Refining the role of de novo protein truncating variants in neurodevelopmental disorders using population reference samples
作者： Jack A. Kosmicki , Kaitlin E. Samocha , Daniel P. Howrigan , Stephan J. Sanders , Kamil Slowikowski
DOI: 10.1101/052886
关键词:
摘要: Recent research has established the significant role of newly arising (de novo) variation in neurodevelopmental disorders. Using aggregated data from 5603 families affected by ASD, intellectual disability (ID), or developmental delay (DD), we show that overall ~1/3 de novo variants are independently observed as standing Exome Aggregation Consortium's (ExAC) cohort 60,706 adults without severe disease, and these do not contribute substantively to risk. We further use a loss-of-function intolerance metric derived ExAC identify small subset genes contain entire signal associated protein truncating (PTVs) disorders (ASD: rate ratio (RR) = 3.24, P < 10-16; ID/DD: RR 6.70, 10-38). These same carry moderate excess PTVs inherited individuals with ASD their unaffected parents (RR 1.16, 0.00985), larger 404 cases 3654 controls (OR 2.66; 6.34 x 10-19), again no association seen outside genes. findings illustrate importance population-based cohorts reference samples for interpretation candidate pathogenic variants, even analysis variation.
sci-hub.st 参考文章(45)
Niklas Krumm, Tychele N Turner, Carl Baker, Laura Vives, Kiana Mohajeri, Kali Witherspoon, Archana Raja, Bradley P Coe, Holly A Stessman, Zong-Xiao He, Suzanne M Leal, Raphael Bernier, Evan E Eichler, Excess of rare, inherited truncating mutations in autism. Nature Genetics. ,vol. 47, pp. 582- 588 ,(2015) , 10.1038/NG.3303
C A Francomano, C A Francomano, R I Ortiz de Luna, W A Horton, M Machado, G A Bellus, I McIntosh, J T Hecht, I Kaitila, T W Hefferon, Achondroplasia is defined by recurrent G380R mutations of FGFR3. American Journal of Human Genetics. ,vol. 56, pp. 368- 373 ,(1995)
Joseph A. Picoraro, Wendy K. Chung, Delineation of New Disorders and Phenotypic Expansion of Known Disorders Through Whole Exome Sequencing Current Genetic Medicine Reports. ,vol. 3, pp. 209- 218 ,(2015) , 10.1007/S40142-015-0079-5
Laurent C Francioli, Paz P Polak, Amnon Koren, Androniki Menelaou, Sung Chun, Ivo Renkens, Genome of the Netherlands Consortium, Cornelia M van Duijn, Morris Swertz, Cisca Wijmenga, Gertjan van Ommen, P Eline Slagboom, Dorret I Boomsma, Kai Ye, Victor Guryev, Peter F Arndt, Wigard P Kloosterman, Paul IW de Bakker, Shamil R Sunyaev, None, Genome-wide patterns and properties of de novo mutations in humans Nature Genetics. ,vol. 47, pp. 822- 826 ,(2015) , 10.1038/NG.3292
Brian J. O’Roak, Laura Vives, Santhosh Girirajan, Emre Karakoc, Niklas Krumm, Bradley P. Coe, Roie Levy, Arthur Ko, Choli Lee, Joshua D. Smith, Emily H. Turner, Ian B. Stanaway, Benjamin Vernot, Maika Malig, Carl Baker, Beau Reilly, Joshua M. Akey, Elhanan Borenstein, Mark J. Rieder, Deborah A. Nickerson, Raphael Bernier, Jay Shendure, Evan E. Eichler, Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations Nature. ,vol. 485, pp. 246- 250 ,(2012) , 10.1038/NATURE10989
J. PRZYBOROWSKI, H. WILENSKI, Homogeneity of results in testing samples from Poisson series, with an application to testing clover seed for dodder. Biometrika. ,vol. 31, pp. 313- 323 ,(1940) , 10.1093/BIOMET/31.3-4.313
Elise B. Robinson, Kaitlin E. Samocha, Jack A. Kosmicki, Lauren McGrath, Benjamin M. Neale, Roy H. Perlis, Mark J. Daly, Autism spectrum disorder severity reflects the average contribution of de novo and familial influences Proceedings of the National Academy of Sciences of the United States of America. ,vol. 111, pp. 15161- 15165 ,(2014) , 10.1073/PNAS.1409204111
Jacob J Michaelson, Yujian Shi, Madhusudan Gujral, Hancheng Zheng, Dheeraj Malhotra, Xin Jin, Minghan Jian, Guangming Liu, Douglas Greer, Abhishek Bhandari, Wenting Wu, Roser Corominas, Áine Peoples, Amnon Koren, Athurva Gore, Shuli Kang, Guan Ning Lin, Jasper Estabillo, Therese Gadomski, Balvindar Singh, Kun Zhang, Natacha Akshoomoff, Christina Corsello, Steven McCarroll, Lilia M Iakoucheva, Yingrui Li, Jun Wang, Jonathan Sebat, None, Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation Cell. ,vol. 151, pp. 1431- 1442 ,(2012) , 10.1016/J.CELL.2012.11.019
Ivan Iossifov, Brian J. O’Roak, Stephan J. Sanders, Michael Ronemus, Niklas Krumm, Dan Levy, Holly A. Stessman, Kali T. Witherspoon, Laura Vives, Karynne E. Patterson, Joshua D. Smith, Bryan Paeper, Deborah A. Nickerson, Jeanselle Dea, Shan Dong, Luis E. Gonzalez, Jeffrey D. Mandell, Shrikant M. Mane, Michael T. Murtha, Catherine A. Sullivan, Michael F. Walker, Zainulabedin Waqar, Liping Wei, A. Jeremy Willsey, Boris Yamrom, Yoon-ha Lee, Ewa Grabowska, Ertugrul Dalkic, Zihua Wang, Steven Marks, Peter Andrews, Anthony Leotta, Jude Kendall, Inessa Hakker, Julie Rosenbaum, Beicong Ma, Linda Rodgers, Jennifer Troge, Giuseppe Narzisi, Seungtai Yoon, Michael C. Schatz, Kenny Ye, W. Richard McCombie, Jay Shendure, Evan E. Eichler, Matthew W. State, Michael Wigler, The contribution of de novo coding mutations to autism spectrum disorder Nature. ,vol. 515, pp. 216- 221 ,(2014) , 10.1038/NATURE13908
Augustine Kong, Michael L. Frigge, Gisli Masson, Soren Besenbacher, Patrick Sulem, Gisli Magnusson, Sigurjon A. Gudjonsson, Asgeir Sigurdsson, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Wendy S. W. Wong, Gunnar Sigurdsson, G. Bragi Walters, Stacy Steinberg, Hannes Helgason, Gudmar Thorleifsson, Daniel F. Gudbjartsson, Agnar Helgason, Olafur Th. Magnusson, Unnur Thorsteinsdottir, Kari Stefansson, Rate of de novo mutations and the importance of father’s age to disease risk Nature. ,vol. 488, pp. 471- 475 ,(2012) , 10.1038/NATURE11396