponnienselvan, Karthik, Liu, Pengpeng, Luk, Kevin, Seruggia, Davide, Lindsley, R. Coleman, Manis, John P., Brendel, Christian, Wolfe, Scot A., Orkin, Stuart H., Yu, Timothy, Shimamura, Akiko, and Bauer, Daniel E.

Published
2022
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250. Common genetic variants, acting additively, are a major source of risk for autism.

Author

Klei, Lambertus, Klei, Lambertus, Sanders, Stephan, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Martin, Christa, Martin, Donna, Morrow, Eric, Walsh, Christopher, Melhem, Nadine, Chaste, Pauline, Sutcliffe, James, State, Matthew, Cook, Edwin, Roeder, Kathryn, Devlin, Bernie, Klei, Lambertus, Klei, Lambertus, Sanders, Stephan, Murtha, Michael, Hus, Vanessa, Lowe, Jennifer, Willsey, Arthur, Moreno-De-Luca, Daniel, Yu, Timothy, Fombonne, Eric, Geschwind, Daniel, Grice, Dorothy, Ledbetter, David, Lord, Catherine, Mane, Shrikant, Martin, Christa, Martin, Donna, Morrow, Eric, Walsh, Christopher, Melhem, Nadine, Chaste, Pauline, Sutcliffe, James, State, Matthew, Cook, Edwin, Roeder, Kathryn, and Devlin, Bernie

Abstract

BACKGROUND: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. METHODS: By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. RESULTS: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. CONCLUSIONS: Our results, when viewed in the context of results from genome-wi

Published
2012

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