Yang Sui, Jiadong Lin, Michelle D. Noyes, Youngjun Kwon, Isaac Wong, Nidhi Koundinya, William T. Harvey, Mei Wu, Kendra Hoekzema, Katherine M. Munson, Gage H. Garcia, Jordan Knuth, Julie Wertz, Tianyun Wang, Kelsey M. Hennick, Druha Karunakaran, Rafael Prieto, Rebecca Meyer-Schuman, Fisher Cherry, Davut Pehlivan, Bernhard Suter, Jonas A. Gustafson, Danny E. Miller, Derek Albracht, Ivan A. Alexandrov, Jamie L. Allen, Alawi A. Alsheikh-Ali, Nicolas Altemose, Casey Andrews, Dmitry Antipov, Lucinda Antonacci-Fulton, Mobin Asri, Marcelo Ayllon, Jennifer R. Balacco, Floris P. Barthel, Halle D. Bender, Andrew P. Blair, Davide Bolognini, Katherine E. Bonini, Christina Boucher, Guillaume Bourque, Silvia Buonaiuto, Shuo Cao, A J Carroll, Ann M. Mc Cartney, Monika Čechová, Pi-Chuan Chang, Xian Chang, Jitender Cheema, Ying Chen, Claúdio Ciofi, Hiram Clawson, Sarah Cody, Vincenza Colonna, Holland C. Conwell, Robert Cook-Deegan, Mark Diekhans, Maria Angela Diroma, Daniel Doerr, Zheng Dong, Danilo Dubocanin, Richard Durbin, Jana Ebler, E. E. Eichler, Jordan M. Eizenga, Parsa Eskandar, Eddie Ferro, Anna-Sophie Fiston-Lavier, Sarah Ford, W. L. Ford, Giulio Formenti, Adam Frankish, Mallory Freeberg, Qichen Fu, Stephanie M. Fullerton, R J Fulton, Yan Gao, Obed Garcia, Joshua M. V. Gardner, Shilpa Garg, Erik Garrison, Nanibaa’ A. Garrison, John E. Garza, Margarita Geleta, Mohammadmersad Ghorbani, Tina A. Graves-Lindsay, Richard E. Green, Cristian Alexandru Groza, Andrea Guarracino, Melissa Gymrek, Maximilian Haeussler, Leanne Haggerty, Ira M. Hall, Nancy F. Hansen, Yue Hao, Mohammad Amiruddin Hashmi, David Haussler, Prajna Hebbar, Peter Heringer, Glenn Hickey
To better understand large-effect pathogenic variation associated with autism, we generated long-read sequencing (LRS) data to construct phased and near-complete genome assemblies (average contig N50 = 43 Mbp, QV = 56) for 189 individuals from 51 families with unsolved cases. We applied read- and assembly-based strategies to facilitate comprehensive characterization of de novo mutations, structural variants (SVs), and DNA methylation. Using LRS pangenome controls, we efficiently filtered >97% of common SVs exclusive to 87 offspring. We find no evidence of increased autosomal SV burden for probands when compared to unaffected siblings yet observe a suggestive trend toward an increased SV burden on the X chromosome among affected females. We establish a workflow to prioritize potential pathogenic variants by integrating autism risk genes and putative noncoding regulatory elements defined from ATAC-seq and CUT&Tag data from the developing cortex. In total, we identified three pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, as well as nine candidate de novo and biallelic inherited homozygous SVs, most of which were missed by short-read sequencing. Our work highlights the potential of phased genomes to discover complex more pathogenic mutations and the power of the pangenome to restrict the focus on an increasingly smaller number of SVs for clinical evaluation.