Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Lim, Elaine T.; Uddin, Mohammed; De Rubeis, Silvia; Chan, Yingleong; Kamumbu, Anne S.; Zhang, Xiaochang; D'Gama, Alissa M.; Kim, Sonia N.; Hill, Robert Sean; Goldberg, Arthur P.; Poultney, Christopher; Minshew, Nancy J.; Kushima, Itaru; Aleksic, Branko; Ozaki, Norio; Parellada, Mara; Arango, Celso; Penzol, Maria J.; Carracedo, Angel; Kolevzon, Alexander; Hultman, Christina M.; Weiss, Lauren A.; Fromer, Menachem; Chiocchetti, Andreas G.; Freitag, Christine M.; Church, George M.; Scherer, Stephen W.; Buxbaum, Joseph D.; Walsh, Christopher A; Aleksic, B; Anney, R; Barbosa, M; Barrett, J; Betancur, C; Bishop, S; Brusco, A; Buxbaum, Jd; Carracedo, A; Chiocchetti, Ag; Bhy, Chung; Cook, E; Coon, H; Cutler, Dj; Daly, M; De Rubeis, S; Doan, R; Fernández-Prieto, M; Ferrero, Gb; Freitag, Cm; Fromer, M; Gargus, J; Geschwind, D; Gill, M; Gómez-Guerrero, L; Hansen-Kiss, E; X, He; Herman, G; Hertz-Picciotto, I; Hultman, C; Iliadou, B; Ionita-Laza, I; Jugessur, A; Knudsen, Gp; Kolevzon, A; Kosmicki, J; Kushima, I; Lee, Sl; Lehner, T; Lennertz, S; Lim, E; Maciel, P; Magnus, P; Manoach, D; Minshew, N; Morrow, E; Mulle, J; Neale, B; Ozaki, N; Palotie, A; Parellada, M; Passos-Bueno, Mr; Pericak-Vance, M; Persico, A; Pessah, I; Reichenberg, A; Reichert, J; Renieri, A; Robinson, E; Samocha, K; Sanders, S; Sandin, S; Santangelo, Sl; Satterstrom, K; Schafer, C; Schellenberg, G; Scherer, S; Senthil, G; Silva, M; Singh, T; Siper, Pm; Soares, G; Stevens, C; Stoltenberg, C; Surén, P; Sutcliffe, Js; Szatmari, P; Tassone, F; Thurm, A; Walsh, C; Weiss, L; Werling, D; Willsey, J; X, Xu; Tw, Yu; Yuen, R; Zwick, Me.

doi:10.1038/nn.4598

We systematically analyzed postzygotic mutations (PZMs) in whole-exome sequences from the largest collection of trios (5,947) with autism spectrum disorder (ASD) available, including 282 unpublished trios, and performed resequencing using multiple independent technologies. We identified 7.5% of de novo mutations as PZMs, 83.3% of which were not described in previous studies. Damaging, nonsynonymous PZMs within critical exons of prenatally expressed genes were more common in ASD probands than controls (P < 1 × 10-6), and genes carrying these PZMs were enriched for expression in the amygdala (P = 5.4 × 10-3). Two genes (KLF16 and MSANTD2) were significantly enriched for PZMs genome-wide, and other PZMs involved genes (SCN2A, HNRNPU and SMARCA4) whose mutation is known to cause ASD or other neurodevelopmental disorders. PZMs constitute a significant proportion of de novo mutations and contribute importantly to ASD risk.

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder / Lim, Elaine T.; Uddin, Mohammed; De Rubeis, Silvia; Chan, Yingleong; Kamumbu, Anne S.; Zhang, Xiaochang; D'Gama, Alissa M.; Kim, Sonia N.; Hill, Robert Sean; Goldberg, Arthur P.; Poultney, Christopher; Minshew, Nancy J.; Kushima, Itaru; Aleksic, Branko; Ozaki, Norio; Parellada, Mara; Arango, Celso; Penzol, Maria J.; Carracedo, Angel; Kolevzon, Alexander; Hultman, Christina M.; Weiss, Lauren A.; Fromer, Menachem; Chiocchetti, Andreas G.; Freitag, Christine M.; Church, George M.; Scherer, Stephen W.; Buxbaum, Joseph D.; Walsh, Christopher A; Aleksic, B; Anney, R; Barbosa, M; Barrett, J; Betancur, C; Bishop, S; Brusco, A; Buxbaum, Jd; Carracedo, A; Chiocchetti, Ag; Chung, Bhy; Cook, E; Coon, H; Cutler, Dj; Daly, M; De Rubeis, S; Doan, R; Fernández-Prieto, M; Ferrero, Gb; Freitag, Cm; Fromer, M; Gargus, J; Geschwind, D; Gill, M; Gómez-Guerrero, L; Hansen-Kiss, E; He, X; Herman, G; Hertz-Picciotto, I; Hultman, C; Iliadou, B; Ionita-Laza, I; Jugessur, A; Knudsen, Gp; Kolevzon, A; Kosmicki, J; Kushima, I; Lee, Sl; Lehner, T; Lennertz, S; Lim, E; Maciel, P; Magnus, P; Manoach, D; Minshew, N; Morrow, E; Mulle, J; Neale, B; Ozaki, N; Palotie, A; Parellada, M; Passos-Bueno, Mr; Pericak-Vance, M; Persico, A; Pessah, I; Reichenberg, A; Reichert, J; Renieri, A; Robinson, E; Samocha, K; Sanders, S; Sandin, S; Santangelo, Sl; Satterstrom, K; Schafer, C; Schellenberg, G; Scherer, S; Senthil, G; Silva, M; Singh, T; Siper, Pm; Soares, G; Stevens, C; Stoltenberg, C; Surén, P; Sutcliffe, Js; Szatmari, P; Tassone, F; Thurm, A; Walsh, C; Weiss, L; Werling, D; Willsey, J; Xu, X; Yu, Tw; Yuen, R; Zwick, Me.. - In: NATURE NEUROSCIENCE. - ISSN 1097-6256. - 20:9(2017), pp. 1217-1224. [10.1038/nn.4598]