%0 Journal Article %J Nature %D 2012 %T Patterns and rates of exonic de novo mutations in autism spectrum disorders. %A Neale, Benjamin M %A Kou, Yan %A Liu, Li %A Ma'ayan, Avi %A Samocha, Kaitlin E %A Sabo, Aniko %A Lin, Chiao-Feng %A Stevens, Christine %A Wang, Li-San %A Makarov, Vladimir %A Polak, Paz %A Yoon, Seungtai %A Maguire, Jared %A Crawford, Emily L %A Campbell, Nicholas G %A Geller, Evan T %A Valladares, Otto %A Schafer, Chad %A Liu, Han %A Zhao, Tuo %A Cai, Guiqing %A Lihm, Jayon %A Dannenfelser, Ruth %A Jabado, Omar %A Peralta, Zuleyma %A Nagaswamy, Uma %A Muzny, Donna %A Reid, Jeffrey G %A Newsham, Irene %A Wu, Yuanqing %A Lewis, Lora %A Han, Yi %A Voight, Benjamin F %A Lim, Elaine %A Rossin, Elizabeth %A Kirby, Andrew %A Flannick, Jason %A Fromer, Menachem %A Shakir, Khalid %A Fennell, Tim %A Garimella, Kiran %A Banks, Eric %A Poplin, Ryan %A Gabriel, Stacey %A DePristo, Mark %A Wimbish, Jack R %A Boone, Braden E %A Levy, Shawn E %A Betancur, Catalina %A Sunyaev, Shamil %A Boerwinkle, Eric %A Buxbaum, Joseph D %A Cook, Edwin H %A Devlin, Bernie %A Gibbs, Richard A %A Roeder, Kathryn %A Schellenberg, Gerard D %A Sutcliffe, James S %A Daly, Mark J %K Autistic Disorder %K Case-Control Studies %K DNA-Binding Proteins %K Exome %K Exons %K Family Health %K Genetic Predisposition to Disease %K Humans %K Models, Genetic %K Multifactorial Inheritance %K Mutation %K Phenotype %K Poisson Distribution %K Protein Interaction Maps %K Transcription Factors %X
Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.
%B Nature %V 485 %P 242-5 %8 2012 Apr 04 %G eng %N 7397 %1 https://www.ncbi.nlm.nih.gov/pubmed/22495311?dopt=Abstract %R 10.1038/nature11011 %0 Journal Article %J Nature %D 2008 %T Somatic mutations affect key pathways in lung adenocarcinoma. %A Ding, Li %A Getz, Gad %A Wheeler, David A %A Mardis, Elaine R %A McLellan, Michael D %A Cibulskis, Kristian %A Sougnez, Carrie %A Greulich, Heidi %A Donna M Muzny %A Morgan, Margaret B %A Fulton, Lucinda %A Fulton, Robert S %A Zhang, Qunyuan %A Wendl, Michael C %A Lawrence, Michael S %A Larson, David E %A Chen, Ken %A Dooling, David J %A Aniko Sabo %A Hawes, Alicia C %A Shen, Hua %A Jhangiani, Shalini N %A Lewis, Lora R %A Hall, Otis %A Zhu, Yiming %A Mathew, Tittu %A Ren, Yanru %A Yao, Jiqiang %A Steven E Scherer %A Clerc, Kerstin %A Ginger A Metcalf %A Ng, Brian %A Milosavljevic, Aleksandar %A Gonzalez-Garay, Manuel L %A Osborne, John R %A Meyer, Rick %A Shi, Xiaoqi %A Tang, Yuzhu %A Koboldt, Daniel C %A Lin, Ling %A Abbott, Rachel %A Miner, Tracie L %A Pohl, Craig %A Fewell, Ginger %A Haipek, Carrie %A Schmidt, Heather %A Dunford-Shore, Brian H %A Kraja, Aldi %A Crosby, Seth D %A Sawyer, Christopher S %A Vickery, Tammi %A Sander, Sacha %A Robinson, Jody %A Winckler, Wendy %A Baldwin, Jennifer %A Chirieac, Lucian R %A Dutt, Amit %A Fennell, Tim %A Hanna, Megan %A Johnson, Bruce E %A Onofrio, Robert C %A Thomas, Roman K %A Tonon, Giovanni %A Weir, Barbara A %A Zhao, Xiaojun %A Ziaugra, Liuda %A Zody, Michael C %A Giordano, Thomas %A Orringer, Mark B %A Roth, Jack A %A Spitz, Margaret R %A Wistuba, Ignacio I %A Ozenberger, Bradley %A Good, Peter J %A Chang, Andrew C %A Beer, David G %A Watson, Mark A %A Ladanyi, Marc %A Broderick, Stephen %A Yoshizawa, Akihiko %A Travis, William D %A Pao, William %A Province, Michael A %A Weinstock, George M %A Varmus, Harold E %A Gabriel, Stacey B %A Lander, Eric S %A Richard A Gibbs %A Meyerson, Matthew %A Wilson, Richard K %K Adenocarcinoma, Bronchiolo-Alveolar %K Female %K Gene Dosage %K Gene Expression Regulation, Neoplastic %K Genes, Tumor Suppressor %K Humans %K Lung Neoplasms %K Male %K Mutation %K Proto-Oncogenes %XDetermining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
%B Nature %V 455 %P 1069-75 %8 2008 Oct 23 %G eng %N 7216 %1 https://www.ncbi.nlm.nih.gov/pubmed/18948947?dopt=Abstract %R 10.1038/nature07423